Clinical trial NCT04599933
Conditions: Presbyopia
Sponsor: Orasis Pharmaceuticals Ltd.
Start date: 2020-10-18; Completion date: 2022-02-19
Enrollment: 309 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 4-visit, multi-center, randomized, double-masked, vehicle-controlled study evaluating the safety and efficacy of CSF-1 in the temporary correction of presbyopia.

Detailed description:

Arms: arm 1: One drop bilaterally twice daily for approximately 2 weeks. arm 2: One drop bilaterally twice daily for approximately 2 weeks.
Interventions: intervention 1: CSF-1 intervention 2: Vehicle
Intervention descriptions: intervention 1: One drop bilaterally twice daily for approximately 2 weeks. intervention 2: One drop bilaterally twice daily for approximately 2 weeks.

Protocol documents:
Prot_000.pdf: 
Orasis Pharmaceuticals 
 
CSF-1 Ophthalmic Solution 
Protocol 20-150-0002 
 
 Version 2.0 (Amendment 1) 
IND # 131464 
 
 January 7, 2021 
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Clinical Trial Protocol 
 
Protocol Title: 
A Multi-Center, Double-Masked, Vehicle-Controlled, 
Evaluation of the Efficacy and Safety of CSF-1 in the 
Temporary Correction of Presbyopia (the NEAR-1 
study: Near Eye-vision Acuity Restoration)  
Protocol Number: 
20-150-0002 
Study Phase: 
3 
Investigational Product Name: 
CSF-1 (pilocarpine hydrochloride 0.4% ophthalmic 
solution) 
IND 
131464 
 
Indication: 
Presbyopia 
Sponsor: 
Orasis Pharmaceuticals, Ltd  
 
  
 
 
Contract Research 
Organization: 
 
 
 
 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico, Suite C, #497 
San Clemente, CA 92673 
949-542-3882 www.alphairb.com 
 
 
 
 
 
Date 
Original Protocol: 
August 17, 2020 
Version 2.0 (Amendment 1): January 7, 2021 
 
 
 
Confidentiality Statement 
 
This protocol contains confidential, proprietary information of 
, Inc. and/or Orasis Pharmaceuticals, 
Ltd. Further dissemination, distribution, or copying of this protocol or its contents is strictly prohibited. 
 
 
 


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CSF-1 Ophthalmic Solution 
Protocol 20-150-0002 
 
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IND # 131464 
 
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MEDICAL MONITOR 
Medical Monitor:  
 
 
 
 PERSONNEL 
Executive Director and 
Therapeutic Area Head, 
Posterior Segment: 
 
 
 
 
 
 
 
 
 
 
 


Orasis Pharmaceuticals 
 
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Protocol 20-150-0002 
 
 Version 2.0 (Amendment 1) 
IND # 131464 
 
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SYNOPSIS 
Protocol Title: 
A Multi-Center, Double-Masked, Vehicle-controlled, Evaluation of the Efficacy and 
Safety of CSF-1 in the Temporary Correction of Presbyopia (the NEAR-1 study: 
Near Eye-vision Acuity Restoration) 
Protocol Number: 
20-150-0002 
Investigational 
Products: 
• 
CSF-1 (pilocarpine hydrochloride 0.4% ophthalmic solution) 
• 
Vehicle  
Study Phase: 
3 
Primary Objective: 
To evaluate the efficacy of CSF-1 (0.4% pilocarpine hydrochloride ophthalmic 
solution) for the temporary correction of presbyopia 
Secondary Objectives 
To evaluate the safety and tolerability of CSF-1 (0.4% pilocarpine hydrochloride 
ophthalmic solution) versus Vehicle. 
Overall Study Design: 
Structure: 
Multi-center, randomized, double-masked, Vehicle-controlled, parallel-group, safety 
and efficacy study 
Duration: 
Approximately 3-4 weeks (screening and 3 study visits) 
Controls: 
Vehicle  
Treatment plan: 
Visit 1 (Screening, Day -14 to -1): Qualified subjects will receive 1 drop of Vehicle 
instilled in each eye, followed by preliminary efficacy assessments to identify 
Vehicle responders at 15 minutes post-vehicle instillation.  
Visit 2 (Day 1): Baseline assessments. Subjects who meet all inclusion and none of 
the exclusion criteria and qualify as Vehicle non-responders, will be randomized 1:1 
to one of the following treatment arms: 
• 
CSF-1 (0.4% pilocarpine hydrochloride ophthalmic solution) 
• 
Vehicle 
Pre-treatment measurements taken at this visit are considered as baseline.  
At the Day 1 clinic visit, study personnel will instill Dose 1 of study drug at 8:30 AM 
± 30 minutes in each eye. Efficacy and safety assessments will be conducted for 2 
hours following Dose 1. Dose 2 will be instilled by study personnel at 10:30 AM ± 
30 minutes in each eye. Efficacy and safety assessments will be conducted for 4 
hours following Dose 2.  
All subjects will be instructed to dose twice daily (BID) with a single drop for 
approximately 1 week in each eye. The first daily dose should occur in the morning, 
with the second dose following 2 hours later (+1 hour). Subjects will be instructed 
not to dose at home on clinic visit days. 
Visit 3 (Day 8): Study personnel will instill Dose 1 of study drug at 8:30 AM ± 30 
minutes in each eye. Efficacy and safety assessments will be conducted for 2 hours 
following Dose 1. Dose 2 will be instilled by study personnel at 10:30 AM ± 30 
minutes in each eye. Efficacy and safety assessments will be conducted for 2 hours 
following Dose 2.  
All subjects will be instructed to dose twice daily (BID) with a single drop  for 
approximately 1 week in each eye. The first daily dose should occur in the morning 
with the second dose following 3 hours later (+1 hour). Subjects will be instructed 
not to dose at home on clinic visit days.  
Visit 4 (Day 15): Study personnel will instill Dose 1 of study drug at 8:30 AM ± 30 
minutes in each eye. Efficacy and safety assessments will be conducted up to 3 hours 
following Dose 1. Dose 2 will be instilled by study personnel at 11:30 AM ± 30 


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minutes in each eye. Efficacy and safety assessments will be conducted for 5 hours 
following Dose 2. 
Measures Taken to 
Reduce Bias: 
Randomization will be used to avoid bias in the assignment of subjects to treatment 
and to enhance the validity of statistical comparisons across treatment groups.  
Double-masked treatment will be used to reduce the potential of bias during data 
collection and the evaluation of clinical endpoints. 
Study Population Characteristics: 
Number of Subjects: 
Approximately 300 subjects (2 arms; 150 subjects per treatment arm) will be 
enrolled. 
Condition/Disease: 
Healthy adult subjects ages 45 to 64 years who have presbyopia  
Inclusion Criteria: 
Subjects must:  
1. Be able and willing to provide written informed consent and sign a Health 
Information Portability and Accountability Act (HIPAA) form prior to any 
study procedure being performed; 
2. Be able and willing to follow all instructions and attend study visits; 
3. Be 45 to 64 years of age of either sex and any race or ethnicity at Visit 1; 
4. 
 
 
 
 
 
 
5. 
 
 
 
 
 
 
 
 
 
 
 
8. Have a negative urine pregnancy test at Visit 1, if female of childbearing 
potential (those who have experienced menarche and who are not surgically 
sterilized [bilateral tubal ligation, hysterectomy, or bilateral oophorectomy] 
or post-menopausal [12 months after last menses]) and must use adequate 
birth control throughout the study period. Adequate birth control is defined 
as hormonal – oral, implantable, injectable, or transdermal contraceptives; 
mechanical – spermicide in conjunction with a barrier such as condom or 
diaphragm; intrauterine device (IUD); or surgical sterilization of partner. 
For non-sexually active females, abstinence may be regarded as an adequate 
method of birth control; 
9. Be able and willing to avoid all prohibited medications for the appropriate 
washout periods and during the study without significant risk to the subject. 
Exclusion Criteria: 
Subjects must not: 
1. Be a female of childbearing potential who is currently pregnant, nursing, or 
planning a pregnancy; 
2. Have known contraindications or a sensitivity to the use of any of the study 
drugs or their components;  
3. Have an active ocular infection at Visit 1 (bacterial, viral, or fungal); 
4. Have active ocular inflammation (e.g., moderate to severe blepharitis, any 
allergic conjunctivitis, peripheral ulcerative keratitis or scleritis) in either 
eye at Visit 1;  


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5. Have a known history or diagnosis of ocular herpetic infection, iritis, 
scleritis, or uveitis in either eye, whether active or inactive; 
6. 
 
 
 
 
 
7. Be unable to or refuse to discontinue soft contact lens wear 7 days prior to 
study Visit 1 and rigid gas permeable (RGP) contact lens wear 14 days prior 
to Visit 1 and for the duration of the study; 
8. Have moderate or severe dry eye defined as total corneal fluorescein 
staining > 2 (
 Scale) in either eye at Visit 1 and/or use 
artificial tears or lubricant eye ointment on a daily basis; 
9. Plan to use artificial tears or lubricant eye ointment on the day of or during 
any study visits; 
10. Have clinically significant abnormal lens findings (e.g., cataract) in either 
eye at Visit 1; 
11. 
 
 
 
 
 
12. 
 
 
13. Have intraocular pressure (IOP) that is < 9 millimeters of mercury (mmHg) 
or > 22 mmHg in either eye at Visit 1, or have a prior diagnosis of ocular 
hypertension or glaucoma or be currently being treated with any type of 
topical IOP-lowering (glaucoma) medication at Visit 1; 
14. Have clinically significant abnormal findings (e.g., central corneal scar) on a 
slit lamp biomicroscopy exam in either eye documented at Visit 1 or a 
known history of a clinically significant slit-lamp finding in either eye; 
15. Have clinically significant abnormal findings on a dilated indirect 
ophthalmoscopy exam in either eye documented at Visit 1 or a known 
history of a clinically significant retinal finding in either eye; 
16. Have had ocular surgical intervention within 6 months prior to Visit 1, or 
planned surgical intervention within 30 days after Visit 4;  
17. Use any of the following prohibited systemic medications during the 
timeframe noted below: 
a. The day of the study visit or within 12 hours prior to a study visit 
(chronic, daily use is not allowed):  
i. nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., Advil®, 
Motrin®)  
ii. narcotic (opiate class) pain medication (e.g., codeine, 
OxyContin®, Vicodin®, Tramadol®) 
b. Two (2) weeks (14 days) prior to Visit 1 or for the duration of the 
study:  
i. bladder medication (e.g., Urecholine®, bethanechol) 
ii. antipsychotics 
iii. antidepressants 
iv. attention-deficit/hyperactivity disorder (ADHD) medications 


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v. alpha-blockers (e.g., tamsulosin [Flomax®], Jayln®, Uroxatral®, 
Rapaflo®) 
vi. anticholinergics (e.g., atropine, belladonna, benztropine, 
dicyclomine, donepezil, hyoscyamine, propantheline, 
scopolamine, trihexphenidyl) 
vii. muscarinic receptor agonists or cholinergic agonists 
(e.g., Salagen®, Evoxac®) other than the study drug 
viii. over-the-counter (OTC) or prescription antihistamines or 
decongestants 
ix. any ophthalmic medications (other than artificial tears or lubricant 
eye ointment [see exclusion 8 and 9 above]) 
x. any other medication affecting the pupil or accommodation 
xi. recreational drug use (e.g., marijuana, methadone, heroin, cocaine) 
18. Have a diagnosis of diabetes mellitus or a history of elevated blood sugar; 
19. Have a condition or a situation that in the investigator’s opinion may put the 
subject at increased risk, confound study data, or interfere significantly with 
the subject’s study participation, including but not limited to unstable 
cardiovascular, hepatic, renal, respiratory, gastrointestinal, endocrine, 
immunologic, dermatologic, hematologic, neurologic, or psychiatric disease. 
Study Treatments 
• 
CSF-1 (pilocarpine hydrochloride 0.4% ophthalmic solution) 
• 
Vehicle 
Efficacy Endpoints 
 
Primary Endpoints: 
Percentage of subjects with a ≥ 3-line (15-letter) gain, from baseline, in best distance-
corrected visual acuity (BDCVA) at 40 cm (Precision Vision chart) and no loss in 
best distance corrected visual acuity ≥ 5 letters (ETDRS chart at 4m) in the study eye 
at Visit 3, following Dose 1, 1 hour post-treatment 
BDCVA at 40 cm is measured using an ‘ETDRS-like’ chart from Precision Vision. 
The 40 cm Precision Vision chart uses the same letter and line spacing as the ETDRS 
chart, only calibrated in size for testing at 40 cm. Similar to the 4m chart, the 
Precision Vision 40 cm chart is placed in light box creating retro illumination for 
testing. 
Secondary Endpoints: 
Percentage of subjects with a ≥ 3-line (15-letter) gain, from baseline, in BDCVA at 
40 cm (Precision Vision chart) and no loss in best distance corrected VA ≥ 5 letters 
(ETDRS chart at 4m) in the study eye at the following Visits, Doses and time points: 
 
Visit 3 (Day 8) 
Dose 1 
• 
Duration of Action: 2 hours following Dose 1 
Dose 2 
• 
1 hour following Dose 2 
• 
Duration of Action: 2 hours following Dose 2 
 
 
 
 
 
 
 
 
 


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Safety Endpoints 
• 
BDCVA (normal and low luminance) at 4m 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness grading 
• 
Study drug drop comfort assessment 
• 
IOP 
• 
Dilated indirect fundoscopy 
• 
Adverse events (AEs) (reported, elicited, and observed) 


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General Statistical Methods and Types of Analyses 
Analysis Sets: 
• 
Full Analysis Set – The full analysis set (FAS) will include all randomized subjects who have received 
at least one dose of the study drug. Subjects in the FAS will be analyzed as randomized. 
• 
Per Protocol Set – The per-protocol (PP) set will include subjects in the FAS who do not have significant 
protocol deviations that affect the primary endpoint analysis. Protocol deviations will be assessed prior 
to database lock and unmasking. Subjects in the PP set will be analyzed as treated. 
• 
Safety Set – The safety set will include all subjects who have received at least one dose of the study 
drug. Subjects in the safety population will be analyzed as treated. 
Unit of Analysis: 
The study eye will be used for all monocular analyses. The fellow eye will inherently be included in all binocular 
analyses. Both eyes will be displayed and analyzed for all ophthalmic safety variables. 
The study eye will be defined by the study Investigator as the eye that meets all enrollment criteria. If both eyes 
meet all enrollment criteria, then the eye with the worse Visit 2 pre-treatment/baseline BDCVA at 40 cm 
(Precision Vision chart) will be the study eye. If both eyes have the same BDCVA at 40 cm, the right eye will be 
the study eye. 
General Considerations: 
In general, quantitative/continuous data will be summarized using descriptive statistics (n, mean, standard 
deviation (SD), median, minimum, and maximum). Qualitative/categorical data will be summarized using 
frequencies and percentages. Statistical testing, unless otherwise indicated, will be performed at a 2-sided 0.05 
significance level. 
For all variables, baseline is defined as the pre-randomization measurement taken at Visit 2 (Day 1), prior to 
administration of study drug. Change from baseline will be calculated as follow-up measure minus baseline 
measure. 
Hypothesis: 
The primary efficacy hypothesis is: 
H01: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, in the percentage 
of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA at 40 cm (Precision Vision chart) 
without a loss in best distance corrected VA of ≥ 5 letters (ETDRS at 4m) at Visit 3 (Day 8), 1 hour post-Dose 1 
= 0. 
H11: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, in the percentage 
of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA at 40 cm (Precision Vision chart) 
without a loss in best distance corrected VA of ≥ 5 letters (ETDRS at 4m) at Visit 3 (Day 8), 1 hour post-Dose 1 
≠ 0. 
The study will be considered a success if the null hypothesis, H01, is rejected at a 2-sided alpha = 0.05 in favor of 
CSF-1 in the alternative hypothesis, H11, tested as delineated in the primary efficacy analysis section, and the 
following secondary efficacy hypotheses will each be tested as stated under adjustments for multiplicity. 
The secondary efficacy hypotheses are: 
Visit 3 
Duration of Action Visit 3 Post-Dose 1 
H02: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, in the percentage 
of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA at 40 cm (Precision Vision chart) 
without a loss in best distance corrected VA of ≥ 5 letters (ETDRS at 4m) at Visit 3 (Day 8), 2 hours post-Dose 1 
= 0. 
H12: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, in the percentage 
of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA at 40 cm (Precision Vision chart) 
without a loss in best distance corrected VA of ≥ 5 letters (ETDRS at 4m) at Visit 3 (Day 8), 2 hours post-Dose 1 
≠ 0. 
Visit 3, 1 Hour Post-Dose 2 


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H03: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, in the percentage 
of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA at 40 cm (Precision Vision chart) 
without a loss in best distance corrected VA of ≥ 5 letters (ETDRS at 4m) at Visit 3 (Day 8), 1 hour post-Dose 2 
= 0. 
H13: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, in the percentage 
of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA at 40 cm (Precision Vision chart) 
without a loss in best distance corrected VA of ≥ 5 letters (ETDRS at 4m) at Visit 3 (Day 8), 1 hour post-Dose 2 
≠ 0. 
Duration of Action Visit 3 Post-Dose 2 
H04: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, in the percentage 
of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA at 40 cm (Precision Vision chart) 
without a loss in best distance corrected VA of ≥ 5 letters (ETDRS at 4m) at Visit 3 (Day 8), 2 hours post-Dose 2 
= 0. 
H14: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, in the percentage 
of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA at 40 cm (Precision Vision chart) 
without a loss in best distance corrected VA of ≥ 5 letters (ETDRS at 4m) at Visit 3 (Day 8), 2 hours post-Dose 2 
≠ 0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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 Version 2.0 (Amendment 1) 
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 Version 2.0 (Amendment 1) 
IND # 131464 
 
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Adjustments for Multiplicity 
The following testing strategy will be employed to adjust for multiplicity: 
 
If the primary null hypothesis, H01, is rejected at a 2-sided alpha = 0.05 in favor of CSF-1 in the alternative 
hypothesis, H11, tested as delineated in the primary efficacy analysis section, then the study will be considered a 
success and the following secondary hypotheses will be tested in hierarchical order, each at a 2-sided alpha = 
0.05, where inference will be made on each null hypothesis only if the prior null hypotheses are rejected in favor 
of CSF-1 
1) Visit 3 (Day 8), 2 hours following Dose 1 (H02) 


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2) Visit 3 (Day 8), 1 hour following Dose 2 (H03) 
3) Visit 3 (Day 8), 2 hours following Dose 2 (H04) 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interim Analysis: 
No interim analysis is planned for this study. 
Sample Size: 
A total sample size of 280 subjects (140 subjects per arm) yields >97.5% power to establish superiority of CSF-1 
to Vehicle in the percentage of study eyes demonstrating a ≥ 3-line (15-letter) gain from baseline in BDCVA at 


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40 cm (Precision Vision chart) and no loss of best distance corrected VA ≥5 letters (ETDRS at 4m), 1-hour post 
each dose on Visit 3 (Day 8) assuming a response rate of 42.5% in CSF-1 and 17.5% in Vehicle using a Pearson 
chi-squared test with a 2-sided significance level of 0.05. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accounting for approximately a 5% discontinuation rate, approximately 150 subjects per arm (approximately 300 
total) will be randomized. 
Estimates were obtained from the Phase 2b study (18-150-0006) Intent-to-Treat (ITT) population response for 
pilocarpine 0.4% vs. diclofenac (control), additionally imputing missing data as failures.  
At least approximately 30% of subjects will have light (i.e., blue, green, gray, and hazel) iris, and at least 
approximately 30% will have a brown iris. The actual percentages will vary based on enrollment. 
Primary Efficacy Analysis: 
The primary efficacy endpoint in this study is the percentage of subjects with a ≥ 3-line (15-letter) gain, from 
baseline, in best distance-corrected visual acuity (BDCVA) at 40 cm (Precision Vision chart) and no loss in best 
distance corrected visual acuity ≥ 5 letters (ETDRS chart) at Visit 3, 1 hour following Dose 1 in the study eye. 
The primary efficacy analysis will be conducted in the FAS with intercurrent events handled in the following 
manners:  
1) Discontinuation of study drug and non-optimal compliance will be ignored [treatment policy strategy]. 
2) Withdrawal due to lack of efficacy or adverse events: missing data will be singly imputed as failure 
[hypothetical strategy]. 
3) Missing data without withdrawal or withdrawal due to reasons other than lack of efficacy or adverse 
events: missing data will be imputed employing Multiple Imputation (MI) using randomized treatment-
based Markov Chain Monte Carlo (MCMC) methodology [hypothetical strategy]. 
No subject data will be excluded from the FAS due to protocol violations/deviations. The FAS will be used for 
the primary efficacy analyses. Note that multiple imputations of missing values will be completed for the 
continuous measures (BDCVA at 40 cm and best distance corrected VA at 4m), then the response variable will be 
determined therefrom. 
Sensitivity analyses on the primary efficacy variable will be performed using the FAS with all missing data 
imputed as failures, the FAS with observed data, and PP set with observed data. Additional sensitivity analyses 
such as control-based pattern mixture model MIs and tipping point may be performed and will be specified in the 
Statistical Analysis Plan (SAP). 
Descriptive statistics will be presented by treatment group. Testing of the percentage of subjects with at least a 3-
line (15-letter) improvement from baseline in BDCVA at 40 cm without a loss of ≥ 5 letters in best distance 
corrected VA at 4m will be completed separately for the 1 hour and 2 hour time points using a generalized linear 
mixed model with a binomial distribution including fixed effects of baseline BDCVA at 40 cm as a covariate, 
daily dose (Dose 1 and Dose 2), treatment, and the interaction of dose with treatment and random effect of 
subject to account for the correlation within a subject between daily doses. The dose-by-treatment interaction 
term will be used to check if there is differential treatment effect between Dose 1 and Dose 2. If the dose-by-


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treatment interaction term is significant (p < 0.10), then the interaction term will remain in the model and testing 
of the treatment effect will be completed within the model separately following Dose 1 and following Dose 2. If 
the dose-by-treatment interaction term is not significant (p ≥ 0.10), then the interaction term will be removed 
from the model and testing of treatment effect will be completed within the model pooled over dose.  
The adjusted odds ratios and marginal proportions and difference in proportions along with corresponding two-
sided 95% Confidence Intervals (CIs) and p-values will be presented. 
Treatment comparisons will also be made separately for each time point and dose using logistic regression model 
including fixed effects of baseline BDCVA at 40 cm as a covariate and treatment, Pearson’s chi-squared test or 
Fisher’s exact test if any of the cell counts are less than five as a sensitivity analysis to the primary model above.  
Secondary Efficacy Analysis:  
For the secondary efficacy endpoints of BDCVA at 40 cm, the percentage of subjects who achieve a ≥ 3-line (15-
letters) improvement from baseline without a loss of ≥ 5 letters in best distance corrected VA at 4m for each 
Visit, time point and daily dose (Dose 1 and Dose 2) will be summarized and analyzed using the same imputation 
as the primary efficacy endpoint. The same modeling strategy will be used as detailed in the primary efficacy 
analysis for any time point that is measured after both doses within the visit 
 
 
 
 
 
 
 Sensitivity analyses will also be performed 
as stated for the primary analysis.  
Exploratory Efficacy Analysis: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Safety Analysis:  
Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory Activities (MedDRA) terms 
and be presented in a data listing. Treatment Emergent AEs (TEAEs), those that occur after the first Dose of 
study drug, will be summarized by treatment group using frequency and percent for each System Organ Class 
(SOC) and Preferred Term (PT) within each SOC. Similar summaries will also be presented for serious TEAEs, 
TEAEs leading to death, TEAEs leading to study drug discontinuation, TEAEs related to IP and TEAEs by 
severity. When reporting the incidence of AEs, a subject will only be counted once if they ever experience an 
event within the SOC and ever experience the individual PT within the SOC. 
Actual results and changes from baseline results in monocular and binocular BCVA at 4m and Low- Luminance 
BCVA, slit-lamp biomicroscopy, conjunctival redness grading, IP drop comfort, IOP, and dilated fundus 
examination will be summarized descriptively at each visit by treatment group. 
Full details of the safety analyses will be specified in the formal SAP. 
 
 


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TABLE OF CONTENTS 
Synopsis ..................................................................................................................................... 3 
Table of Contents ..................................................................................................................... 16 
List of Abbreviations ............................................................................................................... 19 
1 
Introduction ...................................................................................................................... 21 
2 
Study Objectives ............................................................................................................... 23 
2.1 
Primary Objective ....................................................................................................... 23 
2.2 
Secondary Objectives ................................................................................................. 23 
3 
Clinical Hypotheses .......................................................................................................... 23 
4 
Overall Study Design ....................................................................................................... 23 
5 
Study Population .............................................................................................................. 25 
5.1 
Inclusion Criteria ........................................................................................................ 25 
5.2 
Exclusion Criteria ....................................................................................................... 25 
5.3 
Withdrawal Criteria .................................................................................................... 27 
6 
Study Parameters .............................................................................................................. 28 
6.1 
Efficacy Endpoints ...................................................................................................... 28 
6.1.1 
Primary Efficacy Endpoints .................................................................................. 28 
6.1.2 
Secondary Efficacy Endpoints .............................................................................. 28 
6.1.3 
 
6.1.4 
Criteria for Effectiveness ....................................................................................... 29 
6.2 
Safety Endpoints ......................................................................................................... 29 
7 
Study Materials ................................................................................................................. 30 
7.1 
Study Treatments ........................................................................................................ 30 
7.1.1 
Investigational Product .......................................................................................... 30 
7.1.2 
Instructions for Use and Administration ............................................................... 30 
7.1.3 
Subject Instructions ............................................................................................... 30 
8 
Study Methods And Procedures ....................................................................................... 31 
8.1 
Subject Entry Procedures ............................................................................................ 31 
8.1.1 
Overview ............................................................................................................... 31 
8.1.1 
Informed Consent .................................................................................................. 31 
8.1.2 
Washout Intervals .................................................................................................. 31 
8.1.3 
Procedures for Final Study Entry .......................................................................... 31 
8.1.4 
Pregnancy .............................................................................................................. 31 
8.1.5 
Methods for Assignment to Treatment Groups ..................................................... 32 
8.2 
Concurrent Therapies and Medical History ................................................................ 32 
8.2.1 
Prohibited Medications/Treatments ...................................................................... 32 
8.3 
Examination Procedures ............................................................................................. 33 
8.3.1 
Procedures to be performed at the Study Visit with Regard to Study Objective .. 33 
8.4 
Schedule of Visits, Measurements, and Dosing ......................................................... 37 
8.4.1 
Scheduled Visit ...................................................................................................... 37 
8.4.2 
Unscheduled Visits ................................................................................................ 37 
8.5 
Compliance with Protocol .......................................................................................... 37 
8.6 
Subject Disposition ..................................................................................................... 37 
8.6.1 
Completed Subjects ............................................................................................... 37 
8.6.2 
Withdrawn Subjects .............................................................................................. 37 
8.6.3 
Discontinued Subjects ........................................................................................... 37 


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8.7 
Study Termination ...................................................................................................... 38 
8.8 
Study Duration ............................................................................................................ 38 
8.9 
Monitoring and Quality Assurance ............................................................................. 38 
9 
Adverse Events ................................................................................................................. 39 
9.1 
Adverse Event ............................................................................................................. 39 
9.1.1 
Severity .................................................................................................................. 39 
9.1.2 
Relationship to Investigational Product ................................................................ 39 
9.1.3 
Expectedness ......................................................................................................... 40 
9.2 
Serious Adverse Events .............................................................................................. 40 
9.3 
Procedures for Reporting Adverse Events .................................................................. 41 
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction ......................................... 41 
9.3.2 
Reporting a Serious Adverse Event ....................................................................... 41 
9.4 
Procedures for Unmasking (if applicable) .................................................................. 41 
9.4.1 
Type and Duration of the Follow-up of Subjects after Adverse Events ............... 42 
10 Statistical Hypotheses and Methods of Analyses ............................................................. 42 
10.1 General Considerations ............................................................................................... 42 
10.2 Hypotheses .................................................................................................................. 42 
10.3 Study Populations ....................................................................................................... 49 
10.4 Unit of Analysis .......................................................................................................... 49 
10.5 Sample Size ................................................................................................................. 50 
10.6 Demographic and Baseline Characteristics ................................................................ 50 
10.7 Efficacy Analysis ........................................................................................................ 50 
10.7.1 Primary Efficacy Analyses .................................................................................... 50 
10.7.2 Secondary Efficacy Analysis ................................................................................. 51 
10.7.3 
 .............................................................................. 52 
10.8 Safety Analysis ........................................................................................................... 52 
10.9 Interim Analysis .......................................................................................................... 52 
10.10 Missing Data ............................................................................................................... 53 
10.11 Adjustment for Multiplicity ........................................................................................ 53 
11 Compliance with Good Clinical Practices, Ethical Considerations, and Administrative 
Issues ................................................................................................................................ 54 
11.1 Protection of Human Subjects .................................................................................... 54 
11.1.1 Subject Informed Consent ..................................................................................... 54 
11.1.2 IRB Approval ........................................................................................................ 55 
11.2 Ethical Conduct of the Study ...................................................................................... 55 
11.3 Subject Confidentiality ............................................................................................... 55 
11.4 Documentation ............................................................................................................ 55 
11.4.1 Retention of Documentation ................................................................................. 55 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of Study Drug
 .................................................................................................................................... 56 
11.5.1 Labeling/Packaging ............................................................................................... 56 
11.5.2 Storage of Investigational Product ........................................................................ 56 
11.5.3 Accountability of Study Drug ............................................................................... 56 
11.5.4 Return or Disposal of Study Drug ......................................................................... 56 
11.6 Recording of Data on Source Documents and Electronic Case Reports Forms 
(eCRFs) ....................................................................................................................... 56 
11.7 Handling of Biological Specimens ............................................................................. 57 


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12 Publications ...................................................................................................................... 57 
13 References ........................................................................................................................ 58 
14 Appendices ....................................................................................................................... 59 
Appendix 1: Schedule of Assessments .................................................................................. 59 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques .......................... 62 
Appendix 3:  Protocol Amendment Summary ...................................................................... 68 
Appendix 4: Sponsor and 
 Approvals ............................................................................. 85 
Appendix 5: Investigator’s Signature .................................................................................... 86 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADHD 
Attention-Deficit/Hyperactivity Disorder 
AE 
adverse event 
BCVA 
best corrected visual acuity 
BDCVA 
best distance corrected visual acuity 
BID 
twice daily 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CPMP 
Committee for Proprietary Medicinal Products 
eCRF 
electronic case report form 
CRO 
clinical research organization 
D 
diopter 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug Application 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IUD 
intrauterine device 
HIPAA 
Health Information Portability and Accountability Act 
LASEK 
Laser-Assisted Epithelial Keratomileusis 
LASIK 
Laser-Assisted in-Situ Keratomileusis 
LDPE 
Low-Density Polyethylene 
LL 
Low-Luminance 
LogMAR 
logarithm of the minimum angle of resolution 
LS 
least square 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple drug imputation 
mmHG 
millimeters of mercury 
NSAID 
non-steroidal anti-inflammatory drug 
OTC 
over the counter 
PP 
per protocol 
PRK 
photorefractive keratectomy 
PT 
preferred term 
RGP 
rigid gas permeable 
SAE 
serious adverse event 


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Abbreviation 
Definition 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
TBD 
to be determined 
TEAE 
treatment-emergent adverse event 
VA 
visual acuity 


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1 
INTRODUCTION 
Most individuals will develop symptoms of presbyopia by age 50 (Truscott 2009). Worldwide, 
there were 1.8 billion people globally with presbyopia in 2015, with a prevalence of 
approximately 25%, which is growing as the world population is aging. Approximately 45% of 
these cases (~826 million) had near visual impairment (VI) because of lack of or inadequate 
vision correction (Fricke, Tahhan et al. 2018). The primary symptom of this condition is a 
progressive blurring of vision when performing near tasks such as reading, sewing, working at a 
computer, and using a tablet or cellular phone. Other symptoms include headaches and visual 
fatigue, which impair one’s quality of life (Truscott 2009).  
The underlying cause of presbyopia is an inability to change optical power (accommodation) 
(Donders 1864). Accommodation is facilitated by the contraction of the ciliary muscle fibers, 
which change the shape and location of the crystalline lens of the eye. In response to near vision, 
the crystalline lens becomes thicker and more rounded in response to the actions of the ciliary 
muscle fibers (Garner and Yap 1997, Croft, Glasser et al. 2001, Glasser 2006). As an individual 
ages, the lens becomes stiffer and less amenable to changing shape in response to ciliary Muscle 
activity and this culminates in the symptoms of presbyopia. 
Pupil size is determined by the dimensions of sphincter and dilator muscle spindles of the iris. 
The pupil becomes smaller in conjunction to accommodation. This reduction in the size of the 
pupil (termed miosis) improves the resolution of the retinal image by preventing peripheral light 
rays from reaching the retina. A relatively small pupil offers increased depth of field in a way 
similar to that achieved by reducing the aperture of a camera, leading to better visual acuity (VA) 
of close objects. 
Current presbyopia treatment strategies include corrective lenses with single vision or 
bifocal/multifocal lenses, corneal refractive surgery, corneal inlay procedures, and intra-ocular 
lens surgery. Monovision correction improves the near vision of one eye (through the use of 
lenses, contacts, or surgery) while allowing the other eye to be used for distance vision. This 
approach has had variable results and may cause disturbances in depth-perception (Fernandez, 
Schwarz et al. 2013). Lastly, surgical correction of vision in presbyopia includes conductive 
keratoplasty, laser-assisted in-situ keratomileusis (LASIK), laser-assisted epithelial 
keratomileusis (LASEK), photorefractive keratectomy (PRK), corneal inlays, and 
accommodative or multifocal intraocular lenses (IOLs). The results of these procedures are 
variable, at times inconsistent, and contraindicated in some patient groups (Moussa, Jehangir et 
al. 2017). The inconsistencies regarding the success of some of these procedures of presbyopia 
treatment indicate a need for alternative strategies. 
The treatment proposed here repurposes a muscarinic receptor agonist to stimulate effects on iris 
and ciliary contractility via stimulation of muscarinic acetylcholine receptor M3. Pilocarpine, a 
muscarinic agonist, has been successful in treating cases of dilated pupil following ocular 
surgery (Patel, Jenkins et al. 2002) and a broad spectrum of systemic conditions including 
botulism (Monaco, Freddi et al. 1998), leprosy (Lana-Peixoto, Campos et al. 2014), sarcoidosis 
(Bowie and Givre 2003), and Ross syndrome (Weller, Wilhelm et al. 1992, Chemmanam, 
Pandian et al. 2007). 
CSF-1 was initially developed as a combination of a Non-Steroidal Anti-Inflammatory Drug 
(NSAID), diclofenac, with pilocarpine to reduce a potential inflammatory response associated 
with pilocarpine.  


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The safety and efficacy of CSF-1 (the initial combination and current formulation) is well 
established based on several previous clinical studies; an investigator-led feasibility study and 
two Phase 2a studies demonstrated favorable safety and preliminary efficacy. 
A Phase 2b multicenter, randomized, double-masked, parallel groups, clinical study was 
conducted to measure the contribution of each active ingredient to the efficacy and safety of 
CSF-1. Subjects were assigned to one of three treatment arms; diclofenac sodium alone 
(0.006%), pilocarpine HCl (0.2% and 0.4%) combined with diclofenac sodium (0.006%), and 
pilocarpine HCl alone (0.2% and 0.4%, the latter being the current formulation). Results from 
this study showed that diclofenac did not significantly improve tolerability, safety or efficacy of 
pilocarpine in subjects with presbyopia. Furthermore, the percentage of subjects in the CSF-1 
(pilocarpine HCl 0.4%/diclofenac sodium 0.006%) and pilocarpine HCl (0.4%) alone groups 
with ≥ 3-line improvement in monocular BCVA at 40 cm from baseline, 1-hour post-treatment at 
Visit 4 was statistically significant (p-value=0.0015 for CSF-1 group and p-value= 0.0002 for 
pilocarpine HCl group) compared to the diclofenac group, demonstrating success for the primary 
efficacy endpoint in the CSF-1 (pilocarpine HCl 0.4%/diclofenac sodium 0.006%) and 
pilocarpine HCl (0.4%) alone groups. The study thus indicated that 0.4% pilocarpine HCl as a 
single active ingredient was responsible for the temporary correction of presbyopia and that 
diclofenac is not needed in the formulation. For this reason, the Sponsor decided to continue the 
clinical development of CSF-1 with pilocarpine HCl 0.4% alone and to drop diclofenac from the 
clinical formulation 
In addition, a post-hoc analysis was conducted with the additional criteria of no loss of ≥ 5 letters 
in distance VA to the primary endpoint. Results of this post-hoc analysis showed that 22 (43.1%) 
of the subjects in the CSF-1 group, and 21 (42.9%) of the subjects in the pilocarpine HCl group 
had a ≥3 line (15-letter) gain in BCVA at 40 cm and no loss of distance VA of ≥ 5 letters, 1-hour 
post-treatment at Visit 4 (Day 15) from baseline. This post-hoc analysis further solidifies the 
results from the Phase 2b study and suggests that not only is CSF-1 effective for the temporary 
correction of presbyopia (evidenced by a ≥ 3 line gain in BCVA 1-hour post-administration at 
Day 15 compared to baseline) but also that the benefit in BCVA at 40 cm remains after 
considering that no worsening of distance BCVA of ≥5 letters or more occurs. These results 
support the conduct of a multicenter, randomized, double masked, vehicle controlled, 2-arm, 
Phase 3 efficacy and safety study with the current formulation of CSF-1 (pilocarpine 0.4%) 
versus Vehicle, as well as define the choice of the primary end-point in the present study.  
 
 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of CSF-1 (0.4% pilocarpine 
hydrochloride ophthalmic solution) for the temporary correction of presbyopia.  
2.2 
Secondary Objectives 
The secondary objectives of this study are to evaluate the safety and tolerability of CSF-1 (0.4% 
pilocarpine hydrochloride ophthalmic solution) versus Vehicle. 
3 
CLINICAL HYPOTHESES  
The clinical hypothesis of this study is that CSF-1 is superior and/or safer/better tolerated 
compared with Vehicle for improving near vision in subjects with presbyopia. 
4 
OVERALL STUDY DESIGN 
This is a 4-visit multi-center, randomized, double-masked, parallel-group study evaluating the 
safety and efficacy of CSF-1 compared with Vehicle in approximately 300 subjects with 
presbyopia. The study design is summarized in Figure 1. 
Visit 1 (Screening, Day -14 to -1): Qualified subjects will receive 1 drop of Vehicle instilled in 
each eye, followed by preliminary efficacy assessments to identify Vehicle responders at 15 
minutes post-vehicle instillation.  
Visit 2 (Day 1): Baseline assessments. Subjects who meet all inclusion and none of the exclusion 
criteria and qualify as Vehicle non-responders, will be randomized 1:1 to one of the following 
treatment arms: 
• CSF-1 (0.4% pilocarpine hydrochloride ophthalmic solution) 
• Vehicle 
Pre-treatment measurements taken at this visit are considered as baseline. 
At the Day 1 clinic visit, study personnel will instill Dose 1 of study drug at 8:30 AM ± 30 
minutes in each eye. Efficacy and safety assessments will be conducted for 2 hours following 
Dose 1. Dose 2 will be instilled by study personnel at 10:30 AM ± 30 minutes in each eye. 
Efficacy and safety assessments will be conducted for 4 hours following Dose 2. 
All subjects will be instructed to dose twice daily (BID) with a single drop for approximately 1 
week in each eye. The first daily dose should occur in the morning, with the second dose 
following 2 hours later (+1 hour). Subjects will be instructed not to dose at home on clinic visit 
days. 
Visit 3 (Day 8): Study personnel will instill Dose 1 of study drug at 8:30 AM ± 30 minutes in 
each eye. Efficacy and safety assessments will be conducted for 2 hours following Dose 1. Dose 
2 will be instilled by study personnel at 10:30 AM ± 30 minutes in each eye. Efficacy and safety 
assessments will be conducted for 2 hours following Dose 2. 


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All subjects will be instructed to dose twice daily (BID) with a single drop for approximately 1 
week in each eye. The first daily dose should occur in the morning with the second dose 
following 3 hours later (+1 hour). Subjects will be instructed not to dose at home on clinic visit 
days. 
Visit 4 (Day 15): Study personnel will instill Dose 1 of study drug at 8:30 AM ± 30 minutes in 
each eye. Efficacy and safety assessments will be conducted up to 3 hours following Dose 1. 
Dose 2 will be instilled by study personnel at 11:30 AM ± 30 minutes in each eye. Efficacy and 
safety assessments will be conducted for 5 hours following Dose 2. 
Figure 1: Study Design 
Visit 1 
(Day -14 to -1): 
Screening 
Screening Assessments 
1 dose of Vehicle in each eye 
 
 
Visit 2 
(Day 1): 
Baseline 
Baseline 
Randomization 
Dose 1 instillation in each eye 
Efficacy and Safety Assessments Dose #1  
(through 2 hours post dose) 
Dose 2 instillation in each eye 
Efficacy and Safety Assessments Dose #2  
(through 4 hours post dose) 
 
 
BID Dosing: Dose 1 in the morning followed by Dose 2 (2 hours after Dose 1)  
 
 
Visit 3 
(Day 8 ± 1): 
Efficacy and Safety 
Dose 1 instillation in each eye 
Efficacy and Safety Assessments Dose #1  
(through 2 hours post Dose) 
Dose 2 instillation in each eye 
Efficacy and Safety Assessments Dose #2  
(through 2 hours post Dose) 
 
 
BID Dosing: Dose 1 in the morning followed by Dose 2 (3 hours after Dose 1)  
 
 
Visit 4 
(Day 15 ± 2): 
Efficacy and Safety 
Dose 1 instillation in each eye 
Efficacy and Safety Assessments Dose #1  
(through 3 hours post dose) 
Dose 2 instillation in each eye 
Efficacy and Safety Assessments Dose #2  
(through 5 hours post dose) 
 


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5 
STUDY POPULATION 
Approximately, 300 healthy adult subjects (2 arms; 150 subjects per treatment arm) will be 
enrolled between 45 and 64 years of age with presbyopia who also meet the following criteria. 
5.1 
Inclusion Criteria 
Subjects must:  
1. Be able and willing to provide written informed consent and sign a Health Information 
Portability and Accountability Act (HIPAA) form prior to any study procedure being 
performed; 
2. Be able and willing to follow all instructions and attend study visits; 
3. Be 45 to 64 years of age of either sex and any race or ethnicity at Visit 1; 
4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. Have a negative urine pregnancy test at Visit 1, if female of childbearing potential (those 
who have experienced menarche and who are not surgically sterilized [bilateral tubal 
ligation, hysterectomy, or bilateral oophorectomy] or post-menopausal [12 months after 
last menses]) and must use adequate birth control throughout the study period. Adequate 
birth control is defined as hormonal – oral, implantable, injectable, or transdermal 
contraceptives; mechanical – spermicide in conjunction with a barrier such as condom or 
diaphragm; intrauterine device (IUD); or surgical sterilization of partner. For non-
sexually active females, abstinence may be regarded as an adequate method of birth 
control; 
9. Be able and willing to avoid all prohibited medications for the appropriate washout 
periods and during the study without significant risk to the subject. 
5.2 
Exclusion Criteria 
Subjects must not: 
1. Be a female of childbearing potential who is currently pregnant, nursing, or planning a 
pregnancy; 
2. Have known contraindications or a sensitivity to the use of any of the study drugs or their 
components;  
3. Have an active ocular infection at Visit 1 (bacterial, viral, or fungal); 
4. Have active ocular inflammation (e.g., moderate to severe blepharitis, any allergic 
conjunctivitis, peripheral ulcerative keratitis or scleritis) in either eye at Visit 1;  


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5. Have a known history or diagnosis of ocular herpetic infection, iritis, scleritis, or uveitis 
in either eye, whether active or inactive; 
6. 
 
 
 
 
 
7. Be unable to or refuse to discontinue soft contact lens wear 7 days prior to study Visit 1 
and rigid gas permeable (RGP) contact lens wear 14 days prior to Visit 1 and for the 
duration of the study; 
8. Have moderate or severe dry eye defined as total corneal fluorescein staining > 2 (
 
 Scale) in either eye at Visit 1 and/or use artificial tears or lubricant eye 
ointment on a daily basis; 
9. Plan to use artificial tears or lubricant eye ointment on the day of or during any study 
visits; 
10. Have clinically significant abnormal lens findings (e.g., cataract) in either eye at Visit 1; 
11. 
 
 
 
 
 
 
 
13. Have intraocular pressure (IOP) that is < 9 millimeters of mercury (mmHg) or > 22 
mmHg in either eye at Visit 1, or have a prior diagnosis of ocular hypertension or 
glaucoma or be currently being treated with any type of topical IOP-lowering (glaucoma) 
medication at Visit 1; 
14. Have clinically significant abnormal findings (e.g., central corneal scar) on a slit lamp 
biomicroscopy exam in either eye documented at Visit 1 or a known history of a 
clinically significant slit-lamp finding in either eye; 
15. Have clinically significant abnormal findings on a dilated indirect ophthalmoscopy exam 
in either eye documented at Visit 1 or a known history of a clinically significant retinal 
finding in either eye; 
16. Have had ocular surgical intervention within 6 months prior to Visit 1, or planned 
surgical intervention within 30 days after Visit 4; 
17. Use any of the following prohibited systemic medications during the timeframe noted 
below: 
a. The day of the study visit or within 12 hours prior to a study visit (chronic, daily 
use is not allowed):  
i. nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., Advil®, Motrin®)  
ii. narcotic (opiate class) pain medication (e.g., codeine, OxyContin®, 
Vicodin®, Tramadol®) 
b. Two (2) weeks (14 days) prior to Visit 1 or for the duration of the study:  
i. bladder medication (e.g., Urecholine®, bethanechol) 


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ii. antipsychotics 
iii. antidepressants 
iv. attention-deficit/hyperactivity disorder (ADHD) medications 
v. alpha-blockers (e.g., tamsulosin [Flomax®], Jayln®, Uroxatral®, 
Rapaflo®) 
vi. anticholinergics (e.g., atropine, belladonna, benztropine, dicyclomine, 
donepezil, hyoscyamine, propantheline, scopolamine, trihexphenidyl) 
vii. muscarinic receptor agonists or cholinergic agonists (e.g., Salagen®, 
Evoxac®) other than the study drug 
viii. over-the-counter (OTC) or prescription antihistamines or decongestants 
ix. any ophthalmic medications (other than artificial tears or lubricant eye 
ointment [see exclusion 8 and 9 above]) 
x. any other medication affecting the pupil or accommodation 
xi. recreational drug use (e.g., marijuana, methadone, heroin, cocaine) 
18. Have a diagnosis of diabetes mellitus or a history of elevated blood sugar; 
19. Have a condition or a situation that in the investigator’s opinion may put the subject at 
increased risk, confound study data, or interfere significantly with the subject’s study 
participation, including but not limited to unstable cardiovascular, hepatic, renal, 
respiratory, gastrointestinal, endocrine, immunologic, dermatologic, hematologic, 
neurologic, or psychiatric disease. 
5.3 
Withdrawal Criteria  
A subject may withdraw consent to participate in the study at any time for any reason. Subjects 
will be withdrawn from the study if any of the following criteria are met: 
• Be a female of childbearing potential who is currently pregnant, nursing, or planning a 
pregnancy; tests positive to a urine pregnancy test at Visit 4; or refuses to use an adequate 
method of contraception for the duration of the study; 
• Have an active ocular infection (bacterial, viral, or fungal), active ocular inflammation 
(e.g., moderate to severe blepharitis, allergic conjunctivitis, peripheral ulcerative keratitis, 
scleritis, uveitis) at Visit 2, Visit 3, or Visit 4 in either eye.  
• Subjects may also be withdrawn from the study for the following reasons: 
o Adverse Event (AE) 
o Lost to follow-up 
o Death 
o Subject not adequately following required study procedures  
o Study terminated by the Sponsor 
o Other 
Subject withdrawals will be documented on the subjects’ source document. 


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6 
STUDY PARAMETERS 
6.1 
Efficacy Endpoints 
Primary Efficacy Endpoints 
Percentage of subjects with a ≥ 3-line (15-letter) gain, from baseline, in BDCVA at 40 cm 
(Precision Vision chart) and no loss in BDCVA ≥ 5 letters (ETDRS chart at 4m) in the study eye 
at Visit 3, following Dose 1, 1 hour post-treatment 
The BDCVA at 40 cm is measured using an ‘ETDRS-like’ chart from Precision Vision. The 40 
cm Precision Vision chart uses the same letter and line spacing as the ETDRS chart, only 
calibrated in size for testing at 40 cm. Similar to the 4m chart, the Precision Vision 40 cm chart 
is placed in light box, creating retro illumination for testing. 
Secondary Efficacy Endpoints 
Percentage of subjects with a ≥ 3-line (15-letter) gain, from baseline, in BDCVA at 40 cm 
(Precision Vision chart) and no loss in BDCVA ≥ 5 letters (ETDRS chart at 4m) in the study eye 
at the following Visits, Doses and time points: 
Visit 3 (Day 8) 
Dose 1 
• Duration of Action: 2 hours following Dose 1 
Dose 2 
• 1 hour following Dose 2 
• Duration of Action: 2 hours following Dose 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Criteria for Effectiveness 
Changes in BCVA at 40 cm distance will be calculated as the difference, in LogMAR units, 
between the post-treatment monocular (study eye) minus the baseline monocular (study eye). A 
3-line improvement in VA is considered clinically meaningful. 
6.2 
Safety Endpoints 
• BDCVA (normal and low luminance) at 4m 
• Slit-lamp biomicroscopy 
• Conjunctival redness grading 
• Study drug drop comfort assessment 
• IOP 
• Dilated indirect fundoscopy 
• Adverse events (AEs) (reported, elicited, and observed) 


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7 
STUDY MATERIALS 
7.1 
Study Treatments 
Investigational Product 
The investigational product (IP) is CSF-1, a sterile topical eye drop solution. The formulation 
developed by Orasis Pharmaceuticals Ltd. is a preservative-free eye drop, containing the active 
ingredient pilocarpine hydrochloride 0.4%, with the addition of standard pharmacopoeial 
excipients used in sterile ophthalmic solutions. 
The vehicle (CSF-1 placebo) is a topical eye drop solution containing the same ingredients as in 
CSF-1 except for the active ingredient. 
Both IP and Vehicle are packaged in a single-dose transparent low-density polyethylene (LDPE) 
vials, enclosed within a pouch. Each pouch includes five vials. Kits will be dispensed to subjects 
at Visit 2 and Visit 3 with 1 week of at-home dosing in each kit. CSF-1 will be evaluated for 
comparison to Vehicle. 
Instructions for Use and Administration 
All study treatments are topical ophthalmic solutions that should be administered bilaterally.  
Following Visit 2, all subjects will be instructed to dose twice daily (BID) with a single drop in 
each eye for approximately 1 week. The first daily dose should occur in the morning, with the 
second dose following 2 hours later (+1 hour). Subjects will be instructed not to dose at home on 
clinic visit days. 
Following Visit 3, all subjects will be instructed to dose twice daily (BID) with a single drop in 
each eye for approximately 1 week. The first daily dose should occur in the morning with the 
second dose following 3 hours later (+1 hour). Subjects will be instructed not to dose at home on 
clinic visit days. 
Subject Instructions 
After randomization at Visit 2, subjects will receive study drug and a paper dosing diary. Once 
dispensed to the subject, the study drug must be stored in a refrigerator or cooler with ice pack. 
Study drug is packaged as a single dose unit. Subjects will remove one pouch from a single study 
drug kit and remove one vial from the strip. The remaining vials will be returned to the opened 
pouch and placed back into the refrigerator. Each subject will instill one drop of study drug to 
each eye and keep aside the used vial to be returned to the site at next visit for compliance check. 
An open vial should not be re-used. Subjects will be instructed to save and return all used and 
unused study drug and to bring their kits to each study visit. Following Visit 2, subjects will be 
instructed to dose bilaterally BID (with 2 hours (+1 hour) between doses) and record doses in 
their diary until Visit 3. Subjects should not dose at home on day of Visit 3. At Visit 3, subjects 
will receive their doses at the visit by study personnel after the required pre-treatment 
assessments and the current study drug will be collected. After subjects receive their study drug 
and dosing diary, subjects will be instructed to dose bilaterally BID (with 3 hours (+1 hour) 
between doses) and record doses in their diary until Visit 4. Subjects should not dose at home on 
day of Visit 4. At Visit 4, subjects will receive their doses at the visit by study personnel after the 
required pre-treatment assessments and their study drug will be collected. Subjects will exit the 
study after all assessments are complete at Visit 4. 


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8 
STUDY METHODS AND PROCEDURES 
8.1 
Subject Entry Procedures 
Overview 
Subjects as defined by the criteria in Section 5.1 and Section 5.2 will be considered for entry into 
this study. 
Informed Consent 
Prior to a subject’s participation in the trial (i.e., changes in a subject’s medical treatment and/or 
study-related procedures), the study will be discussed with each subject, and subjects wishing to 
participate must give written informed consent using an Informed Consent Form (ICF) and other 
written documentation in accordance with local privacy requirements (where applicable). 
Additional information can be found in Section 11.1.1. 
Washout Intervals 
• Use any of the following prohibited systemic medications during the timeframe noted 
below: 
o The day of the study visit or within 12 hours prior to a study visit (chronic, daily 
use is not allowed):  
▪ nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., Advil®, Motrin®)  
▪ narcotic (opiate class) pain medication (e.g., codeine, OxyContin®, 
Vicodin®, Tramadol®) 
o Two (2) weeks (14 days) prior to Visit 1 or for the duration of the study:  
▪ bladder medication (e.g., Urecholine®, bethanechol) 
▪ antipsychotics 
▪ antidepressants 
▪ attention-deficit/hyperactivity disorder (ADHD) medications 
▪ alpha-blockers (e.g., tamsulosin [Flomax®], Jayln®, Uroxatral®, Rapaflo®) 
▪ anticholinergics (e.g., atropine, belladonna, benztropine, dicyclomine, 
donepezil, hyoscyamine, propantheline, scopolamine, trihexphenidyl) 
▪ muscarinic receptor agonists or cholinergic agonists (e.g., Salagen®, 
Evoxac®) other than the study drug 
▪ over-the-counter (OTC) or prescription antihistamines or decongestants 
▪ any ophthalmic medications (other than artificial tears or lubricant eye 
ointment [see exclusion 8 and 9 above]) 
▪ any other medication affecting the pupil or accommodation 
▪ recreational drug use (e.g., marijuana, methadone, heroin, cocaine) 
Procedures for Final Study Entry 
Subjects must satisfy all inclusion and none of the exclusion criteria in order to be entered into 
the study. 
Pregnancy 
Females must have a negative urine pregnancy test at Visit 1, if female of childbearing potential 
(those who have experienced menarche and who are not surgically sterilized [bilateral tubal 
ligation, hysterectomy, or bilateral oophorectomy] or post-menopausal [12 months after last 


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menses]) and must use adequate birth control throughout the study period. Adequate birth control 
is defined as hormonal – oral, implantable, injectable, or transdermal contraceptives; mechanical 
– spermicide in conjunction with a barrier such as condom or diaphragm; IUD; or surgical 
sterilization of partner. For non-sexually active females, abstinence may be regarded as an 
adequate method of birth control. 
In the event a female has a positive urine pregnancy test at Visit 4, the subject will be withdrawn 
from the study and the investigator will notify 
and the sponsor within 24 hours of knowledge 
of the positive pregnancy test. 
Methods for Assignment to Treatment Groups 
Each subject who signs an ICF will be assigned a subject number. Subject numbers will be 
assigned in sequential order beginning with 001. Once a subject meets all qualification criteria at 
Visit 2, he/she will be randomized in a 1:1 ratio via an Interactive Response Technology (IRT) 
system to one of the following treatment groups: 1: CSF-1 (pilocarpine hydrochloride 0.4% 
ophthalmic solution), 2: Vehicle, and stratified by iris color (brown versus light [i.e., blue, green, 
gray, and hazel]) and by baseline manifest refraction spherical equivalent (-4.5 D to <-0.5 D, -0.5 
D to +0.75 D, and >+0.75 D to +2.0 D); randomization will not be stratified by site.  
At least approximately 30% of subjects will have light (i.e., blue, green, gray, and hazel) iris and 
at least approximately 30% will have a brown iris. The actual percentages will vary based on 
enrollment. 
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase 
the likelihood that known and unknown subject attributes (e.g., iris color and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons across treatment groups. Double-masked treatment will be used to reduce 
the potential of bias during data collection and the evaluation of clinical endpoints.  
8.2 
Concurrent Therapies and Medical History 
The use of any concurrent medication, prescription, or OTC taken within 30 days of Visit 1, is to 
be recorded on the subjects’ source document and corresponding electronic Case Report Form 
(eCRF) along with the reason the medication was taken. 
All significant current and prior ocular medical and surgical history are to be recorded on the 
subjects’ source document and corresponding eCRF. All current and prior significant general 
medical and surgical history is to be recorded on the subject’s source document and 
corresponding eCRF. 
Concurrent enrollment in another investigational drug or medical device study is not permitted. 
Prohibited Medications/Treatments 
Washout intervals as described in Section 8.1.2 should be followed for all prohibited 
medications. Soft contact lenses must be removed at least 7 days prior to study Visit 1 and during 
the study, and RGP contact lenses must be removed at least 14 days prior to study Visit 1 and 
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8.3 
Examination Procedures 
8.3.1 Procedures to be performed at the Study Visit with Regard to Study 
Objective 
The following windows for the post-treatment assessment timepoints for Visits 2, 3 & 4 are as 
 
 
 
 
 
The following procedures should be conducted at each study visit in the following order: 
8.3.1.1 
Visit 1 (Day -14 to -1) 
1. Informed consent/HIPAA 
2. Demographic data 
3. Medical and medication history 
4. Urine pregnancy test (for females of child-bearing potential) 
5. Inclusion and exclusion criteria review 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
  


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8.3.1.2 
Visit 2 (Day 1) 
1. Medical and medication history update  
2. Inclusion and exclusion criteria review 
3. 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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30. Dispense study drug/dosing diary  
8.3.1.3 
Visit 3 (Day 8 ± 1) 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.3.1.4 
Visit 4 (Day 15 ± 2) 
1. Medical and medication history update 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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30. Study exit 
8.4 
Schedule of Visits, Measurements, and Dosing 
Scheduled Visit 
Refer to Appendix 1: Schedule of Visits and Measurements for a schedule of measurements at 
the visit. 
Unscheduled Visits 
In the case of an AE, an unscheduled visit may occur. The investigator may perform additional 
assessments at their discretion. All additional assessments will be documented in the subject’s 
source document. 
8.5 
Compliance with Protocol 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the International Conference on Harmonisation (ICH) 
consolidated Guideline E6 for Good Clinical Practice (GCP) Committee for Proprietary 
Medicinal Products (CPMP/ICH/135/95), and applicable regulatory requirement(s), such as Food 
and Drug Administration (FDA) GCP Regulations and Code of Federal Regulations (CFR) Title 
21, parts 11, 50, 54, 56 and 312, as appropriate. 
8.6 
Subject Disposition 
Completed Subjects 
A completed subject is one who has not been discontinued from the study and successfully 
completes all 4 study visits. 
Withdrawn Subjects 
A subject may be withdrawn for meeting any of the withdrawal criteria as described in 
Section 5.3. 
Discontinued Subjects 
A discontinued subject is one who does not complete the protocol-defined study visits. A subject 
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Board (IRB). Notification of early discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and/or 
 
Prior to discontinuing a subject, every effort should be made to obtain as much follow-up data as 
possible, and to retrieve all study materials. AEs will be followed as described in Section 9. 
8.7 
Study Termination 
The study may be terminated at any time by the investigator, the sponsor, and/or 
with 
appropriate notification. 
8.8 
Study Duration 
This study is comprised of a screening period and 4 study visits over a duration of approximately 
3 to 4 weeks. 
8.9 
Monitoring and Quality Assurance 
During the course of the study the Sponsor, an 
monitor, or designee, may make routine site 
visits to review protocol compliance, assess study drug accountability, and ensure the study is 
being conducted according to the pertinent regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject confidentiality. 
Further details of the study monitoring will be outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies, the Sponsor, and 
 quality 
assurance and/or its designees may carry out on-site inspections and/or audits that may include 
source data checks. Therefore, direct access to the original source data will be required for 
inspections and/or audits. All inspections and audits will be carried out giving consideration to 
data protection as well as subject confidentiality to the extent that local, state, and federal laws 
apply. 
 
 


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9 
ADVERSE EVENTS 
9.1 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence associated with the use of 
an IP in humans, whether it is considered IP-related or not. An AE can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP, without any judgment about causality. An AE can arise from 
any use of the IP (e.g., off-label use, use in combination with another drug or medical device) 
and from any route of administration, formulation, or dose, including an overdose.  
All AEs spontaneously reported by the subject and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will 
be recorded in the subject’s source document and eCRF. Any clinically relevant deterioration in 
clinical finding is considered an AE and must be recorded. When possible, signs and symptoms 
indicating a common underlying pathology should be noted as one comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to IP, expectedness, action(s) taken, seriousness, and outcome of any sign 
or symptom observed by the physician or reported by the patient upon indirect questioning. 
All AEs will be collected from the time a subject signs the ICF through the subjects’ study exit 
visit. 
Severity 
The severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE 
as determined by the investigator or reported to him/her by the patient/subject. The assessment of 
severity is made irrespective of relationship to IP or seriousness of the event and should be 
evaluated according to the following scale: 
• Mild: Event is noticeable to the subject but is easily tolerated and does not interfere with 
the subject’s daily activities. 
• Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere 
with the subject’s daily activities. 
• Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and 
interferes with the subject’s daily activities. 
Relationship to Investigational Product 
The relationship of each AE to the IP should be determined by the investigator using these 
explanations: 
• Suspected: A reasonable possibility exists that the IP caused the AE. 
• Not Suspected: A reasonable possibility does not exist that the IP caused the AE. 
“Suspected adverse reaction” means any AE for which there is a reasonable possibility that the 
IP caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the IP and the AE. Types of evidence that would suggest a causal 
relationship between the IP and the AE include: a single occurrence of an event that is 
uncommon and known to be strongly associated with IP exposure (e.g., angioedema, hepatic 
injury, Stevens-Johnson Syndrome); one or more occurrences of an event that is not commonly 


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associated with IP exposure, but is otherwise uncommon in the population exposed to the IP 
(e.g., tendon rupture); an aggregate analysis of specific events observed in a clinical trial (such as 
known consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates those 
events occur more frequently in the IP-treatment group than in a concurrent or historical control 
group. 
Expectedness 
The expectedness of an AE should be determined based upon existing safety information about 
the IP using these explanations: 
• Unexpected: an AE that is not listed in the Investigator’s Brochure (IB) or is not listed at 
the specificity or severity that has been observed. 
• Expected: an AE that is listed in the IB at the specificity and severity that has been 
observed. 
• Not applicable: an AE unrelated to IP. 
AEs that are mentioned in the IB as occurring with a class of products or as anticipated from the 
pharmacological (or other) properties of the product but are not specifically mentioned as 
occurring with the particular product under investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an AE. The final classification of an 
AE is subject to the sponsor’s determination. 
9.2 
Serious Adverse Events 
An AE is considered serious if, in the view of either the investigator or sponsor, it results in any 
of the following outcomes: 
• Death; 
• A life-threatening AE; 
Note: An AE is considered “life-threatening” if, in the view of either the investigator or 
sponsor, its occurrence places the patient or subject at immediate risk of death. It does not 
include an AE that, had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization; 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even if 
< 24 hours). For chronic or long-term inpatients, inpatient admission includes transfer 
within the hospital to an acute/intensive care inpatient unit. Inpatient hospitalization does 
not include: emergency room visits; outpatient/same-day/ambulatory procedures; 
observation/short stay units; rehabilitation facilities; hospice facilities; nursing homes; or 
clinical research/Phase 1 units. 
Note: The term “prolongation of existing hospitalization” refers to any extension of an 
inpatient hospitalization beyond the stay anticipated or required for the reason for the 
initial admission as determined by the investigator or treating physician. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
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Note: A Serious Adverse Event (SAE) specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g., intraocular 
hemorrhage, retinal detachment, central corneal ulcer, or damage to the optic nerve). 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. The medical monitor will review and determine the 
expectedness of any SAE following the investigator’s assessment.  
9.3 
Procedures for Reporting Adverse Events 
All AEs and their outcomes must be reported to 
the study sponsor, and the IRB as required 
by the IRB, federal, state, or local regulations and governing health authorities and recorded on 
the appropriate subject source document and eCRF. 
Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to 
 the study sponsor, and 
the IRB as required by the IRB, federal, state, or local regulations and governing health 
authorities. 
Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the study drug, must be 
immediately reported by the investigator to 
 and the sponsor within 24 hours of becoming 
aware of the event. All information relevant to the SAE must be recorded on the appropriate 
source document, SAE Report Form, and eCRF, including all pertinent medical records, 
information, and medical judgments from colleagues who assisted in the treatment and follow-up 
of the subject, a complete case history, which includes a statement as to whether the event was or 
was not suspected to be related to the use of the IP. The investigator must also inform the IRB of 
the AE within their guidelines for reporting SAEs. The investigator is obligated to pursue and 
obtain information requested by 
 and/or the sponsor in addition to the information reported 
on the source document, SAE Report Form, and eCRF. All subjects experiencing an SAE must 
be followed-up with, and the outcome reported. 
Contact information for reporting SAEs: 
 
 
 
9.4 
Procedures for Unmasking (if applicable) 
Treatment assignment should not be communicated to the Contract Research Organization 
(CRO) or Sponsor and should not be recorded in any study documents or source document. 
When medically necessary, the investigator may need to determine what treatment has been 
assigned to a subject. When possible (i.e., in non-emergency situations), 
and/or the study 
sponsor should be notified before unmasking the study drug. 


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Type and Duration of the Follow-up of Subjects after Adverse Events 
The investigator will follow unresolved AEs to resolution, until the subject is lost to follow-up or 
until the AE is otherwise explained. Resolution means the subject has returned to baseline state 
of health or the investigator does not expect any further improvement or worsening of the AE. If 
the subject is lost to follow-up, the investigator should make 3 reasonable attempts to contact the 
subject via telephone, post, or certified mail. All follow-up will be documented in the subjects’ 
source document. Non-serious AEs identified on the last scheduled contact must be recorded on 
the source document with the status noted. 
If the investigator becomes aware of any new information regarding an SAE (i.e., resolution, 
change in condition, or new treatment), a new SAE Report Form must be completed and 
faxed/emailed to 
 and/or the study sponsor within 24 hours. The original SAE Report Form is 
not to be altered. The SAE Report Form should describe whether the event has resolved or 
continues and how the event was treated. 
 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES  
10.1 General Considerations  
In general, quantitative/continuous data will be summarized using descriptive statistics (n, mean, 
standard deviation (SD), median, minimum, and maximum). Qualitative/categorical data will be 
summarized using frequencies and percentages. Statistical testing, unless otherwise indicated, 
will be performed at a 2-sided 0.05 significance level.  
For all variables, baseline is defined as the pre-randomization measurement taken at Visit 2 (Day 
1), prior to administration of study drug. Change from baseline will be calculated as follow-up 
measure minus baseline measure. 
10.2 Hypotheses 
The primary efficacy hypothesis is: 
H01: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA 
at 40 cm (Precision Vision chart) without a loss in best distance corrected VA of ≥ 5 letters 
(ETDRS at 4m) at Visit 3 (Day 8), 1 hour post-Dose 1 = 0. 
H11: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA 
at 40 cm (Precision Vision chart) without a loss in best distance corrected VA of ≥ 5 letters 
(ETDRS at 4m) at Visit 3 (Day 8), 1 hour post-Dose 1 ≠ 0. 
The study will be considered a success if the null hypothesis, H01, is rejected at a 2-sided alpha 
= 0.05 in favor of CSF-1 in the alternative hypothesis, H11, tested as delineated in the primary 
efficacy analysis section, and the following secondary efficacy hypotheses will each be tested as 
stated under adjustments for multiplicity. 
 
 


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The secondary efficacy hypotheses are: 
Visit 3 
Duration of Action Visit 3 Post-Dose 1 
H02: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA 
at 40 cm (Precision Vision chart) without a loss in best distance corrected VA of ≥ 5 letters 
(ETDRS at 4m) at Visit 3 (Day 8), 2 hours post-Dose 1 = 0. 
H12: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA 
at 40 cm (Precision Vision chart) without a loss in best distance corrected VA of ≥ 5 letters 
(ETDRS at 4m) at Visit 3 (Day 8), 2 hours post-Dose 1 ≠ 0. 
 
Visit 3, 1 Hour Post-Dose 2 
H03: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA 
at 40 cm (Precision Vision chart) without a loss in best distance corrected VA of ≥ 5 letters 
(ETDRS at 4m) at Visit 3 (Day 8), 1 hour post-Dose 2 = 0. 
H13: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA 
at 40 cm (Precision Vision chart) without a loss in best distance corrected VA of ≥ 5 letters 
(ETDRS at 4m) at Visit 3 (Day 8), 1 hour post-Dose 2 ≠ 0. 
 
Duration of Action Visit 3 Post-Dose 2 
H04: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA 
at 40 cm (Precision Vision chart) without a loss in best distance corrected VA of ≥ 5 letters 
(ETDRS at 4m) at Visit 3 (Day 8), 2 hours post-Dose 2 = 0. 
H14: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in BDCVA 
at 40 cm (Precision Vision chart) without a loss in best distance corrected VA of ≥ 5 letters 
(ETDRS at 4m) at Visit 3 (Day 8), 2 hours post-Dose 2 ≠ 0. 
 
 
 
 
 
 
 
 
 
 
 


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. 


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Adjustments for Multiplicity 
The following testing strategy will be employed to adjust for multiplicity: 
If the primary null hypothesis, H01, is rejected at a 2-sided alpha = 0.05 in favor of CSF-1 in the 
alternative hypothesis, H11, tested as delineated in the primary efficacy analysis section, then the 
study will be considered a success and the following secondary hypotheses will be tested in 
hierarchical order, each at a 2-sided alpha = 0.05, where inference will be made on each null 
hypothesis only if the prior null hypotheses are rejected in favor of CSF-1 
1) Visit 3 (Day 8), 2 hours following Dose 1 (H02) 
2) Visit 3 (Day 8), 1 hour following Dose 2 (H03) 
3) Visit 3 (Day 8), 2 hours following Dose 2 (H04) 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 


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10.3 Study Populations  
• Full Analysis Set – The full analysis set (FAS) will include all randomized subjects who 
have received at least one dose of the study drug. Subjects in the FAS will be analyzed as 
randomized. 
• Per Protocol Set – The per-protocol (PP) set will include subjects in the FAS who do not 
have significant protocol deviations that affect the primary endpoint analysis. Protocol 
deviations will be assessed prior to database lock and unmasking. Subjects in the PP set 
will be analyzed as treated. 
• Safety Set – The safety set will include all subjects who have received at least one dose 
of the study drug. Subjects in the safety population will be analyzed as treated.  
10.4 Unit of Analysis 
The study eye will be used for all monocular analyses. The fellow eye will inherently be 
included in all binocular analyses. Both eyes will be displayed and analyzed for all ophthalmic 
safety variables. 
The study eye will be defined by the study Investigator as the eye that meets all enrollment 
criteria. If both eyes meet all enrollment criteria, then the eye with the worse Visit 2 pre-
treatment/baseline BDCVA at 40 cm (Precision Vision chart) will be the study eye. If both eyes 
have the same BDCVA at 40 cm, the right eye will be the study eye. 


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10.5 Sample Size 
A total sample size of 280 subjects (140 subjects per arm) yields >97.5% power to establish 
superiority of CSF-1 to Vehicle in the percentage of study eyes demonstrating a ≥ 3-line (15-
letter) gain from baseline in BDCVA at 40 cm (Precision Vision chart) and no loss of best 
distance corrected VA ≥5 letters (ETDRS at 4m), 1-hour post each dose on Visit 3 (Day 8) 
assuming a response rate of 42.5% in CSF-1 and 17.5% in Vehicle using a Pearson chi-squared 
test with a 2-sided significance level of 0.05. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accounting for approximately a 5% discontinuation rate, approximately 150 subjects per arm 
(approximately 300 total) will be randomized. 
Estimates were obtained from the Phase 2 study (18-150-0006) Intent-to-Treat (ITT) population 
response for pilocarpine 0.4% vs. diclofenac (control), additionally imputing missing data as 
failures.  
At least approximately 30% of subjects will have light (i.e., blue, green, gray, and hazel) iris, and 
at least approximately 30% will have a brown iris. The actual percentages will vary based on 
enrollment. 
10.6 Demographic and Baseline Characteristics  
Subject demographics including age, gender, race, ethnicity, and iris color will be presented 
using summary statistics (mean, SD, minimum, maximum, and median) or frequency counts and 
percentages as appropriate.  
10.7 Efficacy Analysis  
Primary Efficacy Analyses  
The primary efficacy endpoint in this study is the percentage of subjects with a ≥ 3-line (15-
letter) gain, from baseline, in best distance-corrected visual acuity (BDCVA) at 40 cm (Precision 
Vision chart) and no loss in best distance corrected visual acuity ≥ 5 letters (ETDRS chart) at 
Visit 3, 1 hour following Dose 1 in the study eye. The primary efficacy analysis will be 
conducted in the FAS with intercurrent events handled in the following manners:  


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1) Discontinuation of study drug and non-optimal compliance will be ignored [treatment 
policy strategy]. 
2) Withdrawal due to lack of efficacy or adverse events: missing data will be singly imputed 
as failure [hypothetical strategy]. 
3) Missing data without withdrawal or withdrawal due to reasons other than lack of efficacy 
or adverse events: missing data will be imputed employing Multiple Imputation (MI) 
using randomized treatment-based Markov Chain Monte Carlo (MCMC) methodology 
[hypothetical strategy]. 
No subject data will be excluded from the FAS due to protocol violations/deviations. The FAS 
will be used for the primary efficacy analyses. Note that multiple imputations of missing values 
will be completed for the continuous measures (BDCVA at 40 cm and best distance corrected 
VA at 4m), then the response variable will be determined therefrom. 
 
 
 
 
Descriptive statistics will be presented by treatment group. Testing of the percentage of subjects 
with at least a 3-line (15-letter) improvement from baseline in BDCVA at 40 cm without a loss 
of ≥ 5 letters in best distance corrected VA at 4m will be completed separately for the 1 hour and 
2 hour time points using a generalized linear mixed model with a binomial distribution including 
fixed effects of baseline BDCVA at 40 cm as a covariate, daily dose (Dose 1 and Dose 2), 
treatment, and the interaction of dose with treatment and random effect of subject to account for 
the correlation within a subject between daily doses. 
 
 
 
 
 
 
  
The adjusted odds ratios and marginal proportions and difference in proportions along with 
corresponding two-sided 95% Confidence Intervals (CIs) and p-values will be presented. 
Treatment comparisons will also be made separately for each time point and dose using logistic 
regression model including fixed effects of baseline BDCVA at 40 cm as a covariate and 
treatment, Pearson’s chi-squared test or Fisher’s exact test if any of the cell counts are less than 
five as a sensitivity analysis to the primary model above.  
Secondary Efficacy Analysis 
For the secondary efficacy endpoints of BDCVA at 40 cm, the percentage of subjects who 
achieve a ≥ 3-line (15-letters) improvement from baseline without a loss of ≥ 5 letters in best 
distance corrected VA at 4m for each Visit, time point and daily dose (Dose 1 and Dose 2) will 
be summarized and analyzed using the same imputation as the primary efficacy endpoint. The 
same modeling strategy will be used as detailed in the primary efficacy analysis for any time 
point that is measured after both doses within the visit 
 
 
 
 


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10.8 Safety Analysis 
Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) terms and be presented in a data listing. Treatment Emergent AEs (TEAEs), those 
that occur after the first dose of study drug, will be summarized by treatment group using 
frequency and percent for each System Organ Class (SOC) and Preferred Term (PT) within each 
SOC. Similar summaries will also be presented for serious TEAEs, TEAEs leading to death, 
TEAEs leading to study drug discontinuation, TEAEs related to IP and TEAEs by severity. 
When reporting the incidence of AEs, a subject will only be counted once if they ever experience 
an event within the SOC and ever experience the individual PT within the SOC. 
Actual results and changes from baseline results in monocular and binocular BCVA at 4m and 
Low- Luminance BCVA, slit-lamp biomicroscopy, conjunctival redness grading, IP drop 
comfort, IOP, and dilated fundus examination will be summarized descriptively at each visit by 
treatment group. 
Full details of the safety analyses will be specified in the formal SAP. 
10.9 Interim Analysis 
No interim analyses are planned for this study. 


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10.10 Missing Data 
The primary efficacy analyses will be conducted with missing data and intercurrent events 
handled in the following manners:  
1) Discontinuation of study drug and non-optimal compliance will be ignored 
[treatment policy strategy]. 
2) Withdrawal due to lack of efficacy or adverse events: missing data will be singly 
imputed as failure [hypothetical strategy]. 
3) Missing data without withdrawal or withdrawal due to reasons other than lack of 
efficacy or adverse events: missing data will be imputed employing Multiple 
Imputation (MI) using randomized treatment-based Markov Chain Monte Carlo 
(MCMC) methodology [hypothetical strategy]. 
 
 
 
 
 
10.11 Adjustment for Multiplicity 
If the primary null hypothesis, H01, is rejected at a 2-sided alpha = 0.05 in favor of CSF-1 in the 
alternative hypothesis, H11, tested as delineated in the primary efficacy analysis section, then the 
study will be considered a success and the following secondary hypotheses will be tested in 
hierarchical order, each at a 2-sided alpha = 0.05, where inference will be made on each null 
hypothesis only if the prior null hypotheses are rejected in favor of CSF-1 
1. 
Visit 3 (Day 8), 2 hours following Dose 1 (H02) 
2. 
Visit 3 (Day 8), 1 hour following Dose 2 (H03) 
3. 
Visit 3 (Day 8), 2 hours following Dose 2 (H04) 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 


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11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES  
This study will be conducted in compliance with the protocol, current GCPs, including the ICH 
Guidelines, and will, in general, be consistent with the Declaration of Helsinki. In addition, all 
applicable local, state, and federal requirements relevant to the use of study drug in the countries 
involved will be adhered to. 
11.1  Protection of Human Subjects 
Subject Informed Consent 
Informed consent must take place before any study-specific procedures are initiated. Signed and 
dated written informed consent must be obtained from each subject and/or from the subjects’ 
parent or legal guardian prior to enrollment into the study.  
All ICFs must be approved for use by the sponsor and receive approval/favorable opinion from 
an IRB prior to their use. If the ICF requires revision (e.g., due to a protocol amendment or 
significant new safety information), it is the investigator’s responsibility to ensure that the 
amended informed consent is reviewed and approved by 
 prior to submission to the 
governing IRB and that it is read, signed, and dated by all subjects subsequently enrolled in the 
study as well as those currently enrolled in the study. 


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All subjects have the right to withdraw consent at any time during the study period. If informed 
consent is taken under special circumstances (oral informed consent), then the procedures to be 
followed must be determined by 
 and/or the sponsor and provided in writing by 
and/or 
the sponsor prior to the consent process. 
IRB Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 CFR Part 56.103). 
The investigator must obtain appropriate IRB approval before initiating the study and re-
approval at least annually. 
Only an IRB-approved version of the ICF will be used. 
11.2  Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated with the 
Declaration of Helsinki. 
11.3  Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study should be 
maintained by the investigator and his/her staff with adequate precautions to ensure that the 
confidentiality of the data is in accordance with local, state, and federal laws and regulations. 
Monitors, auditors and other authorized representatives of 
, the sponsor, the IRB approving 
this study, the FDA, the Department of Health and Human Services, other domestic government 
agencies, and other foreign regulatory agencies will be granted direct access to the study 
subjects’ original medical and study records for verification of the data and/or clinical trial 
procedures. Access to this information will be permitted to the aforementioned individuals to the 
extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health authorities 
in any country in which the study drug may ultimately be marketed in, but the subjects’ identity 
will not be disclosed in these documents. 
11.4  Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, the 
investigators’ subject files, as well as the results of diagnostic tests such as radiographs, 
laboratory tests, and electrocardiograms. The investigators’ copy of the eCRFs serves as the 
investigators’ record of a subjects’ study-related data. 
Retention of Documentation 
All study-related correspondence, patient records, consent forms, records of the distribution and 
use of all study drug, and copies of case report forms should be maintained on file for at least 2 
years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region; or until at least two years 
have elapsed since the formal discontinuation of clinical development of the study drug. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
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the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug 
Labeling/Packaging 
Vehicle for screening and study drug will be packaged and labeled into clinical kits for screening 
and treatment. Vehicle for screening will be labeled and packaged into screening kits containing 
1 pouch each. After randomization, each subject will be assigned a single master kit containing 
two smaller (inner) kits of study drug for treatment. Each inner kit will be comprised of 5 
pouches containing one strip of 5 vials containing IP or vehicle. Each master kit will be uniquely 
identified by the kit number; the 2 inner kits inside will bear the same kit number with an 
additional designation indicating the visit at which each is to be dispensed (i.e., Visit 2 or Visit 
3). Screening kit, master kit, and inner kit labels will also include a space for the site to enter 
each subjects’ subject number and initials upon kit assignment.  
Clinical label texts for the packaging will meet applicable regulatory requirements and include 
the statement “Caution: New Drug-Limited by Federal Law to Investigational Use.”  
Storage of Investigational Product 
Study drug and Vehicle for screening must be stored in a secure area of the investigative site, 
accessible only to the investigator or designees, refrigerated between 2° to 8°C (36° to 46°F). A 
temperature log must be recorded throughout the course of the study, once every business day 
with the minimum and maximum temperature. Study drug will be administered/dispensed only 
to subjects entered into the clinical study, in accordance with the conditions specified in this 
protocol. Subjects will be instructed to store dispensed study drug under refrigerated conditions, 
and transport study drug kits to their homes using cooler bags and an ice pack provided by the 
site at the time of dispensation. All study drug will be returned to inventory after use in the 
provided return bags. Please refer to the IP manual for additional information.  
Accountability of Study Drug 
Study drug (IP and Vehicle) is to only be administered by study personnel and is to only be used 
in accordance with this protocol. Study drug must only be distributed to subjects properly 
qualified under this protocol to receive study drug. 
Sites must keep an accurate accounting of the study drug received from the supplier. This 
includes the amount of study drug administered to subjects and the amount returned or disposed 
throughout the course of the study. A detailed inventory must be completed for the study drug. 
Return or Disposal of Study Drug 
All study drug will be returned to the sponsor or their designee or destroyed. The return or 
disposal of study drug will be specified in writing. Any remaining study drug will be collected 
from the subject at Visit 3 and Visit 4 before study exit. Further details on labeling, packaging, 
storage, accountability, and return or disposal of study drug can be found in the IP Manual. 
11.6 Recording of Data on Source Documents and Electronic Case Reports 
Forms (eCRFs) 
The investigator is responsible for ensuring that study data is completely and accurately recorded 
on each subjects’ source document, eCRF, and all study-related material. All study data should 


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also be attributable, legible, contemporaneous, and original. Recorded datum should only be 
corrected in a manner that does not obliterate, destroy, or render illegible the previous entry 
(e.g., by drawing a single line through the incorrect entry and writing the revision next to the 
corrected data). An individual who has corrected a data entry should make clear who made the 
correction and when by adding to the correction his/her initials as well as the date of the 
correction. 
11.7 Handling of Biological Specimens 
Not applicable 
12 PUBLICATIONS 
Authorship and manuscript composition will reflect cooperation among all parties involved in 
the study. Authorship will be established before writing the manuscript. 
and the study 
sponsor will have the final decision regarding the manuscript and publication. 


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13 REFERENCES 
Bowie, E. M. and S. J. Givre (2003). "Tonic pupil and sarcoidosis." Am J Ophthalmol 135(3): 
417-419. 
Chemmanam, T., J. D. Pandian, R. S. Kadyan and S. M. Bhatti (2007). "Anhidrosis: a clue to an 
underlying autonomic disorder." J Clin Neurosci 14(1): 94-96. 
Croft, M. A., A. Glasser and P. L. Kaufman (2001). "Accommodation and presbyopia." Int 
Ophthalmol Clin 41(2): 33-46. 
Donders, F. C. (1864). Accommodation and refraction of the eye Translated by WD Moore 1952 
The New Sydenham Society/Hatton Press, London. 
Fernandez, E. J., C. Schwarz, P. M. Prieto, S. Manzanera and P. Artal (2013). "Impact on stereo-
acuity of two presbyopia correction approaches: monovision and small aperture inlay." Biomed 
Opt Express 4(6): 822-830. 
Fricke, T. R., N. Tahhan, S. Resnikoff, E. Papas, A. Burnett, S. M. Ho, T. Naduvilath and K. S. 
Naidoo (2018). "Global Prevalence of Presbyopia and Vision Impairment from Uncorrected 
Presbyopia: Systematic Review, Meta-analysis, and Modelling." Ophthalmology 125(10): 1492-
1499. 
Garner, L. F. and M. K. Yap (1997). "Changes in ocular dimensions and refraction with 
accommodation." Ophthalmic Physiol Opt 17(1): 12-17. 
Glasser, A. (2006). "Accommodation: mechanism and measurement." Ophthalmol Clin North 
Am 19(1): 1-12, v. 
Lana-Peixoto, M. A., W. R. Campos, P. A. Reis, C. M. Campos and C. A. Rodrigues (2014). 
"Tonic pupil in leprosy." Arq Bras Oftalmol 77(6): 395-396. 
Monaco, S., N. Freddi, E. Francavilla, F. Meneghetti, L. Fenicia, G. Franciosa and P. Cadrobbi 
(1998). "Transient tonic pupils in botulism type B." J Neurol Sci 156(1): 96-98. 
Moussa, K., N. Jehangir, T. Mannis, W. L. Wong and M. Moshirfar (2017). "Corneal Refractive 
Procedures for the Treatment of Presbyopia." Open Ophthalmol J 11: 59-75. 
Patel, J. I., L. Jenkins, L. Benjamin and S. Webber (2002). "Dilated pupils and loss of 
accommodation following diode panretinal photocoagulation with sub-tenon local anaesthetic in 
four cases." Eye (Lond) 16(5): 628-632. 
Truscott, R. J. (2009). "Presbyopia. Emerging from a blur towards an understanding of the 
molecular basis for this most common eye condition." Exp Eye Res 88(2): 241-247. 
Weller, M., H. Wilhelm, N. Sommer, J. Dichgans and H. Wietholter (1992). "Tonic pupil, 
areflexia, and segmental anhidrosis: two additional cases of Ross syndrome and review of the 
literature." J Neurol 239(4): 231-234. 


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14 APPENDICES 
Appendix 1: Schedule of Assessments 


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Appendix 2: Examination Procedures, Tests, Equipment, and Techniques 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 












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Appendix 3:  Protocol Amendment Summary 
AMENDMENT 1 
BACKGROUND AND RATIONALE FOR AMENDMENT 
The purpose of Protocol Amendment 1 is to:  
1) correct Sponsor address 
2) add / define at-home dosing windows 
3) add / define windows for post-vehicle / post-treatment assessment timepoints  
4) revise exclusion criteria #11 to remove 1-hour post-vehicle VA assessment.  
5) revised exclusion criterias #5 & #6 to require the use of negative cylinder for 
assessment of inclusion 
6) correct the numbering / formatting of exclusion criteria #17 
7) update order of assessments/procedures in Section 8 to be corrected to note that 
selection of study eye and randomization occur before the first dose of study 
medication is instilled. 
8) update the order of assessments in Section 8 and in Appendix 1: Schedule of 
Assessments, to note that the 40cm BDCVA assessment will be conducted after 
pupillometry and before the 4m distance and 4m low-luminance testing. 
9) correct wording in Appendix 1, Section 11, Subject-Reported Drop Comfort Scale 
& Questionnaire, to accurately reflect when assessment is completed  
SUMMARY OF CHANGES 
 
In the table below, the protocol text was amended by the following conventions: 
• 
Deletions to the original text are indicated by strike through letters. 
• 
Additions to amended text are indicated by bold letters. 
• 
Replacements of wording in the amended text are indicated by bold and 
italicized letters. 
 


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Appendix 5: Investigator’s Signature 
 
Protocol Title: 
A Multi-Center, Double-Masked, Vehicle-Controlled, Evaluation of 
the Efficacy and Safety of CSF-1 in the Temporary Correction of 
Presbyopia (the NEAR-1 study: Near Eye-vision Acuity Restoration) 
Protocol Number: 
20-150-0002 
I agree to implement and conduct the study diligently and in strict compliance with the protocol, 
the Good Clinical Practice ICH E6 (R2) Guidance, and all applicable laws and regulations. I 
agree to maintain all information supplied by 
and the sponsor in confidence and, when this 
information is submitted to an institutional review board (IRB), ethical review committee or 
another group, it will be submitted with a designation that the material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all aspects. 
 
 
 
Signed: 
 
 
Date:  
 
 
[Name] 
 
Principal Investigator 
 
[Affiliation] 
 
 
 
 
 



SAP_001.pdf: 
 
 STATISTICAL ANALYSIS PLAN (SAP) 
A Multi-Center, Double-Masked, Vehicle-Controlled, Evaluation of the 
Efficacy and Safety of CSF-1 in the Temporary Correction of 
Presbyopia (the NEAR-1 study: Near Eye-vision Acuity Restoration) 
 
 
Sponsor: 
 
Orasis Pharmaceuticals, Ltd 
 
Protocol Number: 
20-150-0002 (Phase 3) 
 
 
Author:  
 
 
 
 
 
 
Date: 
 
 
28FEB2022 
 
Version: 
 
2.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


28FEB2022 
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A Multi-Center, Double-Masked, Vehicle-Controlled, Evaluation of the 
Efficacy and Safety of CSF-1 in the Temporary Correction of 
Presbyopia (the NEAR-1 study: Near Eye-vision Acuity Restoration) 
Protocol Number: 
20-150-0002 (Phase 3) 
SAP Date: 
 
28FEB2022 
SAP Version:  
2.0 
 
SAP Preparation, Review, and Approvals 
 


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Table of Contents 
List of Abbreviations ......................................................................................................................... 5 
1. 
Introduction............................................................................................................................... 6 
2. 
Study Objectives ...................................................................................................................... 6 
2.1 
Study Variables ........................................................................................................................ 6 
2.2 
Primary Efficacy Endpoint ........................................................................................................ 7 
2.3 
Secondary Efficacy Endpoints ................................................................................................. 7 
2.3.1 
Key Secondary Efficacy Endpoints .................................................................................. 7 
2.3.2 
Other Secondary Efficacy Endpoints ............................................................................... 7 
2.4 
Exploratory Efficacy Endpoints ................................................................................................ 8 
2.5 
Safety Endpoints ...................................................................................................................... 9 
2.6 
Statistical Hypotheses .............................................................................................................. 9 
3. 
Study Design and Procedures ............................................................................................... 15 
3.1 
Overall Study Design ............................................................................................................. 15 
3.2 
Schedule of Visits and Measurements ................................................................................... 18 
4. 
Study Treatments ................................................................................................................... 21 
4.1 
Method of Assigning Subjects to Treatment Groups ............................................................. 22 
4.2 
Masking and Unmasking ........................................................................................................ 22 
5. 
Sample Size and Power Considerations ................................................................................ 22 
6. 
Data Preparation .................................................................................................................... 23 
7. 
Analysis Sets .......................................................................................................................... 24 
7.1 
Full Analysis Set ..................................................................................................................... 24 
7.2 
Per Protocol Set ..................................................................................................................... 24 
7.3 
Safety Set ............................................................................................................................... 24 
8. 
General Statistical Considerations ......................................................................................... 24 
8.1 
Unit of Analysis ...................................................................................................................... 24 
8.2 
Missing Data Handling and Sensitivity Analysis .................................................................... 24 
8.3 
Definition of Baseline ............................................................................................................. 25 
8.4 
Data Analysis Conventions .................................................................................................... 25 
8.5 
Adjustment for Multiplicity ...................................................................................................... 26 
9. 
Disposition of Subjects ........................................................................................................... 27 
10. 
Demographic and Baseline Characteristics ........................................................................... 27 
10.1 
Demographics ........................................................................................................................ 27 
10.2 
Baseline Characteristics ......................................................................................................... 28 
11. 
Medical History and Concomitant Medications ...................................................................... 28 
11.1 
Medical History ....................................................................................................................... 28 


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11.2 
Prior and Concomitant Medications ....................................................................................... 28 
12. 
Efficacy Analyses ................................................................................................................... 29 
12.1 
Primary and Key Secondary Efficacy Analysis ...................................................................... 29 
12.2 
Sensitivity Analysis for Primary and Key Secondary Efficacy Endpoints .............................. 30 
12.3 
 
 
 
14. 
Safety Analyses ..................................................................................................................... 33 
14.1 
Adverse Event Summaries..................................................................................................... 33 
14.2 
Best Distance-Corrected Visual Acuity .................................................................................. 34 
14.3 
 
 
 
 
 
 
 
 
 
15. 
Interim Analyses ..................................................................................................................... 36 
16. 
Changes from Protocol-Stated Analyses ............................................................................... 36 
17. 
References ............................................................................................................................. 37 
18. 
Revision History ..................................................................................................................... 37 
19. 
Tables ..................................................................................................................................... 39 
20. 
Listings ................................................................................................................................... 42 
21. 
Figures ................................................................................................................................... 43 
 
List of Tables: 
 
 
 
List of Figures: 
Figure 1. Study Design ........................................................................................................................ 17 
 
 


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List of Abbreviations 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BDCVA 
Best Distance-Corrected Visual Acuity 
BID 
Twice Daily 
CI 
Confidence Interval 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
GEE 
Generalized Estimating Equation 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IMDF 
Imputing Missing Data as Failures 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRT 
Interactive Response Technology 
HIPAA 
Health Information Portability and Accountability Act 
LDPE 
Low-Density Polyethylene 
LL-BDCVA 
Low-Luminance Best Distance-Corrected Visual Acuity 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LS 
Least Square 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
NCS 
Not Clinically Significant 
ODO 
Observed Data Only 
PPS 
Per Protocol Set 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics & Data Corporation 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
TPA 
Tipping Point Analysis 
VA 
Visual Acuity 
WHO 
World Health Organization 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for the 
Orasis 20-150-0002 protocol, Version 2.0 (Amendment 1), dated 07Jan2021 (NEAR-1 study). 
This Version 2.0 SAP replaces the previous finalized and signed Version 1.0 SAP, dated 22Nov2021. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Council for Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. Any additional analyses required to supplement the planned 
analyses described in this SAP will be duly noted in the clinical study report. 
2. Study Objectives 
The primary objective of this study is to evaluate the efficacy of CSF-1 (0.4% pilocarpine hydrochloride 
ophthalmic solution) for the temporary correction of presbyopia.  
The secondary objectives of this study are to evaluate the safety and tolerability of CSF-1 versus Vehicle.  
2.1 
Study Variables 
For all study variables, baseline is defined as the pre-treatment measurement taken at Visit 2 (Day 1). If 
the measurement is not available from Visit 2 (Day 1), then the measurement from Visit 1 (Day -14 to -1) 
will be used as baseline for all treatments/visits. Change from baseline will be calculated as follow-up 
measure minus baseline measure. 
Efficacy variables include best distance-corrected visual acuity (BDCVA) at 40 cm (Precision Vision Chart) 
and BDCVA at 4 m (Early Treatment of Diabetic Retinopathy Study [ETDRS] chart), 
 
 
Safety variables include BDCVA at distance under normal and low-luminance testing conditions, slit-lamp 
biomicroscopy measures, conjunctival redness grading, and study drug drop comfort assessment, as well 
as intraocular pressure (IOP), dilated indirect fundoscopy, and adverse events (AEs). The logarithm of the 
minimum angle of resolution (logMAR) units will be used for all VA safety and efficacy measures. Visual 
acuity will be assessed with best distance-correction determined by the manifest refraction at Visit 1 (Day 
-14 to -1). Further details regarding the procedures for conducting manifest refraction can be found in the 
BCVA protocol. 
 


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2.2 
Primary Efficacy Endpoint 
Percentage of subjects with a ≥ 3-line (15-letter) gain, from baseline, in BDCVA at 40 cm (Precision Vision 
chart) and no loss in BDCVA ≥ 5 letters (ETDRS chart at 4 m) in the study eye at Visit 3 (Day 8), following 
Dose 1, 1 hour post-treatment. 
2.3 
Secondary Efficacy Endpoints 
2.3.1 
KEY SECONDARY EFFICACY ENDPOINTS 
Key secondary efficacy endpoints include the following: 
Percentage of subjects with a ≥ 3-line (15-letter) gain, from baseline, in BDCVA at 40 cm (Precision Vision 
chart) and no loss in BDCVA ≥ 5 letters (ETDRS chart at 4 m) in the study eye at the following Visits, Doses 
and timepoints: 
Visit 3 (Day 8) 
Dose 1 
• 
2 hours following Dose 1 
Dose 2 
• 
1 hour following Dose 2 
• 
2 hours following Dose 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.5 
Safety Endpoints 
The safety endpoints include the following: 
• 
BDCVA (normal and low luminance) at 4 m  
• 
Slit-lamp biomicroscopy 
• 
Conjunctival redness grading 
• 
Study drug drop comfort assessment 
• 
IOP 
• 
Dilated indirect fundoscopy 
• 
AEs (reported, elicited, and observed) 
2.6 
Statistical Hypotheses 
The primary efficacy hypothesis is: 
H01: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in 
BDCVA at 40 cm (Precision Vision chart) without a loss in BDCVA of ≥ 5 letters (ETDRS at 4 
m) at Visit 3 (Day 8), 1 hour post-dose 1 = 0 
H11: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in 
BDCVA at 40 cm (Precision Vision chart) without a loss in BDCVA of ≥ 5 letters (ETDRS at 4 
m) at Visit 3 (Day 8), 1 hour post-dose 1 ≠ 0 
The study will be considered a success if the null hypothesis, H01, is rejected at a 2-sided alpha = 0.05 in 
favor of CSF-1 in the alternative hypothesis, H11, tested as delineated in the primary efficacy analysis 
section, and the following secondary efficacy hypotheses will each be tested as stated under adjustments 
for multiplicity. 
The key secondary efficacy hypotheses are: 
Visit 3 (Day 8) 
Visit 3, 2 Hours Post-Dose 1 


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H02: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in 
BDCVA at 40 cm (Precision Vision chart) without a loss in BDCVA of ≥ 5 letters (ETDRS at 4 
m) at Visit 3 (Day 8), 2 hours post-dose 1 = 0. 
H12: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in 
BDCVA at 40 cm (Precision Vision chart) without a loss in BDCVA of ≥ 5 letters (ETDRS at 4 
m) at Visit 3 (Day 8), 2 hours post-dose 1 ≠ 0. 
Visit 3, 1 Hour Post-Dose 2 
H03: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in 
BDCVA at 40 cm (Precision Vision chart) without a loss in BDCVA of ≥ 5 letters (ETDRS at 4 
m) at Visit 3 (Day 8), 1 hour post-dose 2 = 0. 
H13: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in 
BDCVA at 40 cm (Precision Vision chart) without a loss in BDCVA of ≥ 5 letters (ETDRS at 4 
m) at Visit 3 (Day 8), 1 hour post-dose 2 ≠ 0. 
Visit 3, 2 Hours Post-Dose 2 
H04: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in 
BDCVA at 40 cm (Precision Vision chart) without a loss in BDCVA of ≥ 5 letters (ETDRS at 4 
m) at Visit 3 (Day 8), 2 hours post-dose 2 = 0. 
H14: The difference between study eyes treated with CSF-1 and study eyes treated with Vehicle, 
in the percentage of study eyes with a ≥ 3-line (15-letter) improvement from baseline in 
BDCVA at 40 cm (Precision Vision chart) without a loss in BDCVA of ≥ 5 letters (ETDRS at 4 
m) at Visit 3 (Day 8), 2 hours post-dose 2 ≠ 0. 
 
 
 
 
 
 
 
 


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3. Study Design and Procedures 
3.1 
Overall Study Design 
This is a four-visit multi-center, randomized, double-masked, parallel-group study evaluating the safety and 
efficacy of CSF-1 compared with Vehicle in approximately 300 subjects with presbyopia. The study design 
is summarized in Figure 1. 
Visit 1 (Screening, Day -14 to -1): Qualified subjects will receive 1 drop of Vehicle instilled in each eye, 
followed by preliminary efficacy assessments to identify Vehicle responders at 15 minutes post-vehicle 
instillation.  
Vehicle responder is defined as a subject who had a > 0.14 LogMAR (i.e., 7 letters) improvement in post- 
Vehicle treatment (at 15 minutes post-Vehicle treatment) monocular BDCVA in either eye at 40 cm 


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compared to Visit 1 pre-treatment, or a > 0.14 LogMAR (i.e., 7 letters) improvement in monocular BDCVA 
in either eye at 40 cm between Visit 1 (pre-treatment) and Visit 2 (pre-treatment baseline). 
Visit 2 (Day 1): Baseline assessments. Subjects who meet all inclusion and none of the exclusion criteria 
and qualify as Vehicle non-responders, will be randomized 1:1 to one of the following treatment arms: 
• 
CSF-1 (0.4% pilocarpine hydrochloride ophthalmic solution) 
• 
Vehicle 
Pre-treatment measurements taken at this visit are considered as baseline. 
At the Visit 2 (Day 1) clinic visit, study personnel will instill Dose 1 of study drug at 8:30 AM ± 30 minutes in 
each eye. Efficacy and safety assessments will be conducted for 2 hours following Dose 1. Dose 2 will be 
instilled by study personnel at 10:30 AM ± 30 minutes in each eye. Efficacy and safety assessments will be 
conducted for 4 hours following Dose 2. 
All subjects will be instructed to dose twice daily (BID) with a single drop in each eye for approximately 1 
week. The first daily dose should occur in the morning, with the second dose following 2 hours later (±1 
hour). Subjects will be instructed not to dose at home on clinic visit days. 
Visit 3 (Day 8): Study personnel will instill Dose 1 of study drug at 8:30 AM ± 30 minutes in each eye. 
Efficacy and safety assessments will be conducted for 2 hours following Dose 1. Dose 2 will be instilled by 
study personnel at 10:30 AM ± 30 minutes in each eye. Efficacy and safety assessments will be conducted 
for 2 hours following Dose 2. 
All subjects will be instructed to dose twice daily (BID) with a single drop in each eye, for approximately 1 
week. The first daily dose should occur in the morning with the second dose following 3 hours later (±1 
hour). Subjects will be instructed not to dose at home on clinic visit days. 
Visit 4 (Day 15): Study personnel will instill Dose 1 of study drug at 8:30 AM ± 30 minutes in each eye. 
Efficacy and safety assessments will be conducted up to 3 hours following Dose 1. Dose 2 will be instilled 
by study personnel at 11:30 AM ± 30 minutes in each eye. Efficacy and safety assessments will be 
conducted for 5 hours following Dose 2. 
 
 


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Figure 1. Study Design 
Visit 1 
(Day -14 to -1): 
Screening 
Screening Assessments 
1 dose of Vehicle in each eye 
 
 
Visit 2 
(Day 1): 
Baseline 
Baseline 
Randomization 
Dose 1 instillation in each eye 
Efficacy and Safety Assessments Dose #1  
(through 2 hours post dose) 
Dose 2 instillation in each eye 
Efficacy and Safety Assessments Dose #2  
(through 4 hours post dose) 
 
 
BID Dosing: Dose 1 in the morning followed by Dose 2 (2 hours after Dose 1)  
 
 
Visit 3 
(Day 8 ± 1): 
Efficacy and Safety 
Dose 1 instillation in each eye 
Efficacy and Safety Assessments Dose 1  
(through 2 hours post Dose) 
Dose 2 instillation in each eye 
Efficacy and Safety Assessments Dose 2  
(through 2 hours post Dose) 
 
 
BID Dosing: Dose 1 in the morning followed by Dose 2 (3 hours after Dose 1)  
 
 
Visit 4 
(Day 15 ± 2): 
Efficacy and Safety 
Dose 1 instillation in each eye 
Efficacy and Safety Assessments Dose 1  
(through 3 hours post dose) 
Dose 2 instillation in each eye 
Efficacy and Safety Assessments Dose 2  
(through 5 hours post dose) 
 


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3.2 
Schedule of Visits and Measurements 
  
Table 1 Schedule of Visits and Assessments 


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4. Study Treatments 
The investigational product (IP) is CSF-1, a sterile topical eye drop solution. The formulation developed by 
Orasis Pharmaceuticals Ltd. is a preservative-free eye drop, containing the active ingredient pilocarpine 
hydrochloride 0.4%, with the addition of standard pharmacopoeial excipients used in sterile ophthalmic 
solutions. 
The vehicle (CSF-1 placebo) is a topical eye drop solution containing the same ingredients as in CSF-1 
except for the active ingredient. 
Both IP and Vehicle are packaged in a single-dose transparent low-density polyethylene (LDPE) vials, 
enclosed within a pouch. Each pouch includes five vials. Kits will be dispensed to subjects at Visit 2 (Day 
1) and Visit 3 (Day 8) with 1 week of at-home dosing in each kit. CSF-1 will be evaluated for comparison to 
Vehicle. 
Following the pre-treatment assessments, qualified subjects will be randomized to 1:1 to one of the 
following treatment arms: 
1. CSF-1: Pilocarpine Hydrochloride (0.4%) Ophthalmic Solution 
2. Placebo (Vehicle) 
After randomization at Visit 2 (Day 1), subjects will receive study drug and a paper dosing diary. Each 
subject will instill one drop of study drug to each eye and keep aside the used vial to be returned to the site 


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at next visit for compliance check. Following Visit 2, subjects will be instructed to dose bilaterally BID (with 
2 hours (+1 hour) between doses) and record doses in their diary until Visit 3. Subjects should not dose at 
home on day of Visit 3. Following Visit 3, after subjects receive their study drug and dosing diary, subjects 
will be instructed to dose bilaterally BID (with 3 hours (+1 hour) between doses) and record doses in their 
diary until Visit 4. Subjects should not dose at home on day of Visit 4. At Visit 4, subjects will receive their 
doses at the visit by study personnel after the required pre-treatment assessments and their study drug will 
be collected. Subjects will exit the study after all assessments are complete at Visit 4. 
4.1 
Method of Assigning Subjects to Treatment Groups 
Each subject who signs an informed consent form (ICF) will be assigned a subject number. Subject 
numbers will be assigned in sequential order beginning with 001. Once a subject meets all qualification 
criteria at Visit 2 (Day 1), they will be randomized in a 1:1 ratio via an Interactive Response Technology 
(IRT) system to one of the following treatment groups: (1) CSF-1 or (2) Vehicle, and stratified by iris color 
(brown versus light [i.e., blue, green, gray, and hazel]) and by baseline manifest refraction spherical 
equivalent <-0.5 D, -0.5 D to +0.75 D, and >+0.75 D); randomization will not be stratified by site. 
At least, approximately, 30% of subjects will have a light iris and at least, approximately, 30% will have a 
brown iris. The actual percentages will vary based on enrollment. 
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase the 
likelihood that known and unknown subject attributes (e.g., iris color and baseline characteristics) are evenly 
balanced across treatment groups, and to enhance the validity of statistical comparisons across treatment 
groups. Double-masked treatment will be used to reduce the potential of bias during data collection and the 
evaluation of clinical endpoints.  
4.2 
Masking and Unmasking 
An independent, unmasked biostatistician who is not otherwise involved in the trial will generate the 
complete randomized study drug kit list. The subject, study sponsor, medical investigators, and study staff 
will be masked during the entire randomization process and throughout the course of the study. When 
medically necessary, the investigator may need to determine what treatment has been assigned to a 
particular subject. When possible (i.e., in non-emergent situations), 
 and/or the study sponsor should 
be notified before unmasking the IP. In emergency situations, the investigator must notify the sponsor within 
24 hours after determining that it is necessary to unmask the treatment assignment. The investigator must 
also indicate in source documents and in the electronic case report form (eCRF) that the mask was broken 
and provide the date, time, and reason for breaking the mask. 
5. Sample Size and Power Considerations 
A total sample size of 280 subjects (140 subjects per arm) yields > 97.5% power to establish superiority of 
CSF-1 to Vehicle in the percentage of study eyes demonstrating a ≥ 3-line (15-letter) gain from baseline in 
BDCVA at 40 cm (Precision Vision chart) and no loss of BDCVA ≥ 5 letters (ETDRS at 4 m), 1-hour post 


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each dose on Visit 3 (Day 8) assuming a response rate of 42.5% in CSF-1 and 17.5% in Vehicle using a 
Pearson chi-squared test with a 2-sided significance level of 0.05. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Accounting for approximately a 5% discontinuation rate, approximately 150 subjects per arm 
(approximately 300 total) will be randomized. 
6. Data Preparation 
All reported study data will be recorded on the eCRFs supplied by Statistics & Data Corporation (SDC) 
using iMedNet™. Only the Principal Investigator and authorized study staff according to the Delegation of 
Responsibilities log are entitled to make entries in the eCRF. After data are entered into the clinical study 
database, electronic edit checks, and data review will be performed. All data validation specifications and 
procedures are detailed in the Data Validation Manual as a separate document. When the database has 
been declared to be complete and accurate, the database will be locked. Any changes to the database after 
data have been locked can only be made with the approval of the sponsor and 
. in consultation with 
SDC. 
The final analyses outlined in this document will be carried out only after the following have occurred: 
• 
All data management requirements are met according to SDC standard operating procedures, 
including data entry, performance of edit and validation checks, documentation and resolution of 
data queries, and database lock with written authorization provided by appropriate SDC and 
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• 
Protocol deviations have been identified and status defined (major/minor deviations), and 
completed prior to database lock and study unmasking. 
• 
Analysis populations have been determined, and completed prior to database lock and study 
unmasking. 
• 
Randomized treatment codes have been unmasked. 
7. Analysis Sets 
7.1 
Full Analysis Set 
The full analysis set (FAS) will include all randomized subjects who have received at least one dose of the 
study drug. Subjects in the FAS will be analyzed as randomized. The FAS analysis set will be the primary 
analysis set for the determination of efficacy. 
7.2 
Per Protocol Set 
The per-protocol set (PPS)  will include subjects in the FAS who do not have significant protocol deviations 
that affect the primary efficacy endpoint analyses. Protocol deviations will be assessed prior to database 
lock and unmasking. Subjects in the PPS will be analyzed as treated. The PPS analysis will be supportive 
of the primary and key secondary efficacy analysis performed with FAS. 
7.3 
Safety Set 
The safety set (SAF) will include all subjects who have received at least one dose of the study drug. 
Subjects in the SAF will be analyzed as treated.  
8. General Statistical Considerations 
8.1 
Unit of Analysis 
The study eye will be used for all monocular analyses. The fellow eye will inherently be included in all 
binocular analyses. Both eyes will be displayed and analyzed for all ophthalmic safety endpoints. 
The study eye will be defined by the study Investigator as the eye that meets all enrollment criteria. If both 
eyes meet all enrollment criteria, then the eye with the worse Visit 2 pre-treatment/baseline BDCVA at 40 
cm (Precision Vision chart) will be the study eye. If both eyes have the same BDCVA at 40 cm, the right 
eye will be the study eye. 
8.2 
Missing Data Handling and Sensitivity Analysis 
The primary efficacy analysis and the key secondary analyses will be performed on the FAS, as described 
in section 12.1. In the event of missing data, the primary imputation method will be Multiple Imputation (MI), 
using randomized treatment-based Markov Chain Monte Carlo (MCMC). Sensitivity analyses will also be 
performed on the primary and key secondary efficacy endpoints measured at Visit 3 (Day 8). These 
sensitivity analyses will be considered supportive of the primary and key secondary analyses. 


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8.3 
Definition of Baseline 
For all endpoints, baseline is defined as the pre-randomization measurement taken at Visit 2 (Day 1). If the 
measurement is not available from Visit 2 (Day 1), then the measurement from Visit 1 (Day -14 to -1) will 
be used as baseline. Change from baseline will be calculated as: Post-Baseline Measure – Baseline 
Measure. 
8.4 
Data Analysis Conventions 
All data analysis will be performed by SDC after the study is completed and the database has been locked 
and released for unmasking. Statistical programming and analyses will be performed using SAS® Version 
9.4 or higher. Output will be provided in rich text format for tables and portable document format for tables, 
listings, and figures using landscape orientation. All study data will be listed by subject, treatment, and visit 
(as applicable) based on all randomized subjects unless otherwise specified. 
Summaries for continuous and ordinal variables will include the number of observations, arithmetic mean, 
standard deviation (SD), median, minimum, and maximum. Minima and maxima will be reported with the 
same precision as the raw values; means and medians will be presented to 1 additional decimal place than 
reported in the raw values. Standard deviations will be presented to 2 additional decimal places than 
reported in the raw values. Summaries for discrete variables will include frequency counts and percentages. 
All percentages will be rounded to 1 decimal place (i.e., XX.X%). Change from baseline will be calculated 
as baseline subtracted from the relevant post-baseline visit (Post-Baseline Visit – Baseline Visit), with 
baseline defined in Section 8.3 of this SAP. 
Gains or improvements in BDCVA at 40 cm (Precision Vision chart) of ≥ 3-lines (15-letters) are defined as 
changes from baseline in BDCVA at 40 cm (Precision Vision chart) of ≤ -0.30 logMAR (e.g., -0.30, -0.32, 
… logMAR).   
Gains or improvements in BDCVA at 40 cm (Precision Vision chart) of ≥ 2-line (10-letters) are defined as 
changes from baseline in BDCVA at 40 cm (Precision Vision chart) of ≤ -0.20 logMAR (e.g., -0.20, -0.22, 
… logMAR).   
Similarly, loss in BDCVA of ≥ 5 letters (ETDRS at 4 m) are defined as changes from baseline in BDCVA 
(ETDRS at 4 m) of ≥ 0.10 logMAR (e.g., 0.10, 0.12, … logMAR). 
All statistical tests, unless otherwise indicated, will be 2-sided with a significance level of 0.05 (α = 0.05). 
Confidence intervals (CI) for differences between treatment groups will be 2-sided at 95% confidence. All 
p-values will be rounded to 4 decimal places; p-values less than 0.0001 will be presented as “<0.0001”; p-
values greater than 0.9999 will be presented as “>0.9999.” Unless otherwise specified, summaries will be 
presented by treatment group and, where appropriate, visit. 


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8.5 
Adjustment for Multiplicity 
If the primary null hypothesis, H01, is rejected at a 2-sided alpha = 0.05 in favor of CSF-1 in the alternative 
hypothesis, H11, tested as delineated in the primary efficacy analysis section (Section 12.1), then the study 
will be considered a success and the following key secondary hypotheses will be tested in hierarchical 
order, each at a 2-sided alpha = 0.05, where inference will be made on each null hypothesis only if the prior 
null hypotheses are rejected in favor of CSF-1. 
1. 
Visit 3 (Day 8), 2 hours following Dose 1 (H02) 
2. 
Visit 3 (Day 8), 1 hour following Dose 2 (H03) 
3. 
Visit 3 (Day 8), 2 hours following Dose 2 (H04) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized, completed the study, and discontinued from the study. A discontinued subject is someone who 
does not complete the 4 protocol-defined study visits. Subjects who are not discontinued from the study will 
be considered study completers. Disposition will be summarized by treatment arm for all randomized 
subjects. The reasons for study discontinuation will also be summarized and include: AE, lost to follow-up, 
physician decision, protocol violation, study terminated by sponsor, withdrawal by subject, death, and other. 
A subject listing will be provided which includes the date and reason for study discontinuation. 
The number of subjects in each of the analysis sets (FAS, PPS, and SAF) will be displayed by treatment 
arm, with the number of subjects and percentages calculated using randomized subjects as the 
denominator. The number and percentage of subjects with any (major, or minor) protocol deviations will be 
summarized by treatment arm and overall for all randomized subjects. Protocol deviations will be classified 
as major or minor prior to the closure of the database during a masked review of each protocol deviation. 
Major deviations will be defined as those deviations that potentially affect the analysis of the primary study 
endpoint. 
A subject listing will be provided which includes the date of the deviation, the deviation code and description, 
and the classification of whether the deviation was deemed major or minor. In addition, subject listings will 
include treatment arm and ICF signature date, and exclusions from the PPS. There will also be a listing of 
screen failures. 
10. Demographic and Baseline Characteristics 
10.1 
Demographics 
Subject demographic data collected in this study, age, sex, race, ethnicity, and childbearing potential. 
Subjects who record more than one race will be grouped into a single category denoted as multi-racial, and 
subjects who record more than one iris color (study eye) will be classified as heterochromia. Sex, race, 
ethnicity, childbearing potential, and iris color will be presented using descriptive summary statistics with 
frequency counts and percentages. Age (years) will be summarized with continuous descriptive statistics. 
Categorical variables will be summarized with number and percentage 
Demographic variables along with two baseline characteristics, iris color of study eye and manifest 
refraction spherical equivalent (MRSE), will be summarized for the FAS and PPS by treatment arm and 
overall in tables. A subject listing that includes all summarized demographic and baseline variables will also 
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10.2 
Baseline Characteristics 
Baseline characteristics are measured to ensure the safety and eligibility of subjects at Visit 1 (Day -14 to 
-1). Subject level listings will be used to present pre-treatment information from the FAS at the eye level 
when appropriate. Baseline characteristics will be contained in subject listings only and will include: 
• 
Manifest refraction 
• 
Iris color 
• 
Dark-adapted pupillometry 
• 
Fluorescein staining 
• 
Dilated indirect funduscopy 
11. Medical History and Concomitant Medications 
11.1 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0. 
Non-ocular medical history will be summarized using discrete summary statistics and presented by 
treatment arm at the subject level by System Organ Class (SOC) and Preferred Term (PT) using the SAF. 
Ocular medical history will be similarly summarized at the subject level. If a subject reports the same PT 
multiple times within the same SOC, then that PT will only be reported once within that SOC. As with the 
PT, if a subject reports multiple conditions within the same SOC, then that SOC will only be reported once. 
All SOC and PTs within an SOC category will be ordered by descending frequency based on all subjects. 
Listings of medical history will be generated separately for ocular and non-ocular information. 
11.2 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization (WHO) Drug Dictionary 
(WHODrug Global B3 March 2020) and summarized to the therapeutic drug class (Anatomical Therapeutic 
Chemical [ATC] 4 classification) and preferred name (generic drug name). If the ATC 4 classification is not 
provided, the next lowest classification that is provided in the coding dictionary will be employed. The 
preferred name will be defined as the active ingredient; if the active ingredient is not provided or includes 
more than two ingredients (e.g., multivitamins) then the drug name will be summarized as the preferred 
name. Any uncoded terms will be summarized under the ATC classification of “Uncoded,” but the missing 
preferred term will be replaced by the verbatim term entered in the eCRF. 
Concomitant medications are defined as those medications listed as having been taken (1) prior to initiation 
of study drug administration and continuing for any period of time following the first administration of study 
drug or (2) at any time following the first administration of study drug. Prior medications are defined as 
those medications not concomitant, but taken within 30 days of screening Visit 1 (Day -14 to -1). Prior and 
concomitant medications will be summarized using the SAF. Medications will be tabulated for each 


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treatment arm using frequency counts and percentages. Subjects may have more than one medication per 
ATC text. At each level of subject summarization, a subject will be counted once if reporting one or more 
medications. Percentages will be based on the number of subjects in each treatment arm. The ATC Classes 
and preferred names within an ATC Class will be ordered by descending frequency based on all subjects. 
Summaries will be generated separately for prior and concomitant medications, with ocular and non-ocular 
data also summarized separately using the SAF. Subject listings will group prior and concomitant 
medications together, with ocular and non-ocular information presented separately. 
12. Efficacy Analyses 
The primary efficacy and key secondary efficacy analyses are described in Section 12.1. Sensitivity 
analyses on the primary and key secondary efficacy endpoints are described in Section 12.2. and will be 
performed using the FAS.  
 
 
 
 
12.1 
Primary and Key Secondary Efficacy Analysis 
The primary efficacy endpoint in this study is the percentage of subjects with a ≥ 3-line (15-letter) gain, from 
baseline, in best distance-corrected visual acuity (BDCVA) at 40 cm (Precision Vision chart) and no loss in 
BDCVA ≥ 5 letters (ETDRS chart) at Visit 3, 1 hour following Dose 1 in the study eye. The key secondary 
efficacy endpoints are defined  the same as the primary efficacy endpoint, except for being measured at 2 
hours following Dose 1, 1 hour following Dose 2, and 2 hours following Dose 2, all at Visit 3. 
The primary and key secondary efficacy analysis will be conducted in the FAS with missing data handled 
in the following manners:  
1. Discontinuation of study drug and non-optimal compliance will be ignored [treatment policy 
strategy]. 
2. Withdrawal due to lack of efficacy or AEs: missing data will be singly imputed as failure [hypothetical 
strategy]. 
3. Missing data without withdrawal or withdrawal due to reasons other than lack of efficacy or AEs: 
missing data will be imputed employing Multiple Imputation (MI) using randomized treatment-based 
Markov Chain Monte Carlo (MCMC) methods.  
No subject data will be excluded from the FAS due to protocol violations/deviations. The multiple 
imputation of missing values will be completed for the continuous measures (BDCVA at 40 cm and 
BDCVA at 4 m), then the response variable will be determined therefrom. Imputation of failure due to 
lack of efficacy or AE will be assigned after multiple imputation is performed. 


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Variables for treatment group, baseline for BDCVA at 40 cm and baseline for BDCVA at 4 m will also be 
included in the multiple imputation model. 25 complete imputed datasets will be created.  
Example SAS® code for the multiple imputation: 
PROC MI DATA=DATAIN OUT=MI NIMPUTE=25 SEED=118787 minimum=-0.3 maximum=1; 
          MCMC INITIAL=EM; 
          VAR TRTPN VA40 VA40BL VA4 VA4BL; 
RUN; 
Where  TRTPN = treatment group, coded 1 for CSF-1, else 0 
 
VA40 = value of BDCVA at 40 cm for Visit 3, 1 hour after Dose 1 
  
VA40BL = baseline value of BDCVA at 40 cm  
 
VA4 = value of BDCVA at 4 m for Visit 3, 1 hour after Dose 1 
  
VA4BL = baseline value of BDCVA at 4 m  
For each imputed dataset, a logistic regression model with baseline BDCVA at 40 cm as a covariate and  
treatment as a main effect will be used to obtain the treatment effect estimate, odds ratio, and 95% 
confidence interval (CI) for odds ratio.    
Example SAS® code for the logistic model is shown here: 
PROC LOGISTIC DATA=MI DESCENDING OUTEST=PARMS COVOUT; 
 
BY _IMPUTATION_; 
CLASS TRTP; 
MODEL AVALC = BASE TRTP;  
RUN; 
where 
- 
TRTP is the treatment arm (CSF-1, Vehicle); 
- 
BASE is the baseline of BDCVA (letters) at 40 cm in the study eye; 
- 
AVALC is the indicator for efficacy variable (Y, N). 
SAS®  PROC MIANALYZE will be used to obtain the overall p-value, odds ratio, and  95% confidence 
interval (CI) for odds ratio.   
12.2 
Sensitivity Analysis for Primary and Key Secondary Efficacy Endpoints 
Sensitivity Analysis for the primary and key secondary efficacy endpoints include: 
1. All missing data imputed as failure using the FAS 
2. Observed data only using the FAS 


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3. Observed data only using the PPS  
4. Missing data will be imputed employing tipping point approach. The analysis will be based on the 
FAS 
For #1, #2 and #3 sensitivity analyses, the analysis of primary and key secondary efficacy endpoints will 
be performed using a logistic regression model with baseline BDCVA at 40 cm as a covariate and treatment 
as a main effect. The odds ratio, and 95% confidence interval (CI) for odds ratio will be provided. p-values 
will be presented for the main effect of treatment group using a Wald statistic. 
Tipping Point Analysis of Primary and Key Secondary Efficacy Variables 
Missing primary and key secondary efficacy endpoint values (i.e., binary response values) will be imputed 
using tipping point approach. First set all records in CSF-1 with missing value as failures and all records in 
Vehicle with missing value as successes, that is the worst case. The imputed data will be analyzed using a 
logistic regression model with baseline BDCVA at 40 cm as a covariate and  treatment as a main effect. 
The p-value, odds ratio, and 95% confidence interval (CI) for odds ratio will be provided. If the p-value is 
less or equal to 0.05 for the worst case, then stop there. If the p-value is greater than 0.05 for the worst 
case, then set the missing records as failures or successes in all possible combinations from worse case 
to the best case until the p-value turns from >0.05 to ≤ 0.05.  
 
 
 
 
 
 
 
 
 
 
13. Exploratory Analysis 
 
 
 
 
 
  
 


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14. Safety Analyses 
All safety analyses will be conducted using the SAF. In addition to AEs, BCVA at distance under normal 
and low-luminance testing conditions, findings from slit-lamp biomicroscopy examination, conjunctival 
redness grading, study drug drop comfort assessment, dilated indirect fundoscopy, and IOP measurements 
will be summarized descriptively using quantitative and qualitative summary statistics by treatment arm and 
subject visit, as appropriate. All such measurements related to safety endpoints will also be presented in a 
detailed subject listing. 
14.1 
Adverse Event Summaries 
All AEs will be coded using the MedDRA Version 23.0. A treatment-emergent adverse event (TEAE) is 
defined as any event that has an onset date on or after the first dose of study drug. All AEs collected in the 
eCRFs will be presented in data listings, but only TEAEs will be summarized in data tables. An overall 
summary will be presented that includes the number of TEAEs and the number and percentage of subjects 
who experienced at least one TEAE, by treatment group. This summary will also include breakdowns of 
TEAEs further categorized as (for ocular and non-ocular separately, where appropriate): 
• 
Ocular TEAEs  
• 
Non-ocular TEAEs 
• 
Ocular Non-Serious TEAEs   
• 
Non-ocular Non-Serious TEAEs  
• 
Most Frequent ( > 5% in any arm) Ocular TEAEs   
• 
Most Frequent ( > 5% in any arm) Non-ocular TEAEs  
• 
Expected TEAEs 
• 
Unexpected TEAEs 
• 
Suspected treatment-related TEAEs 
• 
All SAEs 
• 
Suspected treatment-related SAEs 
• 
Not Suspected treatment-related SAEs 


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• 
TEAEs leading to study discontinuation 
• 
TEAEs by maximal severity 
• 
Suspected Treatment-Related Ocular TEAEs by maximal severity 
• 
Suspected Treatment-Related Non-ocular TEAEs by maximal severity 
• 
Not Suspected Treatment-Related Ocular TEAEs by maximal severity 
• 
Not Suspected Treatment-Related Non-ocular TEAEs by maximal severity 
Separate summaries (for ocular and non-ocular, where appropriate) will also be provided for these 
categories of TEAEs by SOC and PT. If a subject reports the same PT multiple times within the same SOC, 
that PT will only be reported once within that SOC. As with the PT, if a subject reports multiple conditions 
within the same SOC, that SOC will only be reported once. In the summary, SOC will be listed in ascending 
alphabetical order; PTs will be listed in order of descending frequency for CSF-1 treated subjects within 
each SOC. 
All AEs will be presented in a subject listing, with ocular AEs listed separately from non-ocular AEs. All 
TEAEs leading to study discontinuation will be listed separately. In addition, all SAEs will be presented in 
a separate listing. 
14.2 
Best Distance-Corrected Visual Acuity 
Safety variables include BDCVA at 4 m under normal and low-luminance testing conditions.  
Monocular BDCVA summaries will specify study eye and fellow eye. Monocular BDCVA and Low-
Luminance BDCVA (LL-BDCVA) at 4 m will be measured at pre-treatment, post-Dose 1 and post-Dose 2 
as mentioned in the schedule of assessments (Section 3.2). The observed BDCVA as well as the change 
from baseline in BDCVA and LL-BDCVA will be summarized by treatment group using continuous 
descriptive summary statistics, and subject-specific BDCVA and LL-BDCVA data will also be presented in 
a listing for each visual range, separately. Tables will also provide the number and percentage of eyes that 
lose 10 or more letters BCDVA at 4 m. 
14.3 
Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination of the eyelid, conjunctiva, cornea, anterior chamber, iris, and lens 
will be conducted on both eyes at all scheduled visits pre-treatment, and an End of Visit slit lamp will also 
be completed at Visit 1 (Day -14 to -1), Visit 2 (Day 1), Visit 3 (Day 8), and Visit 4 (Day 15). Magnification 
will be consistent with the investigator’s standard clinical practice. The subject will be seated for the 
examination. The results will be graded as normal, abnormal not clinically significant (NCS), or abnormal 
clinically significant (CS). A table will summarize the findings with frequency counts and percentages for 
each treatment group at each timepoint and for each eye (study eye and fellow eye). Percentages will be 
based on the number of subjects in each treatment group with responses. A subject listing of the slit-lamp 
parameters will also be produced. 


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14.4 
Conjunctival Redness Assessment 
Pre-treatment ocular redness will be assessed using the 
 Scale #6 at Visit 1 (Day -14 to -1), 
Visit 2 (Day 1), Visit 3 (Day 8), and Visit 4 (Day 15). Post-treatment ocular redness will be assessed at Visit 
2 (Day 1), Visit 3 (Day 8) and Visit 4 (Day 15), at 20 minutes, 1 hour post-dose 1, and End of Visit. The 
 
 Scale #6 uses the following scoring system: 
0 = None 
1 = Mild: Slightly dilated blood vessels; color of vessels is typically pink; can be quadrantal 
2 = Moderate: More apparent dilation of blood vessels; vessel color is more intense (redder); involves 
the majority of the vessel bed 
3 = Severe: Numerous and obvious dilated blood vessels; in the absence of chemosis the color is deep 
red, may be less red or pink in presence of chemosis, is not quadrantic 
4 = Extremely Severe: Large, numerous, dilated blood vessels characterized by unusually severe deep 
red color, regardless of grade of chemosis, which involves the entire vessel bed 
Conjunctival redness grades and changes from baseline will be summarized by treatment group, for the 
study eye and fellow eye separately, using continuous descriptive summary statistics. At each post-
treatment timepoint, proportions of subjects who are Grade 0 (None) and Grade ≤ 1.0 will be summarized 
by count and percentage. The results of the conjunctival redness assessments will also be presented in a 
subject listing. 
14.5 
Study Drug Drop Comfort Assessment 
Study drug drop comfort will be assessed for each eye immediately upon instillation, 30 seconds, and at 1, 
5, and 10 minutes post-treatment at Visit 2 (Day 1), Visit 3 (Day 8), and Visit 4 (Day 15) using the 
 
 Scale. Subjects will subjectively evaluate their own level of ocular comfort and score 
according to the following 0-10 scale: 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
Very Comfortable 
Very Uncomfortable 
Study drug drop comfort scores will be summarized by treatment group, for the study eye and fellow eye 
separately, using continuous descriptive summary statistics. At each post-treatment timepoint, the 
proportions of subjects whose scores are 0, ≤ 1, and ≤ 2 will be summarized by count and percentage. The 
results of the study drug drop comfort assessments will also be presented in a subject listing. 


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14.6 
Intraocular Pressure 
Intraocular pressure will be assessed via Goldmann applanation tonometry at Visit 1 (Day -14 to -1), Visit 
2 (Day 1), Visit 3 (Day 8), and Visit 4 (Day 15). Results will be taken from a single measurement and will 
be recorded in mmHg. The IOP values and changes from baseline for each eye (study eye and fellow eye) 
will be summarized using continuous descriptive statistics by visit and eye for each treatment group. A 
subject listing of IOP results will also be produced. 
14.7 
Dilated Indirect Fundoscopy 
Dilated indirect fundoscopy will be performed at Visit 1 (Day -14 to -1) and Visit 4 (Day 15) using indirect 
ophthalmoscope. Dilated indirect fundoscopy should always be performed after IOP and all other ocular 
examinations. 
Dilated Indirect fundoscopy parameters collected for the left and right eyes include, vitreous, retina, macula, 
choroid, and optic nerve. Each parameter is rated “Normal,” “Abnormal (NCS),” or “Abnormal (CS).” The 
subject listing of dilated indirect fundoscopy will include all ratings collected for each parameter in both eyes 
and the investigator’s findings associated with each parameter at each timepoint. 
15. Interim Analyses 
An interim analysis is not planned for this study. 
16. Changes from Protocol-Stated Analyses 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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17. References 
US Federal Register. (1998) International Conference on Harmonization; Guidance for Industry: Statistical 
Principles for Clinical Trials. Department of Health and Human Services: Food and Drug Administration. 
Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. (E9) 
US Federal Register. (1996) International Conference on Harmonization; Guidance for Industry: Structure 
and Content of Clinical Study Reports. Department of Health and Human Services: Food and Drug 
Administration. Federal Register Vol. 61, July 17, 1996, page 37320. (E3) 
18. Revision History 
This SAP v2.0 amendment was issued following SAP v1.0, issued on 22NOV2021. 


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19. Tables 


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20. Listings 


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21. Figures 
Figures may be produced at the discretion of the study sponsor.