Clinical trial NCT03885011
Conditions: Presbyopia
Sponsor: Orasis Pharmaceuticals Ltd.
Start date: 2019-02-26; Completion date: 2019-07-26
Enrollment: 166 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 4-visit, multi-center, randomized, double-masked, parallel group study evaluating the safety and efficacy of CSF-1 in the treatment of presbyopia.

Detailed description:
This is a 4-visit, multi-center, randomized, double-masked, parallel group study evaluating the safety and efficacy of CSF-1 in the treatment of presbyopia. Approximately 150 subjects will be enrolled across 7 study centers in the United States. At Visit 2, subjects will be randomized 1:1:1 to one of three treatment arms: CSF-1, CSF-1 Component #1, or CSF-1 Component #2. All subjects will dose twice a day in both eyes with a single drop of their assigned treatment for approximately 1 week. At Visit 3, subjects randomized to CSF-1 will now receive a different concentration of CSF-1, subjects randomized to CSF-1 Component #1 will receive a different concentration of CSF-1 Component #1 and subjects randomized to CSF-1 Component #2 will continue dosing with the same concentration of CSF-1 Component #2. All subjects will continue dosing twice a day in both eyes for approximately 1 week.

Arms: arm 1: This treatment arm consists of 2 different concentrations of CSF-1. Subjects randomized to the CSF-1 treatment arm will receive their first dose of CSF-1 in-office at Visit 2. All subjects will dose twice a day in both eyes with a single drop for approximately 1 week. At Visit 3, subjects randomized to the CSF-1 arm will now receive a different concentration of CSF-1. Subjects will continue dosing twice a day in both eyes for approximately 1 week. arm 2: This treatment arm consists of 2 different concentrations of CSF-1 Component #1.

Subjects randomized to the CSF-1 Component #1 treatment arm will receive their first dose of CSF-1 Component #1 in-office at Visit 2. All subjects will dose twice a day in both eyes with a single drop for approximately 1 week. At Visit 3, subjects randomized to the CSF-1 Component #1 arm will now receive a different concentration of CSF-1 Component #1. Subjects will continue dosing twice a day in both eyes for approximately 1 week. arm 3: This treatment arm consists of a single concentration of CSF-1 Component #2. Subjects randomized to the CSF-1 Component #2 treatment arm will receive their first dose of CSF-1 Component #2 in-office at Visit 2. All subjects will dose twice a day in both eyes with a single drop for approximately 1 week. At Visit 3, subjects randomized to the CSF-1 Component #2 arm will continue dosing with the same concentration of CSF-1 Component #2. Subjects will continue dosing twice a day in both eyes for approximately 1 week.
Interventions: intervention 1: CSF-1 intervention 2: CSF-1 Component #1 intervention 3: CSF-1 Component #2
Intervention descriptions: intervention 1: This treatment arm consists of 2 different concentrations of CSF-1. Subjects randomized to the CSF-1 treatment arm will receive their first dose of CSF-1 in-office at Visit 2. All subjects will dose twice a day in both eyes with a single drop for approximately 1 week. At Visit 3, subjects randomized to the CSF-1 arm will now receive a different concentration of CSF-1. Subjects will continue dosing twice a day in both eyes for approximately 1 week. intervention 2: This treatment arm consists of 2 different concentrations of CSF-1 Component #1.

Subjects randomized to the CSF-1 Component #1 treatment arm will receive their first dose of CSF-1 Component #1 in-office at Visit 2. All subjects will dose twice a day in both eyes with a single drop for approximately 1 week. At Visit 3, subjects randomized to the CSF-1 Component #1 arm will now receive a different concentration of CSF-1 Component #1. Subjects will continue dosing twice a day in both eyes for approximately 1 week. intervention 3: This treatment arm consists of a single concentration of CSF-1 Component #2. Subjects randomized to the CSF-1 Component #2 treatment arm will receive their first dose of CSF-1 Component #2 in-office at Visit 2. All subjects will dose twice a day in both eyes with a single drop for approximately 1 week. At Visit 3, subjects randomized to the CSF-1 Component #2 arm will continue dosing with the same concentration of CSF-1 Component #2. Subjects will continue dosing twice a day in both eyes for approximately 1 week.

Protocol documents:
Prot_000.pdf: 
Orasis Pharmaceuticals 
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
IND # 131464 
 
05 June 2019 
Proprietary & Confidential 
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Clinical Trial Protocol 
 
Protocol Title: 
A Multi-Center, Double-Masked Evaluation of the 
Efficacy and Safety of CSF-1 in the Treatment of 
Presbyopia 
Protocol Number: 
18-150-0006 
Study Phase: 
2b 
Investigational Product Name: 
CSF-1 (pilocarpine hydrochloride 0.2% or 0.4% and 
diclofenac sodium 0.006%) Ophthalmic Solution 
IND 
131464 
 
Indication: 
Presbyopia 
Investigators: 
TBD 
Sponsor: 
Orasis Pharmaceuticals, Ltd  
12 Maskit St., P.O.B 12929 
Herzliya 4673312, Israel  
+972 9 8877745 
 
Contract Research 
Organization: 
 
 
IRB/IEC: 
 
 
 
 
 
 
 
Date 
Original Protocol: 
15 November 2018 
Amendment 1: 
08 February 2019 
Amendment 2: 
05 June 2019 
 
Confidentiality Statement 
This protocol contains confidential, proprietary information of 
 and/or Orasis Pharmaceuticals, 
Ltd. Further dissemination, distribution, or copying of this protocol or its contents is strictly prohibited. 
 


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MEDICAL MONITOR 
Medical Monitor: 
 
 
 
 
 PERSONNEL 
Department Sr. Vice President: 
 
 
 
 
Project Manager: 
  
 
 
 
 
 


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Protocol 18-150-0006 
 
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SYNOPSIS 
Protocol Title: 
A Multi-Center, Double-Masked Evaluation of the Efficacy and Safety 
of CSF-1 in the Treatment of Presbyopia  
Protocol Number: 
18-150-0006 
Investigational 
Products: 
• CSF-1: pilocarpine hydrochloride (0.2% [low dose])/(0.4% 
[high dose]) and diclofenac sodium (0.006%) 
• Pilocarpine hydrochloride (0.2% [low dose])/(0.4% [high 
dose])  
• Diclofenac sodium (0.006%) 
Study Phase: 
2b 
Primary Objective: 
• To evaluate the efficacy of CSF-1 for the treatment of presbyopia 
Secondary 
Objectives: 
• To evaluate the safety, tolerability, and efficacy of CSF-1 versus 
the individual components for the treatment of presbyopia  
• To evaluate the safety, tolerability, and efficacy (onset and 
duration) of 2 concentrations of CSF-1 ([0.2%/0.006%] and 
[0.4%/0.006%]) for the treatment of presbyopia  
Overall Study Design: 
Structure: 
Multi-center, randomized, double-masked, parallel-group, safety, and 
efficacy study 
Duration: 
Approximately 2 to 4 weeks (4 study visits) 
Controls: 
Individual components of the combination therapy (pilocarpine 
hydrochloride alone and diclofenac sodium alone) 
Treatment plan: 
Visit 1: Qualified subjects will receive 1 drop of Refresh Classic® 
(placebo) instilled to each eye. 
Visit 2: Following the pre-treatment assessments, qualified subjects 
will be randomized 1:1:1 to 1 of the following treatment arms: CSF-1 
(pilocarpine hydrochloride [0.2%]/diclofenac sodium [0.006%]), 
pilocarpine (0.2%) alone, or diclofenac sodium (0.006%) alone. All 
subjects will dose twice daily 
 
 in both eyes with a single 
drop for approximately 1 week. 
Visit 3: Following the visit 3 assessments, subjects will continue BID 
dosing
 
in both eyes for approximately 1 week. Subjects 
initially randomized to the CSF-1 arm will now receive pilocarpine 
hydrochloride (0.4%)/diclofenac sodium (0.006%); subjects 
randomized to the pilocarpine hydrochloride (0.2%) alone arm will 
now receive pilocarpine hydrochloride (0.4%) alone; and subjects 
randomized to the diclofenac sodium alone arm will continue dosing 
with diclofenac sodium (0.006%) alone. 


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CSF-1 Ophthalmic Solution 
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Amendment 2 (Version 3.0) 
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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 150 subjects (3 arms; 50 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. 
 
 
 
 
 
4. Have best corrected visual acuity (BCVA) at 40 cm ≥ 0.40 and 
≤ 0.90 logarithm of the minimum angle of resolution 
(LogMAR, approximately between 20/50 and 20/160 Snellen) 
in at least 1 eye at visit 1 prior to placebo dosing and in the 
same eye at visit 2 (pre-treatment); 
5. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
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9. 
 
 
 
Exclusion Criteria: 
Subjects must not: 
1. 
 
 
2. Have known contraindications or a sensitivity to the use of any 
of the IPs or their components;  
3. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CSF-1 Ophthalmic Solution 
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Amendment 2 (Version 3.0) 
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Amendment 2 (Version 3.0) 
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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 (0.2% [low dose])/(0.4% 
[high dose]) and diclofenac (0.006%) 
• Pilocarpine hydrochloride (0.2% [low dose])/(0.4% [high 
dose]) 
• Diclofenac sodium (0.006%) 
All patients will dose BID
 
in both eyes with a single drop of 
IP. 
Evaluation Criteria: 
Primary Efficacy 
Endpoint 
Percentage of subjects with a ≥ 3-line (15 letter) gain in BCVA at 40 
cm, 1-hour post-treatment at visit 3 and visit 4 
Secondary Efficacy 
Endpoints 
 
• 
 
 
• Percentage of subjects with a ≥ 2-line (10 letter) gain in BCVA 
at 40 cm at each time point at visit 3 and visit 4 
• 
 
Safety Endpoints 
 
 
 
 
 
 
 
 
 
 
 
• Adverse events (AEs) (reported, elicited, and observed) 
General Statistical Methods and Types of Analyses 
Analysis Sets: 
• Intent-to-Treat Analysis Set – The Intent-to-Treat analysis set (ITT) will include all 
randomized subjects. Subjects in the ITT will be analyzed as randomized. 
• Per Protocol Set – The per-protocol (PP) set will include subjects in the ITT who do not 
have significant protocol deviations that affect the primary endpoint. Protocol deviations 


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Amendment 2 (Version 3.0) 
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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 IP. 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 as the eye that meets all enrollment criteria. If both eyes meet all 
enrollment criteria, then the eye with the worse Visit 2 (Day 1) BCVA at 40 cm will be the 
study eye. If both eyes have the same BCVA 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, 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. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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Amendment 2 (Version 3.0) 
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Safety analyses will be conducted in the safety population. 
Hypothesis: 
H01: 
The difference, between study eyes treated with CSF-1 (0.4%/0.006%) and study eyes 
treated with diclofenac sodium (0.006%), in the percentage of study eyes with a ≥ 3-line (15 
letter) gain in BCVA at 40 cm, 1-hour post-treatment = 0. 
H11: 
The difference, between study eyes treated with CSF-1 (0.4%/0.006%) and study eyes 
treated with diclofenac sodium (0.006%), in the percentage of study eyes with a ≥ 3-line (15 
letter) gain in BCVA at 40 cm, 1-hour post-treatment ≠ 0. 
H02: 
The difference, between study eyes treated with Pilocarpine (0.4%) and study eyes 
treated with diclofenac sodium 0.006%, in the percentage of study eyes with a ≥ 3-line (15 
letter) gain in BCVA at 40cm, 1-hour post-treatment = 0. 
H12: 
The difference, between study eyes treated with Pilocarpine (0.4%) and study eyes 
treated with diclofenac sodium 0.006%, in the percentage of study eyes with a ≥ 3-line (15 
letter) gain in BCVA at 40cm, 1-hour post-treatment ≠ 0. 
The study will be considered a success if either of the null hypotheses, H01 or H02, are rejected 
in favor of their corresponding alternative hypotheses, H11 or H12. The overall Type I error of 
the 2-sided alpha = 0.10 will be preserved through the use of Bonferroni correction procedures 
testing each hypothesis at a 2-sided alpha = 0.05. 
If H01 is rejected and CSF-1 (0.4%/0.006%) is considered a success, then CSF-1 
(0.2%/0.006%) will be tested against diclofenac sodium (0.006%) at a 2-sided alpha = 0.05. 
Similarly, if H02 is rejected and Pilocarpine (0.4%) is considered a success, then Pilocarpine 
(0.2%) will be tested against diclofenac sodium (0.006%) at a 2-sided alpha = 0.05. Within 
these hierarchical frameworks, these hypotheses can be tested at a 2-sided alpha = 0.05 while 
still preserving an overall Type I error of alpha = 0.10. 
 
 
 
 
 
 
 
 
 
 
 
 


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CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
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H14: 
The difference, between study eyes treated with Pilocarpine (0.2%) and study eyes 
 
 
 
 
 
 
Sample Size: 
Fifty subjects per each of the 3 treatment arms (150 total), yields an 85% power to establish 
superiority of CSF-1 (0.4%/0.006%) and Pilocarpine (0.4%) to diclofenac sodium 0.006% 
alone in the percentage of study eyes demonstrating a ≥ 3-line (15-letter) gain in BCVA at 40 
cm, 1-hour post-treatment from the baseline measurement using a Pearson chi-squared test at a 
2-sided alpha = 0.05 assuming that the diclofenac sodium 0.006% alone response is 5% and 
the CSF-1 response is 27%, resulting in an overall 2-sided alpha = 0.10 that accounts for the 2 
tests of hypotheses utilizing Bonferroni correction procedures. 
 
 
Primary Efficacy Analysis: 
 
 
 
 
 
 
 
 
 
 
Descriptive statistics will be presented for each time point by treatment group. Testing of the 
percentage of subjects with a ≥ 3-line (15-letter) improvement from baseline will be completed 
accounting for the correlations between treatments and periods within a subject using a logistic 
(binomial error and logit link) model estimated by generalized estimating equation (GEE) 
methods. Aspects of the model include: 
• Response measure: indicator of whether the subject had a ≥ 3-line (15-letter) 
improvement from baseline in the assessment of BCVA at 40 cm in the study eye 
• Covariate: baseline BCVA at 40 cm in the study eye 
• Fixed effect explanatory measures: treatment 


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Amendment 2 (Version 3.0) 
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• Random effect measure: subject, to account for the correlation between treatments 
within a subject 
• Repeated measures correlation: estimated with an unstructured covariance matrix in the 
GEE model 
Standard errors and confidence intervals (CIs, 90% and 95%) will also be presented for each 
treatment group and the difference between treatment groups. 
 
 
 
 
 
 
 
 
 
 
 
Secondary Efficacy Analysis: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Amendment 2 (Version 3.0) 
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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, those that occur 
after the first dose of IP, 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 treatment-emergent AEs (TEAEs) related to IP and 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 specific 
treatment period. AEs will be reported separately by period. 
 
 
 
 


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TABLE OF CONTENTS 
Synopsis ..................................................................................................................................... 3 
Table of Contents ..................................................................................................................... 13 
List of Abbreviations ............................................................................................................... 16 
1 
Introduction ...................................................................................................................... 17 
2 
Study Objectives ............................................................................................................... 18 
2.1 
 Primary Objective ...................................................................................................... 18 
2.2 
 Secondary Objectives ................................................................................................. 18 
3 
Clinical Hypotheses .......................................................................................................... 18 
4 
Overall Study Design ....................................................................................................... 18 
5 
Study Population .............................................................................................................. 21 
5.1 
 Inclusion Criteria ........................................................................................................ 21 
5.2 
 Exclusion Criteria ...................................................................................................... 21 
5.3 
Withdrawal Criteria .................................................................................................... 23 
6 
Study Parameters .............................................................................................................. 23 
6.1 
 Efficacy Endpoints ..................................................................................................... 23 
6.1.1  Primary Efficacy Endpoints ....................................................................................... 23 
6.1.2  Secondary Efficacy Endpoints ................................................................................... 24 
6.1.3  Criteria for Effectiveness ........................................................................................... 24 
6.2 
Safety Endpoints ......................................................................................................... 24 
7 
Study Materials ................................................................................................................. 24 
7.1 
  Study Treatments ...................................................................................................... 24 
7.1.1   Investigational Product .............................................................................................. 24 
7.1.2   Instructions for Use and Administration ................................................................... 25 
7.1.3   Subject Instructions ................................................................................................... 25 
8 
Study Methods And Procedures ....................................................................................... 26 
8.1 
  Subject Entry Procedures .......................................................................................... 26 
8.1.1   Overview ................................................................................................................... 26 
8.1.2   Informed Consent ...................................................................................................... 26 
8.1.3   Washout Intervals ...................................................................................................... 26 
8.1.4   Procedures for Final Study Entry .............................................................................. 26 
8.1.5   Pregnancy .................................................................................................................. 27 
8.1.6   Methods for Assignment to Treatment Groups ......................................................... 27 
8.2 
  Concurrent Therapies and Medical History .............................................................. 27 
8.3 
  Examination Procedures ............................................................................................ 28 
8.4 
  Schedule of Visits, Measurements and Dosing ......................................................... 31 
8.4.1   Scheduled Visit ......................................................................................................... 31 
8.4.2   Unscheduled Visits .................................................................................................... 31 
8.5 
  Compliance with Protocol ......................................................................................... 31 
8.6 
  Subject Disposition ................................................................................................... 31 
8.6.1   Completed Subjects ................................................................................................... 31 
8.6.2   Withdrawn Subjects .................................................................................................. 31 
8.6.3   Discontinued Subjects ............................................................................................... 31 
8.7 
  Study Termination ..................................................................................................... 31 


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Amendment 2 (Version 3.0) 
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8.8 
  Study Duration .......................................................................................................... 31 
8.9 
  Monitoring and Quality Assurance ........................................................................... 32 
9 
Adverse Events ................................................................................................................. 32 
9.1 
  Adverse Event ........................................................................................................... 32 
9.1.1   Severity ..................................................................................................................... 32 
9.1.2   Relationship to Investigational Product .................................................................... 33 
9.1.3   Expectedness ............................................................................................................. 33 
9.2 
  Serious Adverse Events ............................................................................................. 33 
9.3 
  Procedures for Reporting Adverse Events ................................................................ 34 
9.3.1   Reporting a Suspected Unexpected Adverse Reaction ............................................. 34 
9.3.2   Reporting a Serious Adverse Event .......................................................................... 34 
9.4 
  Procedures for Unmasking (if applicable) ................................................................ 35 
9.5 
  Type and Duration of the Follow-up of Subjects after Adverse Events ................... 35 
10 Statistical Hypotheses and Methods of Analyses ............................................................. 35 
10.1   General Considerations ............................................................................................. 35 
10.2   Hypotheses ................................................................................................................ 36 
10.3   Study Populations ...................................................................................................... 37 
10.4   Unit of Analysis ........................................................................................................ 37 
10.5   Efficacy Endpoints .................................................................................................... 38 
10.5.1   Primary Efficacy Endpoint ........................................................................................ 38 
10.5.2   Secondary Efficacy Endpoints .................................................................................. 38 
10.6   Safety Endpoints ....................................................................................................... 38 
10.7   Sample Size ............................................................................................................... 38 
10.8   Demographic and Baseline Characteristics ............................................................... 38 
10.9   Efficacy Analysis ...................................................................................................... 39 
10.9.1   Primary Efficacy Analyses ........................................................................................ 39 
10.9.2   Secondary Efficacy Analysis .................................................................................... 40 
10.10   Safety Analysis .......................................................................................................... 40 
10.11   Interim Analysis ........................................................................................................ 41 
10.12   Missing Data ............................................................................................................. 41 
10.13   Adjustment for Multiplicity ...................................................................................... 41 
11 Compliance with Good Clinical Practices, Ethical Considerations, and Administrative 
Issues ................................................................................................................................ 41 
11.1   Protection of Human Subjects ................................................................................... 41 
11.1.1   Subject Informed Consent ......................................................................................... 41 
11.1.2   IRB Approval ............................................................................................................ 42 
11.2   Ethical Conduct of the Study .................................................................................... 42 
11.3   Subject Confidentiality .............................................................................................. 42 
11.4   Documentation .......................................................................................................... 42 
11.4.1   Retention of Documentation ..................................................................................... 42 
11.5   Labeling, Packaging, Storage, Accountability, and Return or Disposal of     
            Investigational Product .............................................................................................. 43 
11.5.1   Labeling/Packaging ................................................................................................... 43 
11.5.2   Storage of Investigational Product ............................................................................ 43 
11.5.3   Accountability of Investigational Product................................................................. 43 
11.5.4   Return or Disposal of Investigational Product .......................................................... 43 
11.5.5   IP Manual .................................................................................................................. 44 


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11.6  Recording of Data on Source Documents and Electronic Case Reports Forms    
           (eCRFs) ...................................................................................................................... 44 
11.7  Handling of Biological Specimens ............................................................................ 44 
11.8  Publications ................................................................................................................ 44 
12 REFERENCES ................................................................................................................. 45 
13 Appendices ....................................................................................................................... 48 
 
 
 
 
    
 
    
 
 Appendix 5: Sponsor and 
Approvals ............................................................................ 85 
 Appendix 6: Investigator’s Signature ................................................................................... 86 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADHD 
attention-deficit/hyperactivity disorder 
AE 
adverse event 
BID 
twice daily 
BCVA 
best corrected visual acuity 
cd/m2 
candela per square meter 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
eCRF 
electronic case report form 
D 
diopter 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GEE 
generalized estimating equation 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IND 
investigational new drug application 
IOL 
intraocular lens 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
institutional review board 
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 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHG 
millimeters of mercury 
mPP 
modified per protocol 
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 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
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), and 
approximately 50% of the population with presbyopia does not have adequate corrective lenses, 
resulting in some level of disability when performing tasks requiring near visual acuity (VA) 
(Holden et al 2008). This resulted in a global burden of presbyopia exceeding 1.8 billion people 
in 2015 (Holden et al 2008), and prevalence is increasing. 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 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.  
The neural mechanism of accommodation is the adjustment of the size of the pupil. Pupil size is 
determined by the dimensions of sphincter and dilator muscle spindles of the iris. The pupil 
becomes smaller when the eye accommodates. This reduction in the size of the pupil (termed 
miosis) improves the resolution of the retinal image by preventing diverging light rays hitting the 
periphery of the cornea and lens from reaching the retina. Miosis further increases the depth of 
field of the eye. A relatively small pupil offers increased depth of field in a way similar to that 
achieved by reducing the aperture of a camera.  
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 et 
al 2013). Glasses consisting of a pinhole to block out peripheral rays of light have also been used 
to improve vision in presbyopia (Emsley 1946, Borish 1975). Pinhole glasses severely restrict 
the wearer’s peripheral vision placing the patient at risk while driving or performing other 
similar tasks. 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 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 et al 2002) and a broad spectrum of systemic conditions including botulism 
(Monaco et al 1998), leprosy (Lana-Peixoto et al 2014), sarcoidosis (Bowie and Givre 2003), and 
Ross syndrome (Weller et al 1992, Chemmanam et al 2007). Low dose pilocarpine 


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hydrochloride induced miosis also improves Adie’s pupil (a neurological disorder affecting the 
pupil size) in adults, children (Younge and Buski 1976, Flach and Dolan 1985, Soylev et al 1997, 
Jacobson and Vierkant 1998, Bartlett and Jaanus 2002), dogs (Gerding et al 1986), and cases of 
pharmacologically-induced anisocoria (Jacobson and Olson 1993).  
Muscarinic receptor agonists are known to induce inflammation (Verbout and Jacoby 2012). 
Thus, combining a non-steroidal anti-inflammatory drug (NSAID) with pilocarpine 
hydrochloride may reduce the inflammatory response associated with pilocarpine hydrochloride. 
Diclofenac sodium is a safe and effective NSAID prescribed for the management of pain 
following corneal refractive surgery (Narvaez et al 2004, Colin and Paquette 2006, Parker et al 
2011), inflammation post-cataract extraction (Flach et al 1998, Kocak et al 1998, Flach and 
Dolan 2000), and allergic conjunctivitis (Laibovitz et al 1995).  
CSF-1 Ophthalmic Solution (CSF-1) was well tolerated and resulted in noticeable miosis after 
topical application in an investigator-initiated feasibility study. Two additional clinical studies 
(Phase 2a) demonstrated favorable safety and preliminary efficacy and thus support the 
continued development of CSF-1 as an ophthalmic solution to treat presbyopia. This is a factorial 
study to determine the importance of each active ingredient and the impact of increasing 
pilocarpine hydrochloride concentrations (0.2% versus 0.4%) on the efficacy of CSF-1 for the 
treatment of presbyopia. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to evaluate the efficacy of CSF-1 for the treatment of 
presbyopia. 
2.2 
Secondary Objectives 
The secondary objectives of this study are:  
• To evaluate the safety, tolerability, and efficacy of CSF-1 versus the individual 
components for the treatment of presbyopia  
• 
 
 
3 
CLINICAL HYPOTHESES  
The clinical hypothesis of this study is that CSF-1 (the combination of pilocarpine hydrochloride 
and diclofenac sodium) is superior and/or safer/better tolerated compared with pilocarpine 
hydrochloride alone and diclofenac sodium alone (0.006%) in improving near vision in subjects 
with presbyopia. 
4 
OVERALL STUDY DESIGN 
This is a 4-visit randomized, double-masked, multi-center, parallel-group study evaluating the 
safety and efficacy of CSF-1 compared with pilocarpine hydrochloride alone and diclofenac 


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sodium (0.006%) alone in approximately 150 subjects with presbyopia. Study design is 
summarized in Figure 1. 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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Figure 1 
Study Design 
 


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5 
STUDY POPULATION 
Approximately, 150 healthy adult subjects between 45 and 64 years of age with presbyopia who 
do not have any conditions, in the investigator’s opinion, that may put the subject at increased 
risk, confound study data, or interfere significantly with the subject’s study participation.  
5.1 
Inclusion Criteria 
Subjects must:  
 
1. 
 
 
 
4. Have BCVA at 40 cm ≥ 0.40 and ≤ 0.90 logarithm of the minimum angle of resolution 
(LogMAR, approximately between 20/50 and 20/160 Snellen) in at least 1 eye at visit 1 
prior to placebo dosing and in the same eye at visit 2 (pre-treatment); 
5. Have between -4.50 to +2.00 diopter (D) of sphere in each eye determined by manifest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2 
Exclusion Criteria 
Subjects must not: 
1.
 
 
 
  
 
 


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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  
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 Withdrawal of consent by subject 
o investigator discretion 
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 subject’s source document.  
6 
STUDY PARAMETERS 
6.1 
Efficacy Endpoints 
6.1.1 
Primary Efficacy Endpoints 
• Percentage of subjects with a ≥ 3-line (15 letter) gain in BCVA at 40 cm, 1-hour 
post-treatment at visit 3 and visit 4 


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6.1.2 
Secondary Efficacy Endpoints 
 
 
• Percentage of subjects with a ≥ 2-line (10 letter) BCVA at 40 cm gain at each time point 
at visit 3 and visit 4 
 
 
6.1.3 
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 baseline monocular (study eye). A 3-
line improvement in VA is considered clinically meaningful. 
6.2 
Safety Endpoints 
• BCVA 
• Best-corrected low luminance distance VA 
• Slit lamp biomicroscopy 
• Conjunctival redness grading 
• IP drop comfort assessment 
• IOP 
• AEs (reported, elicited, and observed) 
7 
STUDY MATERIALS 
7.1 
Study Treatments 
7.1.1 
Investigational Product 
The IP is CSF-1, a topical eye drop solution for 
 presbyopia, which 
works by reducing the natural pupil size and increasing the depth of field. The formulation 
developed by Orasis Pharmaceuticals Ltd. is a viscous eye drop containing the active ingredients 
pilocarpine hydrochloride and diclofenac sodium with the addition of excipients, 
 
. The inclusion of an 
NSAID (diclofenac sodium) may reduce the inflammatory response induced by pilocarpine 
hydrochloride. Pilocarpine hydrochloride alone will be evaluated for comparison at both 0.2% 
and 0.4%, with the same formulation tabulated in Table 1, except for the removal of diclofenac 
sodium. Similarly, a control of diclofenac sodium 0.006% alone will be evaluated for 
comparison, likewise, with the same formulation tabulated in Table 1, except for the removal of 
pilocarpine hydrochloride.  
 
 


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Table 1 
CSF-1 formulation 
Ingredient 
Concentration 
[mg/mL] 
Concentration 
[%w/v] 
Purpose 
Pilocarpine Hydrochloride 
2 or 4 
0.2 or 0.4 
Active ingredient 
Diclofenac Sodium 
0.06 
0.006 
Active ingredient 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.1.2 
Instructions for Use and Administration 
All study treatments are topical ophthalmic solutions that should be administered bilaterally. A 
single drop should be instilled in each eye, BID, in the morning and afternoon 
 
. Subjects will be instructed to close their 
eyes for 30 seconds after instillation. 
7.1.3 
Subject Instructions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8 
STUDY METHODS AND PROCEDURES 
8.1 
Subject Entry Procedures 
8.1.1 
Overview 
Subjects as defined by the criteria in Section 5.2 and Section 5.3 will be considered for entry into 
this study. 
8.1.2 
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. 
8.1.3 
Washout Intervals 
Per exclusion criteria #17, subjects must abstain from the use of the following systemic 
medications during the timeframe noted below: 
i. The day of the study visit or within 12 hours prior to a study visit (chronic, daily use 
is not allowed):   
a. nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g. Advil®, Motrin®)  
b. narcotic (opiate class) pain medication (e.g. codeine, OxyContin®, Vicodin®, 
Tramadol®) 
ii. Two (2) weeks (14 days) prior to visit 1 or for the duration of the study:  
c.  bladder medication (e.g. Urecholine®, bethanechol) 
d.  antipsychotics 
e.  antidepressants 
f.  ADHD medications 
g.  alpha-blockers (e.g. tamsulosin [Flomax®], Jayln®, Uroxatral®, Rapaflo®) 
h.  anticholinergics (e.g. atropine, belladonna, benztropine, dicyclomine, 
donepezil, hyoscyamine, propantheline, scopolamine, trihexphenidyl) 
i.  muscarinic receptor agonists or cholinergic agonists (e.g. Salagen®, Evoxac®) 
other than the IP 
j.  OTC or prescription antihistamines or decongestants 
k.  any ophthalmic medications (other than artificial tears or lubricant eye ointment 
[see exclusion criteria 8 and 9]) 
l.  any other medication affecting the pupil or accommodation 
m.  recreational drug use (e.g. marijuana, methadone, heroin, cocaine). 
8.1.4 
Procedures for Final Study Entry 
Subjects must satisfy all inclusion and none of the exclusion criteria in order to be entered into 
the study. 


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8.1.5 
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 
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. 
8.1.6 
Methods for Assignment to Treatment Groups  
Each subject who signs an ICF will be assigned a subject number (a five-digit number starting 
with the 2-digit site number followed by a sequential three-digit number starting with 001). Once 
a subject meets all qualification criteria at visit 2, he/she will be randomized in a 1:1:1 ratio via 
an interactive response technology system to 1 of 3 treatment groups: 1: CSF-1, 2: pilocarpine 
hydrochloride alone, 3: diclofenac sodium alone, 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.  
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 subject’s 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 is to be recorded on the 
subject’s 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 
during the study. 


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8.3 
Examination Procedures 
Procedures to be performed at the Study Visit with Regard to Study Objective 
The following procedures should be conducted at each study visit in the following order: 
8.3.1 
Visit 1 (Day -1 to -14) 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
8.3.2 
Visit 2 (Day 1) 
  
 
 
  
  
 


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IP 
8.3.3 
Visit 3 (Day 8 ± 2) 
 
 
  
  
 
 
 
 
9. Instillation of morning dose of IP 
 
 
 
 
 
 
  
 
  
  
 
  
 
 
 
 
 
 


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21. Collect IP/dosing diary 
8.3.4 
Visit 4 (Day 15 ± 2) 
 
 
 
 
  
 
 
 
 
10. Instillation of morning dose of IP 
 
 
 
 
 
 
  
 
  
  
 
  
 
 
 
 
 
 
23. Study exit 


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8.4 
Schedule of Visits, Measurements and Dosing 
8.4.1 
Scheduled Visit 
Refer to Appendix 1: 
 for a schedule of measurements at 
the visit. 
8.4.2 
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) (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 
8.6.1 
Completed Subjects 
A completed subject is one who has not been discontinued from the study and sucessfullly  
completes Visit 4. 
8.6.2 
Withdrawn Subjects 
A subject may be withdrawn for meeting any of the withdrawal criteria as described in 
Section 5.3. 
8.6.3 
Discontinued Subjects 
A discontinued subject is one who does not complete the 4 protocol-defined study visits. A 
subject may be discontinued at the discretion of the investigator, sponsor, and/or the institutional 
review 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 4 visits over a total duration of approximately 2 to 4 weeks. 


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8.9 
Monitoring and Quality Assurance 
During the course of the study an 
 monitor, or designee, will make routine site visits to 
review protocol compliance, assess IP 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, 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. 
9 
ADVERSE EVENTS 
9.1 
Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered IP-related. 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 subject’s study exit 
visit. 
9.1.1 
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. 


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• Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and 
interferes with the subject’s daily activities. 
9.1.2 
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 
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. 
9.1.3 
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 the 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 medical monitor will 
review and determine the expectedness of any serious adverse event (SAE) following the 
investigator’s assessment. 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; 


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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 
normal life functions; 
Note: An SAE specifically related to visual threat would be interpreted as any potential 
impairment or damage to the subject’s eyes (e.g. intra-ocular 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. 
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. 
9.3.1 
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. 
9.3.2 
Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the IP, 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. 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 a SAE must be followed-up 
with and the outcome reported. 


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In the event of a SAE, the investigator must notify 
and the sponsor immediately; obtain and 
maintain in his/her files all pertinent medical records, information, and medical judgments from 
colleagues who assisted in the treatment and follow-up of the subject; provide 
and the study 
sponsor with 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; and inform the IRB of the AE within their 
guidelines for reporting SAEs. 
Contact information for reporting SAEs: 
Medical Monitor: 
 
 
  
 
Project Manager: 
  
 
 
 
9.4 
Procedures for Unmasking (if applicable) 
When medically necessary, the investigator may need to determine what treatment has been 
assigned to a subject. When possible (i.e. in non-emergent situations), 
 and/or the study 
sponsor should be notified before unmasking the IP. 
9.5 
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 subject’s 
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 a 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 


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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). If the measurement is not available from Visit 2 (Day 1), then the measurement from 
screening Visit 1 (Day -1 to -14) will be used as baseline for all treatments/visits. Change from 
baseline will be calculated as follow-up measure minus baseline measure. 
The primary analyses of the primary and secondary endpoints will be conducted in the PP, 
include observed data only, and use statistical models, which adjust for the correlation between 
treatments within an eye and/or subject.  
The secondary analyses of the primary and secondary endpoints will be conducted in the ITT, 
include observed data only, and use similar statistical models as the primary analyses. No subject 
data will be excluded from the ITT due to protocol violations/deviations.Sensitivity analysis on 
the primary efficacy variable will be performed on both the PP and ITT imputing missing data as 
failures; 
 
 
 
 
 
Safety analyses will be conducted in the safety population. 
10.2 Hypotheses 
H01: 
The difference, between study eyes treated with CSF-1 (0.4%/0.006%) and study eyes 
treated with diclofenac sodium 0.006%, in the percentage of study eyes with a ≥ 3-line (15 letter) 
gain in BCVA at 40 cm, 1-hour post-treatment = 0. 
H11: 
The difference, between study eyes treated with CSF-1 (0.4%/0.006%) and study eyes 
treated with diclofenac sodium 0.006%, in the percentage of study eyes with a ≥ 3-line (15 letter) 
gain in BCVA at 40 cm, 1-hour post-treatment ≠ 0. 
H02: 
The difference, between study eyes treated with Pilocarpine (0.4%) and study eyes 
treated with diclofenac sodium 0.006%, in the percentage of study eyes with a ≥ 3-line (15 letter) 
gain in BCVA at 40 cm, 1-hour post-treatment = 0. 
H12: 
The difference, between study eyes treated with Pilocarpine (0.4%) and study eyes 
treated with diclofenac sodium 0.006%, in the percentage of study eyes with a ≥ 3-line (15 letter) 
gain in BCVA at 40 cm, 1-hour post-treatment ≠ 0. 
The study will be considered a success if either of the null hypotheses, H01 or H02, are rejected in 
favor of their corresponding alternative hypotheses, H11 or H12. The overall Type I error of the 
2-sided alpha = 0.10 will be preserved through the use of Bonferroni correction procedures 
testing each hypothesis at a 2-sided alpha = 0.05. 
If H01 is rejected and CSF-1 (0.4%/0.006%) is considered a success, then CSF-1 (0.2%/0.006%) 
will be tested against diclofenac sodium (0.006%) at a 2-sided alpha = 0.05. Similarly, if H02 is 
rejected and Pilocarpine (0.4%) is considered a success, then Pilocarpine (0.2%) will be tested 
against diclofenac sodium (0.006%) at a 2-sided alpha = 0.05. Within these hierarchical 


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frameworks, these hypotheses can be tested at a 2-sided alpha = 0.05 while still preserving an 
overall Type I error of alpha = 0.10. 
 
 
 
 
 
 
 
 
 
 
 
 
10.3 Study Populations 
• 
Intent-to-Treat Analysis Set – The ITT will include all randomized subjects. Subjects in 
the ITT will be analyzed as randomized. 
• 
Per Protocol Set – The PP set will include subjects in the ITT who do not have significant 
protocol deviations that affect the primary endpoint. 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 1 dose of 
the IP. 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 as the eye that meets all enrollment criteria. If both eyes meet all 
enrollment criteria, then the eye with the worse Visit 2 (Day 1) BCVA at 40 cm will be the study 
eye. If both eyes have the same BCVA at 40 cm, the right eye will be the study eye. 


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10.5 Efficacy Endpoints 
10.5.1 Primary Efficacy Endpoint 
The percentage of subjects with a ≥ 3-line (15 letter) gain in BCVA at 40 cm, 1-hour 
post-treatment at visit 3 and visit 4 from the baseline measurement 
10.5.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
 
 
• Percentage of subjects with a ≥ 2-line (10 letter) gain in BCVA at 40 cm 
 
 at visit 3 and visit 4 
 
 
10.6 Safety Endpoints 
The safety endpoints are: 
• BCVA 
• Best-corrected low luminance distance VA 
• Slit lamp biomicroscopy 
• Conjunctival redness grading 
• IP drop comfort assessment 
• IOP 
• AEs (reported, elicited, and observed) 
10.7 Sample Size 
Fifty subjects per each of the 3 treatment arms (150 total), yields an 85% power to establish 
superiority of CSF-1 (0.4%/0.006%) and Pilocarpine (0.4%) to diclofenac sodium 0.006% alone 
in the percentage of study eyes demonstrating a ≥ 3-line (15-letter) gain in BCVA at 40 cm, 1-
hour post-treatment from the baseline measurement using a Pearson chi-squared test at a 2-sided 
alpha = 0.05 assuming that the diclofenac sodium 0.006% alone response is 5% and the CSF-1 
response is 27%, resulting in an overall 2-sided alpha = 0.10 that accounts for the 2 tests of 
hypotheses utilizing Bonferroni correction procedures. 
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. 
10.8 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). 


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10.9 Efficacy Analysis 
10.9.1 Primary Efficacy Analyses 
The primary efficacy variable in this study is the percentage of study eyes with a ≥ 3-line 
(15-letter) gain in BCVA at 40 cm, 1-hour post-treatment at visit 3 and/or visit 4 from the 
baseline measurement. The primary analysis will use the PP population on observed data only. 
The primary analyses will be completed using Bonferroni alpha adjustment to maintain the 
overall Type I error as detailed in the hypothesis section with statistical inference made on the 
comparisons between CSF-1 (0.4%/0.006%) versus diclofenac sodium 0.006% and between 
Pilocarpine (0.4%) versus diclofenac sodium 0.006% Again as detailed in the hypothesis section, 
only if the higher dose concentrations, for CSF-1 (0.4%/0.006%) and/or Pilocarpine (0.4%), 
respectively, are successful will the corresponding lower dose concentrations, for CSF-1 
(0.2%/0.006%) and/or Pilocarpine (0.2%), respectively, have inference made on the statistical 
test. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.9.2 Secondary Efficacy Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.10 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 IP within each period, 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 TEAEs related to the IP and 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 specific treatment 
period. AEs will be reported separately by period. 
 
 
 
Full details of the safety analyses will be specified in the formal SAP. 


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10.11 Interim Analysis 
An interim analysis may be provided when approximately 50% of the subjects have completed 
the study. If an interim analysis is completed, O’Brien-Fleming alpha spending function will be 
used to specify the interim boundaries for stopping for efficacy and for non-binding futility as 
well as adjusting the final 2-sided alpha level. 
10.12 Missing Data 
Sensitivity analysis on the primary efficacy variable will be performed on both the PP and ITT 
imputing missing data as failures; additional sensitivity analyses such as pattern mixture model 
multiple imputation methodologies and tipping point analyses may be performed and will be 
specified in the SAP. 
10.13 Adjustment for Multiplicity 
For the primary hypotheses, the study will be considered a success if either of the null 
hypotheses, H01 or H02, are rejected in favor of their corresponding alternative hypotheses, H11 or 
H12. The overall Type I error of the 2-sided alpha = 0.10 will be preserved through the use of 
Bonferroni correction procedures testing each hypothesis at a 2-sided alpha = 0.05. 
Again as detailed in the hypothesis section, only if the higher dose concentrations, for CSF-1 
(0.4%/0.006%) and/or Pilocarpine (0.4%), respectively, are successful will the corresponding 
lower dose concentrations, for CSF-1 (0.2%/0.006%) and/or Pilocarpine (0.2%), respectively, 
have inference made on the statistical test. Within these hierarchical frameworks, these 
hypotheses can be tested at a 2-sided alpha = 0.05 while still preserving an overall Type I error 
of alpha = 0.10. 
There will be no adjustment for multiplicity for testing of secondary endpoints. 
 
 
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 IPs in the countries 
involved will be adhered to. 
11.1  Protection of Human Subjects 
11.1.1 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 subject’s 
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 


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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. 
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. 
11.1.2 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 as 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 
subject’s 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 IP may ultimately be marketed in, but the subject’s 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 
investigator’s subject files, as well as the results of diagnostic tests such as X-rays, laboratory 
tests, and electrocardiograms. The investigator’s copy of the eCRFs serves as the investigator’s 
record of a subject’s study-related data. 
11.4.1 Retention of Documentation 
All study-related correspondence, patient records, consent forms, records of the distribution and 
use of all IPs, 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 IP. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 


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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 
responsibility of keeping study records, custody must be transferred to a person who will accept 
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 
Investigational Product 
11.5.1 Labeling/Packaging 
 
 
The IP will be packaged and labeled into clinical kits. Each subject will be assigned a single 
master kit containing two smaller (inner) kits. Each master kit will be uniquely identified by the 
kit number; the 2 smaller kits inside will bear the same kit number with additional designation 
indicating the visit at which each is to be dispensed (i.e., visit 2 or visit 3). 
 
 
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.”  
11.5.2 Storage of Investigational Product 
 
 
 
 
 
  
11.5.3 Accountability of Investigational Product 
For in-office dosing, the IP is to be administered by study site personnel, and is to only be used 
in accordance with this protocol. The IP must only be distributed to subjects properly qualified 
under this protocol to receive IP. 
The investigator must keep an accurate accounting of the IP received from the supplier. This 
includes the amount of IP administered to subjects and the amount returned or disposed 
throughout the course of the study. A detailed inventory must be completed for the IP. 
11.5.4 Return or Disposal of Investigational Product 
All IPs will be returned to the sponsor or their designee or destroyed. The return or disposal of IP 
will be specified in writing. Any remaining IP will be collected from subjects at visit 3 and 
visit 4 before study exit. 


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11.5.5 IP Manual 
Further details on labeling, packaging, storage, accountability, and return or disposal of 
investigational product can be found in the study 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 subject’s source document, eCRF, and all study-related material. All study data should 
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 
11.8 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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12 REFERENCES 
Bartlett, J. D. and S. D. Jaanus (2002). Clinical Ocular Pharmacology London, Butterworth 
Heinemann, Elsevier: 38. 
Borish, I. M. (1975). Subjective testing. Clinical Refraction. Chicago USA, Professional Press 
Inc: 715-798. 
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. 
Colin, J. and B. Paquette (2006). "Comparison of the analgesic efficacy and safety of nepafenac 
ophthalmic suspension compared with diclofenac ophthalmic solution for ocular pain and 
photophobia after excimer laser surgery: a phase II, randomized, double-masked trial." Clin Ther 
28(4): 527-536. 
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. 
Emsley, H. H. (1946). Vision. Visual Optics London UK, Hatton Press: 32-69. 
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. 
Flach, A. J. and B. J. Dolan (1985). "The therapy of Adie's syndrome with dilute pilocarpine 
hydrochloride solutions." J Ocul Pharmacol 1(4): 353-362. 
Flach, A. J. and B. J. Dolan (2000). "Incidence of postoperative posterior capsular opacification 
following treatment with diclofenac 0.1% and ketorolac 0.5% ophthalmic solutions: 3-year 
randomized, double-masked, prospective clinical investigation." Trans Am Ophthalmol Soc 98: 
101-105; discussion 105-107. 
Flach, A. J., B. J. Dolan, M. E. Donahue, E. G. Faktorovich and G. A. Gonzalez (1998). 
"Comparative effects of ketorolac 0.5% or diclofenac 0.1% ophthalmic solutions on 
inflammation after cataract surgery." Ophthalmology 105(9): 1775-1779. 
Garner, L. F. and M. K. Yap (1997). "Changes in ocular dimensions and refraction with 
accommodation." Ophthalmic Physiol Opt 17(1): 12-17. 
Gerding, P. A., A. H. Brightman and J. D. Brogdon (1986). "Pupillotonia in a dog." J Am Vet 
Med Assoc 189(11): 1477. 


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Glasser, A. (2006). "Accommodation: mechanism and measurement." Ophthalmol Clin North 
Am 19(1): 1-12, v. 
Holden, B. A., T. R. Fricke, S. M. Ho, R. Wong, G. Schlenther, S. Cronje, A. Burnett, E. Papas, 
K. S. Naidoo and K. D. Frick (2008). "Global vision impairment due to uncorrected presbyopia." 
Arch Ophthalmol 126(12): 1731-1739. 
Jacobson, D. M. and K. A. Olson (1993). "Influence of pupil size, anisocoria, and ambient light 
on pilocarpine miosis. Implications for supersensitivity testing." Ophthalmology 100(2): 275-
280. 
Jacobson, D. M. and R. A. Vierkant (1998). "Comparison of cholinergic supersensitivity in third 
nerve palsy and Adie's syndrome." J Neuroophthalmol 18(3): 171-175. 
Kocak, I., I. S. Yalvac, A. Kocak, A. Nurozler, N. Unlu, R. Kasim and S. Duman (1998). 
"Comparison of the anti-inflammatory effects of diclofenac and flurbiprofen eye drops after 
cataract extraction." Acta Ophthalmol Scand 76(3): 343-345. 
Laibovitz, R. A., J. Koester, L. Schaich and T. A. Reaves (1995). "Safety and efficacy of 
diclofenac sodium 0.1% ophthalmic solution in acute seasonal allergic conjunctivitis." J Ocul 
Pharmacol Ther 11(3): 361-368. 
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. 
Narvaez, J., P. Krall and T. S. Tooma (2004). "Prospective, randomized trial of diclofenac and 
ketorolac after refractive surgery." J Refract Surg 20(1): 76-78. 
Parker, J., A. Tandon, R. M. Shtein, H. K. Soong, T. N. Cooney, D. C. Musch and S. I. Mian 
(2011). "Management of pain with diclofenac after femtosecond-assisted laser in situ 
keratomileusis." J Cataract Refract Surg 37(3): 569-573. 
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. 
Soylev, M. F., O. Saatci, S. Kavukcu and M. Ergin (1997). "Adie's syndrome in childhood." Acta 
Paediatr Jpn 39(3): 395-396. 
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. 


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Verbout, N. G. and D. B. Jacoby (2012). "Muscarinic receptor agonists and antagonists: effects 
on inflammation and immunity." Handb Exp Pharmacol(208): 403-427. 
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. 
Younge, B. R. and Z. J. Buski (1976). "Tonic pupil: a simple screening test." Can J Ophthalmol 
11(4): 295-299. 


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13 APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
X 
X 


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APPENDIX 3:  PROTOCOL AMENDMENT SUMMARY 
AMENDMENT 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
Proprietary & Confidential 
Page 72 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
Proprietary & Confidential 
Page 73 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
Proprietary & Confidential 
Page 74 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
Proprietary & Confidential 
Page 75 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
IND # 131464 
 
05 June 2019 
Proprietary & Confidential 
Page 76 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
IND # 131464 
 
05 June 2019 
Proprietary & Confidential 
Page 77 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
Proprietary & Confidential 
Page 78 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
Proprietary & Confidential 
Page 79 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
IND # 131464 
 
05 June 2019 
Proprietary & Confidential 
Page 80 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
IND # 131464 
 
05 June 2019 
Proprietary & Confidential 
Page 81 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
IND # 131464 
 
05 June 2019 
Proprietary & Confidential 
Page 82 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
IND # 131464 
 
05 June 2019 
Proprietary & Confidential 
Page 83 of 86 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
Proprietary & Confidential 
Page 84 of 86 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
IND # 131464 
 
05 June 2019 
Proprietary & Confidential 
Page 85 of 86 
 
 
Appendix 5: Sponsor and 
 Approvals 
Protocol Title: 
A Multi-Center, Double-Masked Evaluation of the Efficacy and 
Safety of CSF-1 in the Treatment of Presbyopia 
Protocol Number: 
18-150-0006 
Final Date: 
05 June 2019 
This clinical study protocol was subject to critical review and has been approved by the sponsor. 
The following personnel contributed to writing and/or approving this protocol. 
 
 
 
 
Signature: 
 
Date: 
 
 
 
Orasis Pharmaceuticals 
 
 
Signature:  
 
 
 
 
  
 
Date:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 
 
 
Chief Scientific Officer and Senior Vice President of Strategic Scientific Consulting 
 
 
 
 


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
IND # 131464 
 
05 June 2019 
Proprietary & Confidential 
Page 85 of 86 
 
 
Appendix 5: Sponsor and 
 Approvals 
Protocol Title: 
A Multi-Center, Double-Masked Evaluation of the Efficacy and 
Safety of CSF-1 in the Treatment of Presbyopia 
Protocol Number: 
18-150-0006 
Final Date: 
05 June 2019 
This clinical study protocol was subject to critical review and has been approved by the sponsor. 
The following personnel contributed to writing and/or approving this protocol. 
 
 
 
 
Signature: 
 
Date: 
 
 
Orasis Pharmaceuticals 
 
 
Signature: 
Date:  
 
 
 
 
 
 
Signature: 
 
 
 
 
Signature: 
Date: 
 
 
 
 
 
6/5/2019
6/5/2019
6/5/2019


Orasis Pharmaceuticals  
 
CSF-1 Ophthalmic Solution 
Protocol 18-150-0006 
 
Amendment 2 (Version 3.0) 
IND # 131464 
 
05 June 2019 
Proprietary & Confidential 
Page 86 of 86 
 
 
Appendix 6: Investigator’s Signature 
Protocol Title: 
A Multi-Center, Double-Masked Evaluation of the Efficacy and 
Safety of CSF-1 in the Treatment of Presbyopia 
Protocol Number: 
18-150-0006 
Final Date: 
05 June 2019 
I agree to implement and conduct the study diligently and in strict compliance with the protocol, 
Good Clinical Practices 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] 
 
 
 
 
 
 


Signature Page for VV-CLIN-000221 v1.0
Signature Page for VV-CLIN-000221 v1.0
Approval
07-Jun-2019 10:44:45 GMT+0000

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN (SAP) 
A Multi-Center, Double-Masked Evaluation of the Efficacy and Safety of 
CSF-1 in the Treatment of Presbyopia 
 
 
 
Sponsor: 
 
Orasis Pharmaceuticals, Ltd 
 
Protocol Number: 
18-150-0006 (Phase 2b) 
 
 
Author:  
 
 
 
 
 
 
Date: 
 
 
24 July 2019 
 
Version: 
 
1.0 
 




Page 2 of 31
A Multi-Center, Double-Masked Evaluation of the Efficacy and Safety of 
CSF-1 in the Treatment of Presbyopia
Protocol Number:
18-150-0006 (Phase 2b)
SAP Date:
24 July 2019
SAP Version:
1.0
SAP Preparation, Review, and Approvals
Prepared by:
Reviewed by:
Approved by:
Date
Approved by:
Date
Orasis Pharmaceuticals, Ltd
7/24/2019
Date



Orasis 18-150-0006 SAP, Version 0.1 
 
 
Page 3 of 31 
 
Table of Contents 
1. 
Introduction............................................................................................................................... 6 
2. 
Study Objectives ...................................................................................................................... 6 
2.1 
Study Variables ........................................................................................................................ 6 
2.2 
Primary Variable ....................................................................................................................... 7 
2.3 
Secondary Variables ................................................................................................................ 7 
2.4 
Safety Variables ....................................................................................................................... 7 
2.5 
Statistical Hypotheses .............................................................................................................. 7 
3. 
Study Design and Procedures ................................................................................................. 8 
3.1 
Overall Study Design ............................................................................................................... 8 
3.2 
Schedule of Visits and Measurements ................................................................................... 10 
4. 
Study Treatments ................................................................................................................... 14 
4.1 
Method of Assigning Subjects to Treatment Groups ............................................................. 14 
4.2 
Masking and Unmasking ........................................................................................................ 15 
5. 
Sample Size and Power Considerations ................................................................................ 15 
6. 
Data Preparation .................................................................................................................... 15 
7. 
Analysis Sets .......................................................................................................................... 16 
7.1 
Intent-to-Treat ........................................................................................................................ 16 
7.2 
Per Protocol ........................................................................................................................... 16 
7.3 
Modified Per Protocol ............................................................................................................. 16 
7.4 
Safety ..................................................................................................................................... 16 
8. 
General Statistical Considerations ......................................................................................... 16 
8.1 
Unit of Analysis ...................................................................................................................... 16 
8.2 
Missing Data Handling and Sensitivity Analysis .................................................................... 17 
8.3 
Definition of Baseline ............................................................................................................. 17 
8.4 
Data Analysis Conventions .................................................................................................... 17 
8.5 
Adjustment for Multiplicity ...................................................................................................... 18 
9. 
Disposition of Subjects ........................................................................................................... 18 
10. 
Demographic and Baseline Characteristics ........................................................................... 19 
10.1 
Demographics ........................................................................................................................ 19 
10.2 
Baseline Characteristics ......................................................................................................... 19 
11. 
Medical History and Concomitant Medications ...................................................................... 19 
11.1 
Medical History ....................................................................................................................... 19 
11.2 
Prior and Concomitant Medications ....................................................................................... 20 
12. 
Efficacy Analyses ................................................................................................................... 20 
12.1 
Primary Efficacy Analysis ....................................................................................................... 20 
12.2 
Secondary Efficacy Analysis .................................................................................................. 23 


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13. 
Exploratory Analysis ............................................................................................................... 25 
14. 
Safety Analyses ..................................................................................................................... 25 
14.1 
Adverse Event Summaries..................................................................................................... 26 
14.2 
Best Corrected Visual Acuity (ETDRS) .................................................................................. 26 
14.3 
Slit-Lamp Biomicroscopy Examination ................................................................................... 27 
14.4 
Conjunctival Redness Assessment ........................................................................................ 27 
14.5 
IP Drop Comfort Assessment ................................................................................................ 27 
14.6 
Intraocular Pressure ............................................................................................................... 28 
15. 
Interim Analyses ..................................................................................................................... 28 
16. 
Changes from Protocol-Stated Analyses ............................................................................... 28 
17. 
References ............................................................................................................................. 28 
18. 
Revision History ..................................................................................................................... 29 
19. 
Tables ..................................................................................................................................... 29 
20. 
Listings ................................................................................................................................... 31 
21. 
Figures ................................................................................................................................... 31 
 
 


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List of Abbreviations 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BID 
Bis in die (Twice Daily) 
CI 
Confidence Interval 
CS 
Clinically Significant 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRSE 
Manifest Refraction Spherical Equivalent 
NCS 
Not Clinically Significant 
PP 
Per Protocol 
mPP 
Modified Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
 
 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
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 
protocol 18-150-0006, Phase 2b, Amendment 2 dated 05 June 2019. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on 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 for the treatment of presbyopia. 
The secondary objectives of this study are to evaluate the safety, tolerability, 
 
 of CSF-1 versus the individual components (pilocarpine hydrochloride and diclofenac sodium 
0.006%) for the treatment of presbyopia at two concentrations (0.2% or 0.4% pilocarpine hydrochloride). 
2.1 
Study Variables 
For all study variables, 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 screening Visit 1 (Day 
-1 to -14) 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 monocular and binocular best corrected visual acuity (BCVA) at 40 cm, 
 
 
Safety variables include BCVA at distance under normal and low luminance testing conditions, slit lamp 
biomicroscopy measures, conjunctival redness grading and investigational product (IP) drop comfort 
assessment, as well as intraocular pressure (IOP) and adverse events (AE). 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 -1 to -14). 
Please refer to the BCVA protocol for conducting manifest refraction procedures. 


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2.2 
Primary Variable 
The percentage of study eyes with a ≥3-line (15 letter) gain from baseline (Day 1) in BCVA at 40 cm, 1-
hour post-treatment at Day 8 and Day 15. 
2.3 
Secondary Variables 
The secondary efficacy variables include the following: 
• 
 
 
• 
Percentage of study eyes with a ≥2-line (10 letter) gain from baseline (Day 1) in BCVA at 40 cm 
 
 1 hour, 
 post-treatment at Day 8 and Day 15 
• 
 
 
15 
2.4 
Safety Variables 
The safety variables include the following: 
• 
BCVA 
• 
Best corrected low luminance distance VA 
• 
Findings from slit lamp biomicroscopy examination 
• 
Conjunctival redness grading  
• 
IP drop comfort assessment 
• 
IOP measurements 
• 
Incidence of AEs (reported, elicited, and observed) 
2.5 
Statistical Hypotheses 
The null and alternative hypotheses, based on the study objectives and primary variable, are as follows: 
H01: 
The difference, between study eyes treated with CSF-1 (0.4%/0.006%) and study 
eyes treated with diclofenac sodium (0.006%), in the percentage of study eyes with a ≥3-
line (15 letter) gain in BCVA at 40 cm, 1-hour post-treatment = 0. 
H11: 
The difference, between study eyes treated with CSF-1 (0.4%/0.006%) and study 
eyes treated with diclofenac sodium (0.006%), in the percentage of study eyes with a ≥3-
line (15 letter) gain in BCVA at 40 cm, 1-hour post-treatment ≠ 0. 


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H02: 
The difference, between study eyes treated with Pilocarpine (0.4%) and study 
eyes treated with diclofenac sodium (0.006%), in the percentage of study eyes with a ≥3-
line (15 letter) gain in BCVA at 40 cm, 1-hour post-treatment = 0. 
H12: 
The difference, between study eyes treated with Pilocarpine (0.4%) and study 
eyes treated with diclofenac sodium (0.006%), in the percentage of study eyes with a ≥3-
line (15 letter) gain in BCVA at 40 cm, 1-hour post-treatment ≠ 0. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. Study Design and Procedures 
3.1 
Overall Study Design 
This is a 4-visit randomized, double-masked, multi-center, parallel-group study evaluating the safety and 
efficacy of CSF-1 compared with pilocarpine hydrochloride alone and diclofenac sodium (0.006%) alone in 
approximately 150 subjects with presbyopia. 
Visit 1 (Day -1 to -14): Subjects will be screened through ophthalmic assessments and both near and 
distance BCVA tests. 
 
 
Visit 2 (Day 1): Pre-treatment ophthalmic assessments will be repeated at Visit 2. Following the pre-
treatment assessments, qualified subjects will be randomized to 1:1:1 to one of the following treatment 
arms: 


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• 
CSF-1: pilocarpine hydrochloride (0.2% [low dose])/(0.4% [high dose]) and diclofenac sodium 
(0.006%) 
• 
Pilocarpine hydrochloride (0.2% [low dose])/(0.4% [high dose]) 
• 
Diclofenac sodium (0.006%) 
All subjects will be instructed to dose each eye twice daily (
 
 in both eyes with a single drop for approximately 1 week until the 
afternoon before study Visit 3. Subjects randomized to the CSF-1 arm will receive pilocarpine hydrochloride 
0.2%/diclofenac sodium 0.006% (CSF-1 low dose); subjects randomized to the pilocarpine hydrochloride 
alone arm will receive pilocarpine hydrochloride (0.2%) alone; and, subjects randomized to diclofenac 
sodium alone arm will dose with diclofenac sodium (0.006%) alone. 
Visit 3 (Day 8 ± 2): Pre-treatment ophthalmic assessments will be repeated at Visit 3. The morning dose of 
IP will be administered by study site personnel followed by ophthalmic safety and efficacy assessments 
 
 After the Visit 3 assessments, subjects will continue BID dosing (
 
) in both eyes for approximately 1 week. 
Subjects initially randomized to the CSF-1 arm will now receive pilocarpine hydrochloride 0.4%/diclofenac 
sodium 0.006% (CSF-1 high dose); subjects randomized to the pilocarpine hydrochloride alone arm will 
now receive pilocarpine hydrochloride (0.4%) alone; and, subjects randomized to diclofenac sodium alone 
arm will continue dosing with diclofenac sodium (0.006%) alone. 
Visit 4 (Day 15 ± 2): Pre-treatment ophthalmic assessments will be repeated at Visit 4. The morning dose 
of IP will be administered by study site personnel followed by ophthalmic safety and efficacy assessments 
. After the Visit 4 assessments, subjects will subsequently exit the study. 
Figure 1 provides a graphical representation of the study design and study visitation. 
Study visits will be referred to in all tables and listings as the planned study day corresponding to the visit 
to enable reviewers to understand the assessment timing without referring to the protocol visit schedule. 
Table 1 shows the scheduled study visits, their planned study day, and the acceptable visit window for each 
study visit: 
Table 1. Scheduled Study Visits 
Scheduled Visit 
Planned Study Day 
Visit Window 
Visit 1 
Day -1 to -14 
N/A 
Visit 2 
Day 1 
N/A 
Visit 3 
Day 8 
+/- 2 Days 
Visit 4 
Day 15 
+/- 2 Days 


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3.2 
Schedule of Visits and Measurements 
The schedule of visits and assessments is provided in Table 2. 


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Figure 1. Study Design and Study Visitation 
 
 
 


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Table 2. Schedule of Visits and Assessments 


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4. Study Treatments 
The IP is CSF-1, a topical eye drop solution for 
 presbyopia, which works by 
reducing the natural pupil size and correspondingly increasing the depth of field. The formulation developed 
by Orasis Pharmaceuticals Ltd. is a viscous eye drop containing the active ingredients pilocarpine 
hydrochloride and diclofenac sodium with the addition of excipients, 
 
. The inclusion of a non-steroidal anti-inflammatory drug (diclofenac 
sodium) may reduce the inflammatory response induced by pilocarpine hydrochloride. Pre-treatment 
ophthalmic assessments will be repeated at Day 1. Following the pre-treatment assessments, qualified 
subjects will be randomized to 1:1:1 to one of the following treatment arms: 
• 
CSF-1: pilocarpine hydrochloride (0.2% [low dose])/(0.4% [high dose]) and diclofenac sodium 
(0.006%) 
• 
Pilocarpine hydrochloride (0.2% [low dose])/(0.4% [high dose]) 
• 
Diclofenac sodium (0.006%) 
After randomization, subjects will receive IP and a dosing diary. Once dispensed to the subject, IP 
 
 Subjects will be instructed to save and return 
all used and unused IP and to bring their kits to each study visit. Subjects will be instructed to dose bilaterally 
BID in the morning and afternoon (
 
and record doses in their diary (paper). Subjects should not dose before the morning of Day 8. At Day 8, 
subjects will receive their morning dose from study site personnel, after the required pre-treatment 
assessments, and the current IP will be collected. 
Subjects will be assigned a new IP at the conclusion of Day 8 and instructed on the use of a new dosing 
diary. The afternoon dose, from the new IP, will be instilled in-office during Day 8. After subjects receive 
their IP and dosing diary, subjects will be instructed to dose bilaterally BID in the morning and afternoon 
(
) and record doses in their diary 
until Day 15. Subjects should not dose before the morning of Day 15. At Day 15, subjects will receive their 
last dose from study site personnel, after the required pre-treatment assessments, and the current IP will 
be collected. Subjects will exit the study after all assessments are complete at Day 15. 
4.1 
Method of Assigning Subjects to Treatment Groups 
At Visit 1 (Day -1 to -14), each subject who signs an informed consent form (ICF) will be assigned a subject 
number (a five-digit number starting with the 2-digit site number followed by a sequential three-digit number 
starting with 001). The five-digit subject number will be used to identify subjects in all datasets and listings 
for this study. Once a subject meets all qualification criteria at Day 1, they will be randomized in a 1:1:1 
ratio via an interactive response technology system to one of three treatment groups: A, CSF-1; B, 
pilocarpine hydrochloride alone; C, diclofenac sodium alone; and stratified by iris color (brown versus light 
[i.e. blue, green, gray, and hazel]) and by baseline manifest refraction spherical equivalent ([
 


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; randomization will not be stratified by site. 
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase the 
likelihood that known (e.g. iris color and baseline characteristics) and unknown subject attributes 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 
Fifty subjects per each of the three treatment arms (150 total), yields an 85% power to establish the 
superiority of CSF-1 (0.4%/0.006%) and Pilocarpine (0.4%) to diclofenac sodium (0.006%) alone in the 
percentage of study eyes demonstrating a ≥3-line (15-letter) gain in BCVA at 40 cm, 1-hour post-treatment 
from the baseline measurement using a Pearson chi-squared test at a 2-sided α = 0.05, assuming that the 
diclofenac sodium (0.006%) alone response is 5% and the CSF-1 response is 27%, resulting 
 
. At least 
approximately 30% of subjects should have a light (i.e. blue, green, gray, and hazel) iris and at least 
approximately 30% should have a brown iris. The actual iris proportions will vary based on the actual 
subjects enrolled and treated. 
6. Data Preparation 
All reported study data will be recorded on the eCRFs supplied by 
 
using 
. 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 
. 


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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 
 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 
 and 
sponsor personnel. 
• 
Protocol deviations have been identified and status defined (major/minor deviations). 
• 
Analysis populations have been determined. 
• 
Randomized treatment codes have been unmasked. 
7. Analysis Sets 
7.1 
Intent-to-Treat 
The intent-to-treat analysis set (ITT) will include all randomized subjects. Subjects in the ITT will be 
analyzed as randomized. 
7.2 
Per Protocol 
The per protocol (PP) set will include subjects in the ITT who do not have significant protocol deviations 
that affect the primary endpoint. Protocol deviations will be assessed prior to database lock and unmasking. 
Subjects in the PP set will be analyzed as treated. 
7.3 
Modified Per Protocol 
 
 
 
 
 
 
 
7.4 
Safety 
The safety set will include all subjects who have received at least one dose of the IP. Subjects in the safety 
analysis set 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 variables. The study 
eye will be defined as the eye that meets all enrollment criteria. If both eyes meet all enrollment criteria, 


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then the eye with the worse Day 1 BCVA at 40 cm will be the study eye. If both eyes have the same BCVA 
at 40 cm, then the right eye will be deemed the study eye. 
8.2 
Missing Data Handling and Sensitivity Analysis 
All analyses, including the primary efficacy analysis described in Section 12.1, will include observed 
data only. 
 
 
 
 
8.3 
Definition of Baseline 
For all variables, 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 screening Visit 1 (Day -1 to 
-14) will be used as baseline for all treatments/visits. Change from baseline will be calculated as: Follow-
up Measure – Baseline Measure. 
8.4 
Data Analysis Conventions 
All data analysis will be performed by 
after the study is completed and the database has been locked 
and released for unmasking. Statistical programming and analyses will be performed using 
 
. 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, 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 follow-up visit (Follow-up Visit – Baseline Visit), with baseline 
defined in Section 8.3 of this SAP. 
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 
For the primary statistical hypotheses described in Section 2.5 of this SAP, the study will be considered a 
success if either of the null hypotheses, H01 or H02, are rejected in favor of their corresponding alternative 
hypotheses, H11 or H12. Rejecting H01 and/or H02 implies that CSF-1 (0.4%/0.006%) and/or Pilocarpine 
(0.4%) are signficantly (α = 0.05) better than diclofenac sodium (0.006%), provided that the 
differencefavors CSF-1 and/or Pilocarpine, in achieving a ≥3-line (15 letter) gain from baseline in BCVA at 
40 cm (1-hour post-treatment). This primary efficacy variable was specifically selected to align with the 
primary objective of the study: to evaluate the efficacy of CSF-1 for the treatment of presbyopia. 
The overall Type I error of the 2-sided α = 0.10 will be preserved through the use of Bonferroni correction 
procedures testing each hypothesis individually at a 2-sided α = 0.05. If H01 is rejected and CSF-1 
(0.4%/0.006%) is considered a success, then CSF-1 (0.2%/0.006%) will be tested against diclofenac 
sodium (0.006%) at a 2-sided α = 0.05. Similarly, if H02 is rejected and Pilocarpine (0.4%) is considered a 
success, then Pilocarpine (0.2%) will be tested against diclofenac sodium (0.006%) at a 2-sided α = 0.05. 
Within these hierarchical frameworks, these hypotheses can be tested at a 2-sided α = 0.05 while still 
preserving an overall Type I error of α = 0.10. For this Phase 2 study, all secondary and safety endpoints 
will be tested without adjustment for multiplicity. 
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 four 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, 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 (ITT, PP, and Safety) 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 major protocol 
deviations, which could affect analysis of the primary endpoint, 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. 


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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 PP set. 
10. Demographic and Baseline Characteristics 
10.1 
Demographics 
The subject demographic data collected in this study include age, sex, race, ethnicity, and iris color. 
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 will be classified as heterochromia. Sex, race, ethnicity, 
and iris color will be presented using descriptive summary statistics with frequency counts and percentages. 
Age (years) will be summarized, overall and by treatment arm, using continuous descriptive statistics. Age 
will be reported in years and calculated using the following formula: 
Age = (Informed Consent Date – Date of Birth) / 365.25, truncated as an integer 
Demographic variables will be summarized for the ITT and PP by treatment arm and overall in tables.  
A subject listing that includes all demographic variables will also be provided. 
10.2 
Baseline Characteristics 
Baseline characteristics are measured to ensure the safety and eligibility of subjects at Visit 1 (Day -1 to -
14) and to confirm their previous results obtained within three months of Visit 1 (Day -1 to -14) have not 
changed significantly. Subject level listings will be used to present pre-treatment information from the ITT 
analysis set at the eye level when appropriate. Baseline characteristics will be contained in subject listings 
only and will include: 
• 
Manifest refraction 
• 
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 21.1. 
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 Safety 
analysis set. 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 


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with the PT, if a subject reports multiple conditions within the same SOC, then that SOC will only be reported 
once. 
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, September 2018) 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 (eg, multivitamins) then the drug name will be summarized as the 
preferred name. Any uncoded terms will be summarized under the ATC classification and preferred name 
of “Uncoded.” 
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. Prior and concomitant 
medications will be summarized using the Safely analysis set. Medications will be tabulated for each 
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.  
Summaries will be generated separately for prior and concomitant medications, with ocular and non-ocular 
data also summarized separately. Subject listings will group prior and concomitant medications together, 
with ocular and non-ocular information presented separately. 
12. Efficacy Analyses 
12.1 
Primary Efficacy Analysis 
The primary efficacy variable in this study is the percentage of study eyes with a ≥3-line (15 letter) gain 
from baseline (Day 1) in monocular BCVA at 40 cm, one-hour post-treatment at Day 8 and Day 15. Early 
Treatment of Diabetic Retinopathy Study format VA charts will be employed to assess VA at all ranges. All 
VA measurements will be assessed via best distance-correction determined by the manifest refraction at 
screening Visit 1. The primary efficacy analysis of the primary efficacy variable will utilize the PP analysis 
set on observed data only. 
The primary analyses will be completed using 
 to maintain the overall Type I error, 
as detailed in Section 8.5 of this SAP, with statistical inference made on the comparisons between CSF-1 
(0.4%/0.006%) versus diclofenac sodium (0.006%) and between Pilocarpine (0.4%) versus diclofenac 


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sodium (0.006%). As also detailed in the Section 8.5, only if the higher dose concentrations for CSF-1 
(0.4%/0.006%) and/or Pilocarpine (0.4%) are successful will the corresponding lower dose concentrations 
for CSF-1 (0.2%/0.006%) and/or Pilocarpine (0.2%), respectively, have inference made on the statistical 
test. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
) 
Standard errors and CIs (90% and 95%) will also be presented for each treatment group and the difference 
between treatment groups. 
 
 
 
 
 


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12.2 
Secondary Efficacy Analysis 
The key secondary efficacy analysis will be the same analysis as the primary analysis, but instead 
employing the ITT analysis set. 


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For the assessment of BCVA at 40 cm, the percentage of study eyes achieving a ≥3-line (15-letters) and 
≥2-line (10-letters) improvement from baseline for 
 1 
 
hours post-treatment) will be conducted using the PP analysis set. 
 
 analyses of 
these secondary efficacy variables will then be repeated using the ITT analysis set. 
 
 
 The observed 
BCVA as well as the change from baseline in BCVA will be summarized by treatment group using 
continuous descriptive summary statistics, and subject-specific BCVA data will also be presented in a listing 
for each visual range, separately. 
 
 
 
 
 
 


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13. Exploratory Analysis 
 
 
ther. 
14. Safety Analyses 
All safety analyses will be conducted using the safety analysis set. BCVA at distance under normal and low 
luminance testing conditions, findings from slit lamp biomicroscopy examination, conjunctival redness 
grading and IP drop comfort assessment, as well as IOP measurements will be summarized descriptively 


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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 21.1. A Treatment-emergent adverse event (TEAE) is 
defined as any event that has an onset date on or after the first dose of IP. 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 
• 
 
 
 
 
 
• 
All SAEs 
• 
 
 
 
• 
TEAEs leading to study discontinuation 
• 
TEAEs by Maximum 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 all 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 
 
 
 
 
 
 
 


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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 Visits 1, 3, and 4. 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 
utilizing frequency counts and percentages for each treatment group at each time point 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. 
14.4 
Conjunctival Redness Assessment 
A conjunctival redness assessment is conducted at pre-treatment for all visits and at post-treatment for 
Visits 3 and 4 utilizing the 
 Redness Scale #6.0 Conjunctival Redness Assessments. The investigator 
will evaluate ocular redness of the three vessel beds (under the slit lamp) and grade according to the 
following scale: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.5 
IP Drop Comfort Assessment 


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14.6 
Intraocular Pressure 
Intraocular pressure will be assessed via Goldmann applanation tonometry at Visits 1, 3, and 4. 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. 
15. Interim Analyses 
An interim analysis has not been planned or performed for this study. 
16. Changes from Protocol-Stated Analyses 
As of the date of this SAP, the protocol-stated analyses have not been changed. 
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) 
Kenward MG and Roger JH (1997), “Small Sample Inference for Fixed Effects from Restricted Maximum 
Likelihood,” Biometrics, 53, 983–997. DOI: 10.2307/2533558 


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18. Revision History 
Documentation of revision to the SAP will commence after the approval of Version 0.1. 
19. Tables 
Tables that will be included in the topline delivery are shown in boldface italics. 


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