Clinical trial NCT05665387
Conditions: Presbyopia
Keywords: Santen, Presbyopia, Eye
Sponsor: Santen Inc.
Start date: 2022-12-22; Completion date: 2023-07-27
Enrollment: 79 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase IIa study to assess efficacy and safety of STN1013600 ophthalmic solution (0.1%, and 0.3 %), twice daily when compared to Placebo in subjects diagnosed with presbyopia. This study will consist of a Screening Period of up to 15 days followed by a 2 Month Treatment Period. After the Treatment Period subjects will be followed for a one-month treatment free period.

Detailed description:

Arms: arm 1: 0.1% STN1013600 ophthalmic solution 1 drop BID arm 2: 0.3% STN1013600 ophthalmic solution 1 drop BID arm 3: Placebo (Vehicle) ophthalmic solution BID
Interventions: intervention 1: 0.1% STN1013600 ophthalmic solution intervention 2: 0.3% STN1013600 ophthalmic solution intervention 3: Placebo
Intervention descriptions: intervention 1: 0.1% STN1013600 ophthalmic solution 1 drop BID for 2 months intervention 2: 0.3% STN1013600 ophthalmic solution 1 drop BID for 2 months intervention 3: Placebo ophthalmic solution 1 drop BID for 2 months

Protocol documents:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:   
OPSIS: A Phase IIa, Randomized, Double-Masked, Placebo-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety of 
STN1013600 Ophthalmic Solution 0.1% and 0.3% Compared with Placebo 
in Subjects with Presbyopia 
 
 
NCT Number:  
NCT05665387 
 
Date of the document: 
23 SEPT 2022  
 
 
 


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PROTOCOL 101360002IN 
Protocol Title: OPSIS: A Phase IIa, Randomized, Double-Masked, Placebo-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety of STN1013600 
Ophthalmic Solution 0.1% and 0.3% Compared with Placebo in Subjects with Presbyopia 
Protocol Number: 101360002IN 
Compound: STN1013600 Ursodeoxycholic Acid, UCDA (DE-136) 
Study Phase: Phase IIa 
Sponsor Name: Santen Inc. 
Legal Registered Address: 6401 Hollis Street, Suite 125, Emeryville CA 94608, USA 
Regulatory Agency Identifier Number(s): IND Number: 153534 
Protocol Version / Approval Date: Original / 23 September 2022 
 
I have read the 101360002IN protocol and agree to conduct the study as outlined.  I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.  I will not initiate the study until I have obtained written approval by the appropriate 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and have complied 
with all financial and administrative requirements of the governing body of the clinical 
institution and Santen as the Sponsor.  I will obtain written informed consent from each study 
subject prior to performing any study-specific procedures.  I understand that my electronic 
signature on an electronic case report form (eCRF) indicates that the data there in has been 
reviewed and accepted by me as the investigator.  
INVESTIGATOR: 
Date:  
 
_________________________________ 
 
Signature: 
 
_________________________________ 
 
Name:  
 
_________________________________ 
 
Address:  
 
_________________________________ 
 
 
_________________________________ 
 
Phone: 
 
_________________________________ 
This study will be conducted in accordance with applicable Good Clinical Practices (GCP), 
United States Code of Federal Regulations, International Conference on Harmonization (ICH) 
guidelines, and the Declaration of Helsinki. 
 
 


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TABLE OF CONTENTS 
PROTOCOL 101360002IN .............................................................................................................1 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................3 
1. 
PROTOCOL SUMMARY ............................................................................................9 
1.1. 
Synopsis ........................................................................................................................9 
1.2. 
Schema ........................................................................................................................17 
1.3. 
Schedule of Assessments (SoA) .................................................................................18 
2. 
INTRODUCTION ......................................................................................................21 
2.1. 
Background .................................................................................................................21 
2.2. 
Study Rationale ...........................................................................................................21 
2.3. 
Benefit/Risk Assessment ............................................................................................22 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................23 
4. 
STUDY DESIGN .......................................................................................................24 
4.1. 
Overall Design ............................................................................................................24 
4.2. 
Scientific Rationale for Study Design ........................................................................25 
4.3. 
Justification for Dose ..................................................................................................25 
4.4. 
End of Study Definition ..............................................................................................25 
5. 
STUDY POPULATION .............................................................................................25 
5.1. 
Inclusion Criteria ........................................................................................................25 
5.2. 
Exclusion Criteria .......................................................................................................26 
5.3. 
Contraception Requirements ......................................................................................28 
5.4. 
Screen Failures ............................................................................................................29 
6. 
STUDY INTERVENTION ........................................................................................29 
6.1. 
Study Medications Administered ...............................................................................29 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................30 
6.2.1. 
Study Medication Storage ...........................................................................................30 
6.2.2. 
Study Medication Administration...............................................................................30 
6.2.3. 
Study Medication Accountability ...............................................................................30 
6.2.4. 
Study Medication Handling and Disposal ..................................................................31 
6.3. 
Measures to Minimize Bias: Randomization and Masking ........................................31 
6.4. 
Study Intervention Compliance ..................................................................................32 
6.5. 
Concomitant Therapy .................................................................................................32 


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6.5.1. 
Collection of Prior and Concomitant Medication Information ...................................33 
6.5.2. 
Prohibited Medications or Therapies ..........................................................................33 
6.6. 
Rescue Medicine .........................................................................................................34 
6.7. 
Dose Modification ......................................................................................................34 
6.8. 
Intervention after the End of the Study .......................................................................34 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL .......................................34 
7.1. 
Discontinuation of Study Intervention........................................................................34 
7.1.1. 
Temporary Discontinuation ........................................................................................34 
7.1.2. 
Rechallenge .................................................................................................................34 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................34 
7.3. 
Lost to Follow up ........................................................................................................35 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................35 
8.1. 
Visit Details ................................................................................................................35 
8.1.1. 
Visit 1 (Screening) ......................................................................................................36 
8.1.2. 
Visit 2 (Baseline, Day 1) ............................................................................................38 
8.1.3. 
Double-Masked Treatment Period, Visit 3 (Day 7) ....................................................38 
8.1.4. 
Double-Masked Treatment Period, Visit 4 (Day 14) ..................................................39 
8.1.5. 
Double-Masked Treatment Period, Visit 5 (Month 1) ................................................40 
8.1.6. 
Double-Masked Treatment Period, Visit 6 (Month 2) ................................................40 
8.1.7. 
Double-Masked Treatment-free Period, Visit 7 (Month 3), Exit/Early 
Termination .................................................................................................................41 
8.1.8. 
Unscheduled Visits .....................................................................................................42 
8.2. 
Safety Assessments .....................................................................................................42 
8.2.1. 
Vital Signs ..................................................................................................................42 
8.2.2. 
Clinical Safety Laboratory Assessments ....................................................................42 
8.3. 
Adverse Events and Serious Adverse Events .............................................................43 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................43 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................44 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................44 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................44 
8.3.5. 
Pregnancy Testing, Monitoring, and Reporting .........................................................44 
8.3.5.1. 
Pregnancy Testing ......................................................................................................44 


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8.3.5.2. 
Pregnancy Monitoring and Reporting Procedures ......................................................45 
8.3.6. 
Adverse Events of Special Interest .............................................................................46 
8.4. 
Treatment of Overdose ...............................................................................................46 
8.5. 
Pharmacokinetics ........................................................................................................46 
8.6. 
Pharmacodynamics .....................................................................................................46 
8.7. 
Genetics ......................................................................................................................46 
8.8. 
Biomarkers ..................................................................................................................46 
8.9. 
Immunogenicity Assessments ....................................................................................46 
8.10. 
Health Economics/Medical Resource Utilization .......................................................47 
9. 
STATISTICAL CONSIDERATIONS .......................................................................47 
9.1. 
Statistical Hypotheses .................................................................................................47 
9.2. 
Sample Size Determination ........................................................................................47 
9.3. 
Populations for Analyses ............................................................................................48 
9.3.1. 
Safety Population ........................................................................................................48 
9.3.2. 
Full Analysis Set .........................................................................................................48 
9.3.3. 
Per-Protocol Set ..........................................................................................................48 
9.4. 
Statistical Analyses .....................................................................................................48 
9.4.1. 
General Considerations ...............................................................................................48 
9.4.2. 
Handling of Missing Values .......................................................................................48 
9.4.3. 
Primary Endpoint ........................................................................................................49 
9.4.4. 
Secondary Endpoints ..................................................................................................49 
9.4.5. 
Exploratory Endpoints ................................................................................................49 
9.4.6. 
Safety Analyses ..........................................................................................................49 
9.5. 
Interim Analyses .........................................................................................................50 
9.6. 
Santen Steering Committee (SSC) ..............................................................................50 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................50 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................50 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................50 
10.1.2. 
Obligations of Investigators ........................................................................................51 
10.1.3. 
Financial Disclosure ...................................................................................................52 
10.1.4. 
Informed Consent Process ..........................................................................................52 
10.1.5. 
Data Protection ...........................................................................................................53 


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10.1.6. 
Committees Structure .................................................................................................54 
10.1.7. 
Data Quality Assurance ..............................................................................................54 
10.1.8. 
Source Documents ......................................................................................................54 
10.1.9. 
Study and Site Start and Closure ................................................................................55 
10.1.10. 
Publication Policy .......................................................................................................56 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................56 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................58 
10.3.1. 
Definition of AE .........................................................................................................58 
10.3.2. 
Definition of SAE .......................................................................................................59 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................59 
10.3.4. 
Reporting of SAEs ......................................................................................................61 
10.4. 
Procedures for Assessments .......................................................................................61 
10.4.1. 
Symptom Assessment iN Dry Eye Questionnaire (SANDE) .....................................61 
10.4.2. 
Near Activity Visual Questionnaire ............................................................................62 
10.4.3. 
Objective Refraction ...................................................................................................62 
10.4.4. 
Subjective Refraction (Manifest Refraction) ..............................................................62 
10.4.5. 
Distance Corrected Near Visual Acuity (DCNVA) ....................................................62 
10.4.6. 
Distance Corrected Intermediate Visual Acuity (DCIVA) .........................................62 
10.4.7. 
Best Corrected Distance Visual Acuity Testing (BCDVA) .......................................62 
10.4.8. 
Subjective Accommodative Amplitude Testing (Defocus Curve Testing) ................63 
10.4.9. 
Lens and Corneal Elasticity Testing ...........................................................................63 
10.4.10. 
Slit-Lamp Biomicroscopy ...........................................................................................64 
10.4.11. 
Pupil Measurement .....................................................................................................66 
10.4.12. 
Tear Film Break Up Time (TFBUT) ..........................................................................66 
10.4.13. 
Corneal Fluorescein Staining (CFS) Assessment with Oxford Scale .........................67 
10.4.14. 
Intraocular Pressure (IOP) ..........................................................................................67 
10.4.15. 
Ophthalmoscopy .........................................................................................................68 
10.4.16. 
Cycloplegic Refraction ...............................................................................................68 
10.4.17. 
Patient Global Rating of Treatment ............................................................................68 
10.4.18. 
Post-Study Clinical Trial Experience Survey .............................................................69 
10.4.19. 
Vital Signs ..................................................................................................................73 
10.5. 
Symptom Assessment iN Dry Eye Questionnaire (SANDE) .....................................73 


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10.6. 
Near Activity Visual Questionnaire ............................................................................74 
10.7. 
Appendix 9: Abbreviations .........................................................................................74 
10.8. 
Appendix 10: Protocol Amendment History ..............................................................75 
11. 
REFERENCES ...........................................................................................................76 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................18 
Table 3: 
Objectives and Endpoints ...........................................................................................23 
Table 4: 
Descriptions of Study Medications .............................................................................29 
Table 5: 
Protocol-Required Safety Laboratory Assessments ...................................................57 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................17 
Figure 2: 
Oxford Scale ...............................................................................................................67 
 
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Sponsor/Company:  
Santen Inc. 
6401 Hollis Street, Suite 125 
Emeryville, CA  94608, USA 
Name of Investigational Product: 
STN1013600 Ophthalmic Solution 
Name of Active Ingredient: 
Ursodiol, Ursodeoxycholic acid (UDCA) 
Title of Study: OPSIS: A Phase IIa, Randomized, Double-Masked, Placebo-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety of STN1013600 
Ophthalmic Solution 0.1% and 0.3% Compared with Placebo in Subjects with Presbyopia 
Protocol Number: 101360002IN 
Number of Subjects (Planned): Approximately 75 subjects with Presbyopia.  
Study Center(s): Approximately 13 Sites in the United States 
Study Period: Approximately 6 months  
Phase of Development:  Phase Ⅱa 
Study Objectives and Endpoints: 
Study Objectives 
Corresponding Study Endpoints 
Primary Efficacy Objective: 
To assess the efficacy of two concentrations 
of STN1013600 ophthalmic solution  
(0.1% and 0.3%) twice daily dosing when 
compared to Placebo in subjects aged from 
47 to 55 years with presbyopia. 
 
Primary Efficacy Endpoint: 
 Mean change from baseline in 
Binocular DCNVA at Month 2 


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Secondary Efficacy Objective: 
To assess the dose response of STN1013600 
ophthalmic solution. 
Secondary Efficacy Endpoints: 
 Mean change from baseline in Study 
Eye DCNVA at all visits 
 Mean change from baseline in 
Binocular DCNVA at all visits 
 Proportion of subjects who improve 
1/2/3-lines or more in Study Eye and 
Binocular DCNVA at each visit   
 Mean change from baseline in quality 
of life assessed with Near Activity 
Visual Questionnaire (NAVQ) at 
Month 2 and Month 3 
 Subject treatment satisfaction as 
assessed by Patient Global Rating of 
Treatment at Month 2 
 
Safety Objective: 
To assess the safety of two concentrations of 
STN1013600 ophthalmic solution (0.1% and 
0.3%) twice daily dosing when compared to 
Placebo in subjects aged from 47 to 55 years 
with presbyopia. 
Safety Endpoint: 
 Safety of STN1013600 will be 
assessed by adverse events (AEs), 
Intra-ocular Pressure (IOP),  
slit-lamp bio-microscopy, 
ophthalmoscopy, and laboratory tests 
(serum chemistry, hematology, and 
urinalysis). 
 


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Duration of Treatment: 2 months, and 1 month of follow up without treatment. 
Methodology: 
This is a Phase IIa, randomized, double-masked, placebo-controlled, parallel-group study 
assessing the efficacy and safety of STN1013600 ophthalmic solution (0.1% and 0.3%) in 
subjects with Presbyopia. 
Subjects with Presbyopia who meet all eligibility criteria at Visit 1 (Screening) will be 
randomized at Visit 2 (Baseline) to receive treatment for 2 months. 
Approximately 75 subjects who meet all eligibility criteria at Visit 1 (Screening) will be 
randomized at Visit 2 (Baseline) in a 2:2:1 ratio to one of the following three treatment arms: 

0.1% STN1013600 ophthalmic solution BID (08:00 & 20:00 ± 60 min)

0.3% STN1013600 ophthalmic solution BID (08:00 & 20:00 ± 60 min)

Placebo (Vehicle) BID (08:00 & 20:00 ± 60 min)
Subjects will be treated for 2 months, followed by a 1-month safety follow-up without 
treatment. 
Study Design: (Refer to Figure 1) 
This study will consist of a Screening Period of up to 15 days, followed by a 2-month 
Treatment Period and subsequently 1-month Treatment-free follow-up Period.  
At the Visit 1 (Screening), subjects will be screened against the inclusion and exclusion 
criteria and if subject meets all eligibility criteria, subjects will proceed to Visit 2 (Baseline). 
Per study design, subjects who qualify per eligibility criteria will be treated bilaterally (both 
eyes). 
The study eye will be the eye that qualifies with the worse DCNVA per eligibility criteria at 
Visit 2. If both eyes have the same DCNVA, the right eye will be designated as the study eye. 
Treatment Period (2 months): 
At Visit 2 (Baseline), approximately 75 eligible subjects will be randomized to receive either 
0.1% STN1013600 ophthalmic solution BID or 0.3% STN1013600 ophthalmic solution BID 
or Placebo BID in a 2:2:1 ratio. Subjects will be treated for 2 months with scheduled 
assessment visits at 
.  
At Visit 2 (Baseline), subjects will administer their first dose of study medication (study eye 
drops) as per their assigned/randomized study treatment at 20:00 (± 60 min). The next  
day (Day 2), subjects will subsequently dose with their assigned study medication at 08:00 & 
20:00 (± 60 min) and continue dosing through Visit 6 (Month 2). 
Treatment-free Follow-up Period (1 month): 
After Treatment Period, subjects will be followed for 1 month with scheduled study 
assessment (including safety assessments) visits at Visit 7 (Month 3). 
Pharmacogenomics/Genomics: 
Not applicable 


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Santen Steering Committee: 
An internal Santen steering committee (SSC) whose members will not be participating in the 
OPSIS study conduct will serve as an advisory board to the Santen senior management team. 
 The 
verning 
charter. 
Masking:  
This is a double-masked study. The subjects, Investigators, Examiners and Santen personnel 
involved in the conduct of the study will be masked to the study treatments. An authorized 
unmasked study staff member at the investigator site who is not the Investigator or Examiner 
will dispense and collect study medication(s). Patient medication compliance diary will be 
reviewed. 
Subjects will be instructed not to show the bottles or discuss the eye drops to either the 
Masked Investigator or the Masked Examiner or other study subjects. 
Inclusion criteria: 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. 
2. Phakic presbyopic subjects, Male or Female between 47 and 55 years of age. 
3. Distance-corrected near visual acuity (DCNVA) for each eye, as well as for binocular 
vision, 70 EDTRS letters or worse (equivalent to 0.3 logMAR or worse; or 20/40 
Snellen or worse) at 40 cm. To be reconfirmed at Visit 2 (Baseline). 
4. Best-corrected distance visual acuity (BCDVA) for each eye of 85 ETDRS letters or 
better (equivalent to 0.00 logMAR or better; or 20/20 Snellen or better) at 4 m. To be 
reconfirmed at Visit 2 (Baseline). 
5. 


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6.
7.
8.
 
Exclusion Criteria:  
Participants are excluded from the study if any of the following criteria apply: 
 
Ocular Conditions: 
1. 
2. 
3. 
4. 
5. 
6. 
7. 
8. 
9. 


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10
 
11. 
 
 
 
 
 
 
 
   
12. 
 
13
 
14
 
15. 
 
16. Secondary cause of presbyopia in either eye as assessed by investigator (e.g., damage 
to lens, zonules or ciliary muscle, multiple sclerosis, cardiovascular accidents, vascular 
insufficiency, myasthenia gravis, anemia, influenza, measles). 
17. Any history of ocular surgery (including ocular laser surgery) in either eye or plan of 
ocular surgery (including ocular laser surgery) during the course of the study.  
18. Prior invasive therapy for presbyopia (e.g., ciliary body electrostimulation, corneal 
implants). 
 Prior medical therapy for Presbyopia (e.g., supplements, miotic medications, 
training exercises) within 30 days of Visit 1 (Screening) 
 Subjects with prior non-surgical optical correction (e.g., corrective eyeglasses) are 
eligible for the study  
Concomitant Medications: 
19. 
 
 
 
20. 
 
21. 
 
 
22. 
 
 
 


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Non-Ocular Conditions: 
23.
t 
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
Reference Therapy, Dosage and Mode of Administration:  
Subjects will be randomly assigned 2:2:1 ratio to one of three treatment arms to receive either: 
0.1% STN1013600 ophthalmic solution BID (08:00 & 20:00 ± 60 min), 0.3% STN1013600 
ophthalmic solution BID (08:00 & 20:00 ± 60 min), or placebo (vehicle) BID (08:00 & 20:00 
± 60 min) as described below: 
Investigational Product: 
0.1% STN1013600 ophthalmic solution contains 0.1% STN1013600. 
 


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0.3% STN1013600 ophthalmic solution contains 0.3% STN1013600. 
 
Vehicle: 
The vehicle is identical to the investigational product but does not contain the active ingredient 
STN1013600. 
Route of Administration of Investigational Product: Topical ocular 
Statistical methods: 
 
 
 
 
 
 
 
 
 
 
An interim analysis may be performed when the first 40 subjects complete Day 14 Visit. There 
are two goals for this interim analysis: (1) to assess for futility and (2) to assess for efficacy. 
More details on the interim analysis plan will be provided in the SAP. 
 


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1.2. 
Schema 
Figure 1: 
Study Design Schema 
 
 
 
 


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1.3. 
Schedule of Assessments (SoA) 
Table 2: 
Schedule of Assessments 
  
Treatment Period 
Follow Up 
Without 
Treatment 
  
Study Procedures 
Visit 1 / 
Screening 
Up to 15 days 
Before Day 1 
Visit 2 
Baseline / 
Day 1 
Visit 3  
Day 7  
+ 2 Days 
Visit 4  
Day 14     
 + 2 Days 
Visit 5 
Month 1 
+ 3 Days 
Visit 6 
Month 2 
+ 3 Days 
Visit 7 Month 3 
+ 3 Days/ 
Early 
Discontinuation 
Informed consenta 
X 
 
Inclusion and Exclusion criteria 
X 
X 
 
 
 
 
 
 
b 
 
 
 
 
 
 
 
b 
 
 
Demographic information 
X 
 
 
 
 
 
 
Ocular and systemic medical history 
X 
 
Vital Signs (Blood Pressure, Heart Rate, 
Temperature) 
X 
X 
X 
X 
X 
X 
X 
Height and weight 
 
X 
 
Previous and current concomitant  
ocular and systemic medications  
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Distance Corrected Near Visual Acuity Test 
(40 cm)d 
X 
X 
X 
X 
X 
X 
X 
d 
 


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Table 2: 
Schedule of Assessments (Continued) 
  
Treatment Period 
Follow Up 
Without 
Treatment 
  
Study Procedures 
Visit 1 / 
Screening 
Up to 15 Days 
Before Day 1 
Visit 2 
Baseline / 
Day 1 
Visit 3  
Day 7  
+ 2 Days 
Visit 4  
Day 14     
 + 2 Days 
Visit 5 
Month 1 
+ 3 Days 
Visit 6 
Month 2 
+ 3 Days 
Visit 7 Month 3 
+ 3 Days/ 
Early 
Discontinuation 
Best Corrected Distance Visual Acuity Test 
(4m)d 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Slit lamp biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
Pupil size 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intraocular Pressure (IOP) 
X 
X 
X 
X 
X 
X 
X 
Ophthalmoscopy  
X g 
X 
X 
X 
X 
X 
X g 
Patient global rating of treatment 
 
X 
Post-Study Clinical Trial Experience 
Survey 
 
 
 
 
 
 
X 
Urine pregnancy test (women of 
childbearing potential only)h 
X 
 
X 
X 
Blood Chemistry and Hematology (CBC, 
CMP) 
X 
 
 
 
X 
X 
 
Hemoglobin A1c 
X 
 
 
 
 
 
 


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Table 2: 
Schedule of Assessments (Continued) 
  
Treatment Period 
Follow Up 
Without 
Treatment 
  
Study Procedures 
Visit 1 / 
Screening 
Up to 15 Days 
Before Day 1 
Visit 2 
Baseline / 
Day 1 
Visit 3  
Day 7  
+ 2 days 
Visit 4  
Day 14     
 + 2 days 
Visit 5 
Month 1 
+ 3 days 
Visit 6 
Month 2 
+ 3 days 
Visit 7 Month 3 
+ 3 Days/ 
Early 
Discontinuation 
Urinalysis  
X 
 
X 
X 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
a
h Urine pregnancy test (women of childbearing potential only) may be repeated at each visit as per request of IRB/IECs or at the 
Investigator’s discretion. 
i Only patients fulfilling eligibility criteria will be enrolled and receive the study medication. 
 


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2. 
INTRODUCTION 
2.1. 
Background 
Presbyopia refers to a condition in which the accommodative function of the eye gradually 
decreases with age, making it difficult to focus on close objects. Presbyopia is a common visual 
system condition in which the aging eye gradually develops impairment in the ability to focus on 
near and intermediate objects, starting around 40 years of age (Stokes et al., 2022). 
Santen is developing STN1013600 (DE-136), a formulation of Ursodeoxycholic Acid (UCDA) 
as an ophthalmic solution for the treatment of presbyopia. This study is being conducted to 
evaluate the safety and efficacy of STN1013600 ophthalmic solution in subjects with presbyopia. 
This Phase IIa study 1013600IN (OPSIS) will evaluate the efficacy and safety of ophthalmic 
solution of DE-136 0.1% and 0.3% administered BID for the treatment of Presbyopia. 
 
 
 
 
  
2.2. 
Study Rationale 
In 2015, an estimated 1.1–1.8 billion people worldwide were impacted by presbyopia, and the 
number is predicted to reach 2.1 billion by 2030 (Stokes et al., 2022). Until recently the 
treatment and management options for presbyopia were either optical techniques, e.g., spectacles 
and contact lenses, or surgical interventions, e.g., laser in-situ keratomileusis (Presby LASIK), 
corneal inlay, and multi-focal intraocular lenses. However, these options have disadvantages, 
including reduced visual quality at one or more distances (Charman, 2014) and the risks 
associated with surgical intervention. Hence, there is an unmet need for a noninvasive treatment 
that is effective in restoring accommodative function and providing good vision at all distances 
(Grzybowski et al., 2020).  
Pharmacological treatment for presbyopia has the potential to address this unmet need. Two 
different classes of drugs have been investigated for this purpose. The recent approval in 2021 of 
VUITY® (pilocarpine hydrochloride ophthalmic solution) represents the first in this class of 
miotics. These drugs increase the depth of focus by decreasing pupil size, creating a pinhole 
effect. 
The long-term outcome on efficacy, safety, and acceptance of VUITY as a standard of care 
remains to be evaluated. 
The other class of drugs in development for presbyopia postulates that lens stiffening and loss of 
flexibility result in decreased distortion of the lens during accommodation. Although various 
factors may contribute to the lowering of accommodative function, sclerosis of the lens via 
oxidation-induced disulfide bonds between the crystalline lens protein seems to be a significant 
factor (Rowen, 2020, Wolffsohn et al., 2019). Garner et al. found that the antioxidant lipoic acid, 
reduced disulfide bonds in lens proteins of aged mice and increased lens elasticity in a 


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concentration-dependent manner. Further, synthesized choline esters were shown to improve the 
translocation of lipoic acid to the aqueous humor for a more efficient effect (Garner et al., 2016).  
 
 
 
 
 
 
 
 
 
2.3. 
Benefit/Risk Assessment 
Risks associated with participation in this study are considered to be minimal. 
 
 
 
  
 
  
 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 3: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Efficacy Objective: 
To assess the efficacy of two concentrations 
of STN1013600 ophthalmic solution (0.1% 
and 0.3%) twice daily dosing when compared 
to Placebo in subjects aged from 47 to 55 
years with presbyopia. 
Primary Efficacy Endpoint: 
 Mean change from baseline in 
Binocular DCNVA at Month 2 
Secondary Efficacy Objective: 
To assess the dose response of STN1013600 
ophthalmic solution. 
Secondary Efficacy Endpoints: 
 Mean change from baseline in Study 
Eye DCNVA at all visits 
 Mean change from baseline in 
Binocular DCNVA at all visits 
 Proportion of subjects who improve 
1/2/3-lines or more in Study Eye and 
Binocular DCNVA at each visit   
 Mean change from baseline in quality 
of life assessed with Near Activity 
Visual Questionnaire (NAVQ) at 
Month 2 and Month 3 
 Subject treatment satisfaction as 
assessed by Patient Global Rating of 
Treatment at Month 2 
 


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Table 3: 
Objectives and Endpoints (Continued) 
Objectives 
Endpoints 
Safety Objective: 
To assess the safety of two concentrations of 
STN1013600 ophthalmic solution (0.1% and 
0.3%) twice daily dosing when compared to 
Placebo in subjects aged from 47 to 55 years 
with presbyopia. 
Safety Endpoint: 
Safety of STN1013600 will be assessed by 
adverse events (AEs), Intra-ocular Pressure 
(IOP), slit-lamp bio-microscopy, 
ophthalmoscopy, and laboratory tests (serum 
chemistry, hematology, and urinalysis). 
 
 
 
 
 
 
 
 
 
 
 
 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a Phase IIa, randomized, double-masked, placebo-controlled, parallel-group study 
assessing the efficacy and safety of STN1013600 ophthalmic solution (0.1% and 0.3%) in 
subjects with Presbyopia. 
Approximately 75 subjects who meet all eligibility criteria at Visit 1 (Screening) will be 
randomized at Visit 2 (Baseline) in a 2:2:1 ratio to one of the following three treatment arms:  
 0.1% STN1013600 ophthalmic solution BID (08:00 & 20:00 ± 60 min) 
 0.3% STN1013600 ophthalmic solution BID (08:00 & 20:00 ± 60 min) 
 Placebo (vehicle) BID (08:00 & 20:00 ± 60 min) 
 
If both eyes of a subject qualify for the study, then the eye with the worse DCNVA will be 
determined as the study eye. If DCNVA in both qualifying eyes is the same, then the right eye 
should be designated as the study eye. 


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Subjects will be treated for 2 months, followed by 1 month safety follow-up without treatment. 
The total duration of participation for each subject is expected to be approximately 15 weeks. 
4.2. 
Scientific Rationale for Study Design 
The purpose of this phase IIa study is to evaluate the safety and efficacy of 2 doses of 
STN1013600 in subjects with presbyopia. The randomized, placebo-controlled, parallel-group 
study design is standard for the demonstration of efficacy and safety in multiple-arm clinical 
trials. The study is randomized and double masked to minimize bias and to reduce the risk of a 
placebo effect. 
 
4.3. 
Justification for Dose 
 
 
 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including Month 3 Visit.  
The end of the study is defined as the date of the last visit of the last participant in the study.  
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. 
 
2. Phakic presbyopic subjects, Male or Female between 47 and 55 years of age  
3. Distance-corrected near visual acuity (DCNVA) for each eye, as well as for binocular 
vision, 70 EDTRS letters or worse (equivalent to 0.3 logMAR or worse; or 20/40 Snellen 
or worse) at 40 cm. To be reconfirmed at Visit 2 (Baseline). 
4. Best-corrected distance visual acuity (BCDVA) for each eye of 85 ETDRS letters or 
better (equivalent to 0.00 logMAR or better; or 20/20 Snellen or better) at 4 m. To be 
reconfirmed at Visit 2 (Baseline). 
5. 
 


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6. 
 
 
7. 
 
 
8. 
 
 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Ocular Conditions 
1. 
 
 
2. 
 
3. 
 
 
4. 
 
5. 
 
6. 
 
7. 
.  
8. 
 


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9. 
 
10. 
 
11. 
 
 
 
 
  
 
 
   
12. 
 
13. 
 
14. 
  
15. 
 
 
16. Secondary cause of presbyopia in either eye as assessed by investigator (e.g., damage to 
lens, zonules or ciliary muscle, multiple sclerosis, cardiovascular accidents, vascular 
insufficiency, myasthenia gravis, anemia, influenza, measles). 
17. Any history of ocular surgery (including ocular laser surgery) in either eye or plan of 
ocular surgery (including ocular laser surgery) during the course of the study.  
18. Prior invasive therapy for presbyopia (e.g., ciliary body electrostimulation, corneal 
implants). 
 Prior medical therapy for Presbyopia (e.g., supplements, miotic medications, training 
exercises) within 30 days of Visit 1 (Screening) 
 Subjects with prior non-surgical optical correction (e.g., corrective eyeglasses) are 
eligible for the study  
 
19. 
 
 
 
20. 
 
21. 
 


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22. 
 
 
 
 
23. 
 
  
24. 
 
 
25. 
 
 
26. 
 
27. 
 
 
  
28. 
 
29. 
 
30. 
 
31. 
 
 
32. 
 
33. 
 
 
 
5.3. 
Contraception Requirements 
 


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5.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomly assigned to a study medication/entered in the study. 
 
 
6. 
STUDY INTERVENTION 
6.1. 
Study Medications Administered 
Table 4: 
Descriptions of Study Medications 
ARM Name 
STN1013600, 0.3% 
STN1013600, 0.1% 
Placebo 
Intervention 
Name 
STN1013600 
STN1013600 
Placebo 
Type  
Drug 
Drug 
Drug 
Dose Formulation 
Ophthalmic Solution 
Ophthalmic Solution 
Ophthalmic Solution 
Unit Dose 
Strength(s) 
0.3% 
0.1% 
Not Applicable 
Dosage Level(s) 
One drop, BID, both 
eyes throughout the 
2-month Treatment 
Period 
One drop, BID, both 
eyes throughout the 
2-month Treatment 
Period 
One drop, BID, both 
eyes throughout the 
2-month Treatment 
Period 
Route of 
Administration 
Topical ocular 
Topical ocular 
Topical ocular 
Use 
Experimental 
Experimental 
Placebo- comparator 
IMP and NIMP 
IMP 
IMP 
IMP 


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Table 4: 
Descriptions of Study Medications (Continued) 
ARM Name 
STN1013600, 0.3% 
STN1013600, 0.1% 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2. 
Preparation/Handling/Storage/Accountability 
6.2.1. 
Study Medication Storage 
 
 
 
 
 
 
 
6.2.2. 
Study Medication Administration 
During the Double-Masked Treatment Period, subjects will instill one drop of study medication 
in each eye at approximately 08:00 + 60 min and 20:00 + 60 min daily from Visit 2 (Baseline) to 
Visit 6 (Month 2). 
 
 
6.2.3. 
Study Medication Accountability 
The Principal Investigator is responsible for ensuring that an inventory is conducted upon receipt 
of the clinical supplies. 
 


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6.2.4. 
Study Medication Handling and Disposal 
 
 
6.3. 
Measures to Minimize Bias: Randomization and Masking 
 
 
 
This is a double-masked study. 
 
 
 
 
 
 
 
 


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6.4. 
Study Intervention Compliance 
To obtain reliable efficacy and safety data, the following precautions will be taken to ensure 
compliance with the study medication during the study: 
 Subjects will receive verbal and written instructions for proper instillation of the 
study medication, the dosing regimen, and the conditions of the study medication 
storage. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 Subjects may be discontinued from the study at the discretion of the investigator if the 
subject cannot be brought into compliance. 
 
A record of the number of kit cartons dispensed to and taken by each subject must be maintained 
and reconciled with study medication and compliance records. Medication start and stop dates, 
including dates for medication delays and/or dose reductions will also be recorded on the CRF. 
6.5. 
Concomitant Therapy 
Medication or therapy considered necessary for the subject’s welfare may be given at the 
discretion of the Investigator. Subjects may continue participation in the study if the instituted 
medication or therapy will not interfere with the evaluation of the study medication. Whenever 
possible, medications should be administered in dosages that remain constant throughout the 
study. Any treatment other than the study medication during the study duration will be 
considered as a concomitant treatment. The information of concomitant treatment must be 
recorded in the subject’s source documents and on the eCRF.  
 Concomitant medication: name of medication, route of administration, treated eye(s) 
(if applicable), dose, frequency, indication, start date, and stop date. 


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 Concomitant therapy: name of therapy, treated eye(s) (if applicable), indication, start 
date, and stop date. 
 
6.5.1. 
Collection of Prior and Concomitant Medication Information 
At Screening, information on prior and concomitant medications taken within the previous  
90 days will be collected and to satisfy assessment of study Inclusion and Exclusion Criteria. At 
each study visit, subjects should be questioned concerning any new medications or changes in 
their current medications since their previous study visit and the information should be recorded 
in the eCRF. For all medications, the generic name, indication, route of administration, 
frequency, dose, start date, and stop date (if applicable) will be collected; for combination 
products, the brand name will also be documented. 
6.5.2. 
Prohibited Medications or Therapies 
 
 
 
 
  
 
 
 
 
 
 
 Any history of ocular surgery (including ocular laser surgery) in either eye or plan of 
ocular surgery (including ocular laser surgery) during the course of the study.  
 Prior invasive therapy for presbyopia (e.g., ciliary body electrostimulation, corneal 
implants). 
 Prior medical therapy for Presbyopia (e.g., supplements, miotic medications, 
training exercises) within 30 days of Visit 1 (Screening) 
 Subjects with prior non-surgical optical correction (e.g., corrective eyeglasses) are 
eligible for the study  
 Subjects with any history or current use of contact lenses, or plan of use during course 
of study 
 Current or planned participation in any other clinical study involving an 
investigational product or device within 4 weeks prior to Visit 1 or at any time during 
this study. 
 


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6.6. 
Rescue Medicine 
Not applicable. There are no alternative standard medicinal therapies for the condition being 
treated.  
6.7. 
Dose Modification 
Dose modifications are not allowed in this study. 
6.8. 
Intervention after the End of the Study 
No subsequent intervention is planned for subjects after completing the study. Standard of care 
will resume at the investigator’s discretion.  
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is definitively discontinued, study assessments should be 
completed per SoA including Exit Visit. All efforts should be made to complete an early 
discontinuation exit visit. If study medication is definitively discontinued and the subject has an 
AE related to study medication, he/she will remain in the study to be evaluated until the 
resolution of the AE. See the SoA for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed. 
Discontinuation of study intervention for any safety concern should be considered if the 
investigator believes that it is in best interest of the participant. 
If a clinically significant finding is identified (including, but not limited to clinically significant 
changes from baseline in any laboratory evaluation) after enrollment, the investigator or 
qualified designee will determine if the participant can continue in the study and if any change in 
participant management is needed. Any new clinically relevant finding should be reported as an 
AE. 
7.1.1. 
Temporary Discontinuation 
Temporary discontinuation of study medication is not applicable in this study. 
7.1.2. 
Rechallenge 
Not applicable to this study. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
 A participant may withdraw from the study at any time at his/her own request or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 


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 At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need 
to be completed. 
 The participant will be permanently discontinued both from the study intervention 
and from the study at that time. 
 If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
 If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 
 
7.3. 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
 Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
 
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Visit Details 
 Study procedures and their timing are summarized in the SoA (Table 2). Protocol 
waivers or exemptions are not allowed. 


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 Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
 Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
 Procedures conducted as part of the participant’s routine clinical management  
(e.g., blood count) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 The primary efficacy analysis will be assessed at the 2 Month visit.  
8.1.1. 
Visit 1 (Screening) 
 Explain the purpose and conduct of the study to the subject and obtain written 
individual informed consent. Informed consent for the optional BOSS™ testing must 
be obtained prior to lens elasticity measurement at Visit 1 (Screening). Ensure the 
subject understands that if he/she does not wish to participate in BOSS™ testing that 
their decision will have no influence on their participation in the main study. BOSS™ 
testing is only available at a subset of clinical sites. 


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 Prepare the list of screening/registration of subjects. 
 
 
 Obtain demographics. 
 Obtain medications, procedures/therapies, and medical and surgical history including 
all lifetime ocular medical history to the extent possible, non-ocular medical history 
within 10 years, diagnosis, ocular surgical history, current ocular, and systemic 
conditions. 
 Measure vital signs 
 Measure height and weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Obtain urine and perform a urine pregnancy test, if the subject is a female of  
child-bearing potential. 
 Instruct subject to complete clinical lab collection (urinalysis, hematology, chemistry 
and HbA1c). Results of clinical lab must be received and reviewed prior to Visit 2 
(Baseline). 
 Assess for adverse events (occurring after the signing of the informed consent) 
 Assess eligibility of subject by reviewing the inclusion and exclusion criteria. A 
subject who does not meet eligibility criteria or will not otherwise continue in the 
study is considered a screen failure. 
 Enter the subject information into the EDC system for Visit 1 (Screening) to obtain 
the subject ID 
 


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8.1.2. 
Visit 2 (Baseline, Day 1) 
 
 
 Measure vital signs 
 Update concomitant medications and procedures/therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Measure pupil size 
 Measure Intraocular Pressure 
 
 
 Assess for adverse events 
 Perform final review of eligibility criteria. If all eligibility criteria, the subject will 
then be randomized, via IRT. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.3. 
Double-Masked Treatment Period, Visit 3 (Day 7) 
 Measure vital signs 
 Update concomitant medications and procedures/therapies 


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 
 
 
 
 
 
 
 
 
 
 
 
 
 Perform slit-lamp Biomicroscopy 
 Measure pupil size 
 Measure Intraocular Pressure 
 
 
 Assess for adverse events 
 
 
 
8.1.4. 
Double-Masked Treatment Period, Visit 4 (Day 14) 
 Measure vital signs 
 Update concomitant medications and procedures/therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Perform slit-lamp Biomicroscopy 
 Measure pupil size 
 Measure Intraocular Pressure 
 
 
 Assess for adverse events 
 
 
 
 


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8.1.5. 
Double-Masked Treatment Period, Visit 5 (Month 1) 
 Measure vital signs 
 Update concomitant medications and procedures/therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Perform slit-lamp Biomicroscopy 
 Measure pupil size 
 Measure Intraocular Pressure 
 
 
 Instruct subject to complete clinical lab collection (urinalysis, hematology, and 
chemistry analysis). 
 Assess for adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.6. 
Double-Masked Treatment Period, Visit 6 (Month 2) 
 
 
 Measure vital signs 
 Update concomitant medications and procedures/therapies 
 
 


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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Perform slit-lamp Biomicroscopy 
 Measure pupil size 
 Measure Intraocular Pressure 
 
 
 
 
 Obtain urine and perform a urine pregnancy test if the subject is a female of  
child-bearing potential. 
 Instruct subject to complete clinical lab collection (urinalysis, hematology, and 
chemistry analysis).  
 Assess for adverse events 
 
 
 
 
 
 
 
8.1.7. 
Double-Masked Treatment-free Period, Visit 7 (Month 3), Exit/Early 
Termination 
 
 
 Measure vital signs 
 Update concomitant medications and procedures/therapies 
 
 
 
 
 
 
 
 
 
 


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 
 
 
 
 
 Perform slit-lamp Biomicroscopy 
 Measure pupil size 
 Measure Intraocular Pressure 
 
 
 
 
 Obtain urine and perform a urine pregnancy test if the subject is a female of  
child-bearing potential. 
 Assess for adverse events 
 Exit the subject from the study.  
 
NOTE: 
If the study medication administration is discontinued, then to the extent possible, all procedures 
for Study Exit/Early Termination as per SoA (Table 2) will be performed on the day of early 
termination. Subjects who are discontinued from the study early will not be replaced. 
8.1.8. 
Unscheduled Visits 
If subject requires an unscheduled visit, procedures and assessments will be performed as 
needed.  
8.2. 
Safety Assessments 
8.2.1. 
Vital Signs 
 Blood pressure and heart rate measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. 
 Blood pressure and heart rate measurements should be preceded by at least 5 minutes 
of rest in a seated position and in a quiet setting without distractions (e.g., television, 
cell phones).  
 Temperature will be collected as per site’s standard of care. 
 
8.2.2. 
Clinical Safety Laboratory Assessments 
 See Section 10.2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.  


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 The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant’s condition. 
 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 1 month after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. 
 If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified, and the sponsor 
notified. 
 All protocol-required laboratory assessments, as defined in Section 10.2, must be 
conducted in accordance with the laboratory manual and the SoA.  
 If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (e.g., SAE 
or AE or dose modification), then the results must be recorded in the CRF. 
 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 10.3. 
AEs will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study medication. 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from the signing of the Informed Consent Form (ICF) until subject 
withdrawal or the scheduled exit visit. (Note: Although AEs will be monitored for and collected 
prior to IP administration, the statistical data analysis will determine and summarize treatment-
emergent AEs, i.e., those AEs that began or worsened in severity after the first IP 
administration.) 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 10.3. The investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time after 


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a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the investigator must promptly notify the 
sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and AEs of special interest (as defined in  Section 10.3), 
will be followed until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up (as defined in Section 10.3). Further information on follow-up procedures is 
provided in Section 10.3. 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
 Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met. 
 The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
 For all studies investigator safety reports must be prepared for suspected unexpected 
serious adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary. 
 An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
 
8.3.5. 
Pregnancy Testing, Monitoring, and Reporting 
8.3.5.1. 
Pregnancy Testing 
If the subject is a woman of child-bearing potential urine samples will be collected for pregnancy 
tests at screening and prior to IP administrations as specified in the SoA (Table 2). Samples will 
be analyzed at the site with results available prior to administration of IP. 


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8.3.5.2. 
Pregnancy Monitoring and Reporting Procedures 
Pregnancy in female subjects and female partners of male subjects will be monitored starting 
from screening through the End of study duration/Exit/Early Termination visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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8.3.6. 
Adverse Events of Special Interest  
 
 
 
 
 
 
 
 
 
 
 
8.4. 
Treatment of Overdose 
The intervention in this study is a topical ophthalmic solution. Overdose of study medication is 
not anticipated. In case of any concerns regarding potential overdose, the Medical Monitor 
should be consulted. 
8.5. 
Pharmacokinetics 
Not applicable. 
8.6. 
Pharmacodynamics 
Not applicable. 
8.7. 
Genetics 
Not applicable. 
8.8. 
Biomarkers 
Not applicable. 
8.9. 
Immunogenicity Assessments 
Not applicable. 


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8.10. 
Health Economics/Medical Resource Utilization  
Not applicable. 
9. 
STATISTICAL CONSIDERATIONS 
This section outlines the topics related to the statistical methods used in the design and analysis 
of the study. A more detailed description of all the analyses and methods is provided in the 
statistical analysis plan (SAP). 
 
9.1. 
Statistical Hypotheses 
The primary endpoint is change from baseline in binocular distance-corrected near visual acuity 
(DCNVA) at Month 2. 
 
 
 
 
 
 
 
 
9.2. 
Sample Size Determination 
 
 Based on the feasibility of conducting the trial, a total of approximately 75 subjects 
will be randomized into a 2:2:1 ratio to 0.1% STN1013600, 0.3% STN1013600, and placebo 
arms. That is, an approximately 30 subjects and 15 subjects will be randomized into each of 
STN1013600 treatment arms and placebo arm, respectively. 
 
 
 
 
 
 


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9.3. 
Populations for Analyses 
9.3.1. 
Safety Population 
The Safety Population will include all randomized subjects who received at least one dose of the 
study medication. 
 
9.3.2. 
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized subjects who received at least one dose 
of study medications and provided at least one post-baseline efficacy measurement. 
 
 
9.3.3. 
Per-Protocol Set 
Then Per-Protocol Set (PPS) is a subset of the FAS, restricted to the subjects who fulfill the 
protocol in terms of the eligibility, medications, and outcome measurement. 
 
 
9.4. 
Statistical Analyses 
The statistical analysis plan will be finalized prior to database lock, and it will include a more 
technical and detailed description of the statistical analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints including 
primary and key secondary endpoints. 
9.4.1. 
General Considerations 
 
 
 
9.4.2. 
Handling of Missing Values 
 
 
 


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 For medical events including AEs and medical history, completely or partially missing onset 
and resolution dates will be imputed in a conservative fashion to be detailed in the SAP. Similar 
rules will be followed to impute the completely or partially missing start and end dates of non-
study medications. 
 
 
9.4.3. 
Primary Endpoint 
The primary efficacy endpoint is change from baseline in binocular DCNVA at Month 2.
 
 
 
  
 
 
 
  
 
9.4.4. 
Secondary Endpoints 
 
 
 
Subgroup analyses may be performed for primary and secondary endpoints using descriptive 
statistics. 
9.4.5. 
Exploratory Endpoints 
 
 
9.4.6. 
Safety Analyses 
 All safety outcome measures will be summarized descriptively for the Safety Population. The 
safety outcome measures include AEs and evaluation with slit-lamp biomicroscopy, 


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ophthalmoscopy, intraocular pressure (IOP), pupil size and laboratory tests (serum chemistry, 
hematology, and urinalysis). 
AEs will be coded using the latest version of MedDRA. Subjects with any AE(s) will be 
tabulated by system organ class (SOC) and preferred term specified in MedDRA dictionary. 
Similarly, subjects with any ocular and non-ocular AEs will be tabulated separately. AEs, ocular 
and non-ocular AEs will be summarized by relationship to treatment and maximum severity. In 
addition, SAEs, and discontinuations due to AEs will be summarized. 
Safety parameters listed in safety assessments Section 8.2 will be summarized using descriptive 
statistics by actual treatment received. Changes from baseline in these safety parameters will also 
be summarized by treatment. 
9.5. 
Interim Analyses  
An interim analysis may be performed when the first 40 subjects complete Day 14 Visit. 
 
 
 
9.6. 
Santen Steering Committee (SSC) 
An internal Santen steering committee (SSC) whose members will not be participating in the 
OPSIS study conduct will serve as an advisory board to the Santen management team. 
 
 
 The organization, responsibilities, and procedures of the SSC will be specified in a 
governing charter. 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
 This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
 Applicable ICH Good Clinical Practice (GCP) Guidelines. 
 Applicable laws and regulations. 


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 The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated.  
 Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.  
 The investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations. 
 
10.1.2. 
Obligations of Investigators 
The Principal Investigator must agree to the following obligations: 
 Obtain informed consent from every subject before the subject’s participation in any 
study-related activity and maintain records of consent as part of the study records. 
 Obtain approval from the IRB or IEC before involving any subject in any study-
related activity; submit verification of the approval to Santen; submit periodic 
progress reports (at least annually) and final report to IRB or IEC. 
 Conduct the study according to the protocol and applicable regulations and inform 
Santen of all deviations from the protocol. 
 Inform the IRB or IEC of all protocol amendments/modifications; send Santen a copy 
of the letter from the IRB or IEC approving the amendment/modification. 
 Report to Santen any AEs and report to the IRB or IEC any reportable AEs that occur 
in the course of the investigation. 
 Keep complete and accurate records of all clinical study data; maintain records of all 
materials submitted to the IRB or IEC and of all correspondence by the IRB or IEC 
regarding the study. 
 Make study records available for inspection by Santen and representatives of 
regulatory agencies and the IRB or IEC; keep records until notified by Santen that 
they may be destroyed.  
 Maintain proper control and documentation of all test and control articles. 


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 Submit to Santen and/or maintain the following: 
I. Before the beginning of the study provide to Santen: 
a. A signed Form FDA 1572, Statement of Investigator, if applicable. 
b. A signed Financial Disclosure Form. 
c. A current curriculum vitae (CV) if not submitted previously or if updated. 
d. CVs for all Sub-Investigators. 
e. A letter from the IRB or IEC indicating that the protocol was approved, 
including the name and address of the IRB or IEC. 
f. A copy of the consent form approved by the IRB or IEC. 
g. A list of current members of the IRB or IEC. 
h. A copy of the source data location list. 
i. A copy of delegation list/log. 
j. A copy of training log. 
 
II.  While the study is in progress: 
a. Acknowledgment of receipt of the test and control articles; documentation of 
disposition of all test and control articles. 
b. eCRFs for each subject enrolled in the study. 
c. Information regarding all deviations from the protocol. 
d. Information regarding all AEs occurring to a subject while enrolled in the 
study. 
e. Annual progress report (if study is on-going for more than one year). Letter 
from the IRB or IEC indicating approval of the annual progress report. 
 
III.  Upon completion of the study: 
a. Disposition of all used and/or unused test and control articles, as well as 
documentation of all and drug accountability. 
 
10.1.3. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.4. 
Informed Consent Process 
 The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
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 Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.  
 The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
 Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
 A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
 A subject who is rescreened is not required to sign another ICF if the rescreening 
occurs within 30 days from the previous ICF signature date.  
 The ICF will contain a separate section that addresses exploratory research. The 
investigator or authorized designee will explain to each participant the objectives of 
the exploratory research. Participants will be told that they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the 
study period. A separate signature will be required to document a participant's 
agreement to comply with procedures for exploratory research. Participants who 
decline to participate in this optional research will not provide this separate signature. 
 
10.1.5. 
Data Protection 
 Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred.  
 The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the informed consent  
 The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
 


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10.1.6. 
Committees Structure 
An SSC charter will be developed to document the structure, frequency of meetings and rules for 
this committee. 
10.1.7. 
Data Quality Assurance 
 All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (e.g., laboratory data). 
The investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF.  
 The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.  
 The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
 Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical  
Risk-Based Monitoring), methods, responsibilities, and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or  
on-site monitoring) are provided in the Monitoring Plan and contracts. 
 The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
 The sponsor assumes accountability for actions delegated to other individuals  
(e.g., Contract Research Organizations). 
 Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
 Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator until notified by Santen that the records 
may be destroyed. No records may be destroyed during the retention period without 
the written approval of Santen. No records may be transferred to another location or 
party without written notification to Santen. 
 
10.1.8. 
Source Documents 
The Principal Investigator must maintain detailed source documents on all study subjects who 
provide informed consent. Source documents provide evidence for the existence of the subject 
and substantiate the integrity of the data collected. Source documents include subject medical 
records, hospital charts, clinic charts, study files, as well as the results of diagnostic tests  
(e.g., laboratory tests). Source documents are filed at the investigator’s site. 


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The following minimum information should be entered into the subject’s medical record: 
 The date the subject entered the study and the subject number 
 The study protocol number and the name of Santen 
 The date that informed consent was obtained 
 Evidence that the subject meets study eligibility requirements (e.g., medical history, 
study procedures, and/or evaluations) 
 The dates of all study-related subject visits (scheduled and unscheduled) 
 Evidence that required procedures and/or evaluations were completed 
 Use of any concomitant medications 
 Documentation of study medication accountability 
 Occurrence and status of any AEs 
 The date the subject exited the study and a notation as to whether the subject 
completed or terminated early from the study, including the reason for early 
termination 
 If unmasking at the site occurred, proper documentation and notifications were made 
 
10.1.9. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
subjects. 
The first act of recruitment is the first site open and will be the study start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of subjects by the investigator 
 Discontinuation of further study medication development 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
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organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the subject and 
should assure appropriate subject therapy and/or follow-up. 
10.1.10. 
Publication Policy 
The existence of this clinical study is confidential, and it should not be discussed with persons 
outside of the study. 
 
 
 
 
 
In signing this protocol, the Principal Investigator agrees to the release of the data from this 
study and acknowledges the above publication policy. 
10.2. 
Appendix 2: Clinical Laboratory Tests 
 
 
 Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5 of the protocol. 
 Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
 Investigators must document their review of each laboratory safety report. 
 
Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria. 
 
 
 
 


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Table 5: 
Protocol-Required Safety Laboratory Assessments 
 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
Definition of AE 
AE Definition 
 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study intervention. 
Events Meeting the AE Definition  
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator (i.e., not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
AE or SAE if they fulfil the definition of an AE or SAE. Also, “lack of efficacy” or “failure of 
expected pharmacological action” also constitutes an AE or SAE. 
Events NOT Meeting the AE Definition  
 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which 
are associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s condition. 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 
 


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10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
1. Results in death 
2. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is 
not considered an AE. 
4. Results in persistent disability/incapacity 
 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
 
This definition is not intended to include experiences of relatively minor medical significance  
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
5. Is a congenital anomaly/birth defect 
6. Other situations: 
 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately  
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
 
10.3.3. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 


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AE and SAE Recording 
 
The investigator will then record all relevant AE/SAE information in the CRF. 
 
It is not acceptable for the investigator to send photocopies of the participant's medical records to 
Santen in lieu of completion of the AE/SAE CRF page. 
 
There may be instances when copies of medical records for certain cases are requested by Santen. 
In this case, all participant identifiers, with the exception of the participant number, will be 
redacted on the copies of the medical records before submission to Santen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the study 
and assign it to 1 of the following categories:  
 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort, and not 
interfering with everyday activities. 
 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should 
not be confused with a SAE. Severe is a category utilized for rating the intensity of an event; and 
both AEs and SAEs can be assessed as severe. 
 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study intervention administration will be 
considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for 
marketed products, in his/her assessment. 
 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to Santen. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial transmission 
of the SAE data to Santen. 
 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
 
The causality assessment is one of the criteria used when determining regulatory reporting 
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AE and SAE Recording 
Follow-up of AEs and SAEs 
 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by Santen to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
 
If a participant dies during participation in the study or during a recognized follow-up period, the 
investigator will provide Santen with a copy of any post-mortem findings including 
histopathology  
 
New or updated information will be recorded in the originally completed CRF. 
 
The investigator will submit any updated SAE data to Santen within 24 hours of receipt of the 
information. 
10.3.4. 
Reporting of SAEs 
SAE Reporting to Santen via an Electronic Data Collection Tool 
 
The primary mechanism for reporting an SAE to Santen will be the electronic data collection 
tool. 
 
If the electronic system is unavailable, then the site will use the paper SAE data collection tool 
(see next section) in order to report the event within 24 hours. 
 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
 
After the study is completed at a given site, the electronic data collection tool will be taken off-
line to prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then the 
site can report this information on a paper SAE form (see next section) or to the Santen Safety 
Team by telephone. 
 
Contacts for SAE reporting can be found in Table 1. 
SAE Reporting to Santen via Paper CRF (If Electronic Data Collection Tool is Unavailable) 
 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Santen Safety Team. 
 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier service. 
 
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE CRF pages within the designated reporting time frames. 
Contacts for SAE reporting can be found in Table 1. 
10.4. 
Procedures for Assessments 
10.4.1. 
Symptom Assessment iN Dry Eye Questionnaire (SANDE) 
 
 


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10.4.2. 
Near Activity Visual Questionnaire 
 
 
10.4.3. 
Objective Refraction 
 
 
 
10.4.4. 
Subjective Refraction (Manifest Refraction) 
 
 
10.4.5. 
Distance Corrected Near Visual Acuity (DCNVA) 
The distance corrected near visual acuity (DCNVA) will be measured in right eye, left eye and 
both eyes at all visits using the distance manifest refraction.  The total number of letters at 40 cm 
will be recorded. Refer to Visual Acuity Manual of Procedures for details of the visual acuity 
assessments. 
10.4.6. 
Distance Corrected Intermediate Visual Acuity (DCIVA) 
 
10.4.7. 
Best Corrected Distance Visual Acuity Testing (BCDVA) 
The best-corrected distance visual acuity (BCDVA) will be recorded for right eye, left eye and 
both eyes at all visits using ETDRS charts.  The total number of letters at 4 meters and 1 meter 
will be recorded. If a subject’s visual acuity is so poor that he/she cannot read any chart letters 
when tested at 1 meter, then the subject’s ability to count fingers, detect hand motion, or have 


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light perception should be evaluated. Refer to Visual Acuity Manual of Procedures for details of 
the visual acuity assessments. 
10.4.8. 
Subjective Accommodative Amplitude Testing (Defocus Curve Testing) 
 
10.4.9. 
Lens and Corneal Elasticity Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.4.10. 
Slit-Lamp Biomicroscopy  
Slit-lamp biomicroscopy examinations will be used to examine eye structures for both eyes 
during screening and at each follow-up study visit. Magnification will be consistent with 
standard clinical practice. The patient will be seated while being examined. Grading will be done 
using the following scales: 
The lid, conjunctiva, cornea, iris, and lens will be observed and graded on a 4-point scale  
(0-3 scale). Anterior chamber cells and flare will be observed and graded using the SUN scale 
(0-4 scale). 
 
Lid Hyperemia 
None 
(0) = Normal 
Mild 
(1) = Redness of most or all the lid(s) margin OR skin 
Moderate (2) = Redness of most or all the lid(s) margin AND skin 
Severe 
(3) =  Marked diffuse redness of both lid(s) margin AND skin 
 
Lid Edema 
None 
(0) = Normal 
Mild 
(1) = Localized to a small region of the lid(s) 
Moderate (2) = Diffuse, most or all the lid(s) but not  prominent/protruding 
Severe 
(3) = Diffuse, most or all the lid(s) AND prominent/protruding 
 
Conjunctival (Palpebral and Bulbar) Hyperemia 
None 
(0) = Normal 
Mild 
(1) = Slight localized injection 
Moderate (2) = Pink color, confined to palpebral OR bulbar conjunctiva 
Severe 
(3) = Red color of the palpebral AND/OR bulbar conjunctiva 
 
Conjunctival Chemosis 
None 
(0) = Normal 
Mild 
(1) = Slight localized swelling 
Moderate (2) = Mild/medium localized swelling or mild diffuse swelling 
Severe 
(3) = Moderate diffuse swelling 
 


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Corneal Edema 
None 
(0) = Normal 
Mild 
(1) = Mild, diffuse stromal haze 
Moderate (2) = Dense, diffuse stromal haze or bullae 
Severe 
(3) = Dense, diffuse bullae or stromal haze AND stromal edema 
 
Corneal Staining (with fluorescein) 
None 
(0) = Normal 
Mild 
(1) = Localized, occasional punctate staining 
Moderate (2) = Localized, dense OR diffuse occasional punctate staining 
Severe 
(3) = Diffuse, dense punctate staining which may be confluent staining 
 
Keratic Precipitate 
None 
(0) = Normal 
Mild 
(1) = Slight pigmentation or keratic precipitate 
Moderate (2) = Moderate pigmentation or keratic precipitate  
Severe 
(3) = Dense pigmentation or keratic precipitate 
 
Anterior Synechiae of Iris 
None 
(0) = No anterior synechiae of iris is found 
Mild 
(1) = <25% anterior synechiae of iris is found 
Moderate (2) = 25% to 50% anterior synechiae of iris is found 
Severe 
(3) = >50% anterior synechiae of iris is found 
 
Posterior Synechiae of Iris 
None 
(0) = No posterior synechiae of iris is found 
Mild 
(1) = <25% posterior synechiae of iris is found 
Moderate (2) = 25% to 50% posterior synechiae of iris is found 
Severe 
(3) = >50% posterior synechiae of iris is found 
 
 


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Lens 
The lens will be noted as phakic, aphakic, or pseudophakic. Phakic lens will be graded as 
described below: 
None 
(0) =  No lens discoloration nor opacification 
Mild 
(1) =  Yellow lens discoloration or small lens opacity (axial or peripheral) 
Moderate (2) =  Amber lens discoloration or medium lens opacity (axial or peripheral) 
Severe 
(3) =  Brunescent lens discoloration or complete lens opacification (no red reflex) 
 
Anterior Chamber Cells 
(0)  = 
 No cells 
(0.5) =  
1-5 cells 
(1)  =  
6-15 cells 
(2)  =  
16-25 cells 
(3)  =  
26-50 cells 
(4)  =  
>50 cells 
 
Anterior Chamber Flare 
(0)   =   None 
(1)   =   Faint 
(2)   =   Moderate (iris/lens details clear) 
(3)   =   Marked (iris/lens details hazy) 
(4)   =   Intense (fibrin/plastic aqueous) 
 
10.4.11. 
Pupil Measurement 
Pupil measurement will be performed with ambient lighting conditions (10-12 lux) with an 
automated device. The same device should be used for all visits on a subject. 
10.4.12. 
Tear Film Break Up Time (TFBUT)  
Tear break-up time (TBUT) will be measured by determining the time to tear break-up. The 
TBUT will be performed with fluorescein strips with sterile saline.  To thoroughly mix the 
fluorescein with the tear film, the patient will be instructed to blink several times. In order to 
achieve maximum fluorescence, the examiner should wait approximately 30 seconds after 
instillation before evaluating TBUT. With the aid of a slit lamp using cobalt blue illumination, 
the examiner will monitor the integrity of the tear film, noting the time it takes to form lacunae 


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(clear spaces in the tear film) from the time that the eye is opened after the last blink. The TBUT 
will be measured twice during the first minute after the instillation of the fluorescein. If the  
2 readings differ by more than 2 seconds, then a third reading will be taken. 
The TBUT value will be the average of the 2 or 3 measurements. 
10.4.13. 
Corneal Fluorescein Staining (CFS) Assessment with Oxford Scale 
 
 
 
 
 
10.4.14. 
Intraocular Pressure (IOP) 
Intraocular Pressure (IOP) will be measured using a Goldmann Applanation Tonometer during 
screening and at each follow-up study visit.  The investigator’s standard technique will be used 
throughout the study.  
 


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All tonometers must be calibrated according to manufacturer’s instructions. 
10.4.15. 
Ophthalmoscopy 
 
 
 
 
 
 
Health of the optic nerve with cup to disc ratio and abnormality in retina, macula, choroid, and 
vitreous will also be evaluated across all visits.  
10.4.16. 
Cycloplegic Refraction 
 
 
 
 
10.4.17. 
Patient Global Rating of Treatment 
 
 
 
 
 
 
 
 


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10.4.18. 
Post-Study Clinical Trial Experience Survey  
 
 


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10.4.19. 
Vital Signs 
Vital signs consist of blood pressure, heart rate and temperature and will be collected at all visits.  
Blood pressure should be measured only after the subject has been in a sitting position for at 
least 5 minutes and will be recorded in millimeters of mercury (mmHg). Measurement with an 
automated sphygmomanometer is acceptable. Heart rate should be measured only after the 
subject has been in a sitting position for at least 2 minutes and will be recorded in beats per 
minute (bpm).  Temperature will be collected as per site’s standard of care. 
10.5. 
Symptom Assessment iN Dry Eye Questionnaire (SANDE) 
 


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10.6. 
Near Activity Visual Questionnaire 
 
10.7. 
Appendix 9: Abbreviations 
Abbreviation or Term 
Definition/Explanation 
AE 
Adverse Events 
BCDVA  
Best Corrected Distance Visual Acuity 
BID  
Twice a Day 
BOSS/BOSS™ 
Brillouin Optical Scanner System  
CFS 
Corneal Fluorescein Staining  
COVID 
Coronavirus disease 
D 
Diopter 
DCIVA 
Distance corrected intermediate visual acuity  
DCNVA 
Distance corrected near visual acuity 
eCRF 
Electronic care report forms 
ESI  
Events of Special Interest 


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Appendix 9: Abbreviations (Continued) 
Abbreviation or Term 
Definition/Explanation 
ETDRS 
Early Treatment Diabetic Retinopathy Study  
FAS  
Full Analysis Set 
GCP  
Good Clinical Practice 
ICF  
Informed Consent Form 
ICH  
International Conference on Harmonization 
IEC  
Independent Ethics Committee 
IMP 
Investigational Medicinal Products 
IOP  
Intraocular Pressure 
IRB  
Institutional Review Board 
logMAR 
Logarithm of the Minimum Angle of Resolution 
IRT 
Interactive Response Technology  
NIMP 
Non-investigational Medicinal Products 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute 
mmHg 
millimeters of mercury  
MMRM 
Mixed-effects Model for Repeated Measures 
NAVQ 
Near Activity Visual Questionnaire  
OD 
Right Eye 
OS 
Left Eye 
OU 
Both Eyes 
SAE 
Serious Adverse Event 
SANDE 
Symptom Assessment iN Dry Eye Questionnaire  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TBUT 
Tear breakup test 
UCDA 
Ursodeoxycholic Acid 
10.8. 
Appendix 10: Protocol Amendment History 
Not applicable. This is the first version of the protocol. 


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11. 
REFERENCES 
1. 
Charman, W. N. (2014) Developments in the correction of presbyopia I: spectacle and 
contact lenses. Ophthalmic Physiol Opt.34(1):8-29. 
2. 
Garner, W. H., Garner, M. H. (2016) Protein Disulfide Levels and Lens Elasticity 
Modulation: Applications for Presbyopia. Invest Ophthalmol Vis Sci.57(6):2851-63. 
3. 
Grzybowski, A., Markeviciute, A., Zemaitiene, R. (2020) A Review of Pharmacological 
Presbyopia Treatment. Asia Pac J Ophthalmol (Phila).9(3):226-33. 
4. 
Korenfeld, M. S., Robertson, S. M., Stein, J. M., Evans, D. G., Rauchman, S. H., Sall, K. 
N., Venkataraman, S., Chen, B. L., Wuttke, M., Burns, W. (2021) Topical lipoic acid 
choline ester eye drop for improvement of near visual acuity in subjects with presbyopia: 
a safety and preliminary efficacy trial. Eye (Lond). 
5. 
Qi, H. P., Wei, S. Q., Gao, X. C., Yu, N. N., Hu, W. Z., Bi, S., Cui, H. (2012) 
Ursodeoxycholic acid prevents selenite-induced oxidative stress and alleviates cataract 
formation: In vitro and in vivo studies. Mol Vis.18:151-60. 
6. 
Rowen, S. (2020) Pharmacologic Solutions to Presbyopia. Cataract & Refractive Surgery 
Today. 
7. 
Stokes, J., Shirneshan, E., Graham, C. A., Paulich, M., Johnson, N. (2022) Exploring the 
Experience of Living with and Managing Presbyopia. Optom Vis Sci.99(8):635-44. 
8. 
Wolffsohn, J. S., Davies, L. N. (2019) Presbyopia: Effectiveness of correction strategies. 
Prog Retin Eye Res.68:124-43. 
 



SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:   
OPSIS: A Phase IIa, Randomized, Double-Masked, Placebo-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety of 
STN1013600 Ophthalmic Solution 0.1% and 0.3% Compared with Placebo 
in Subjects with Presbyopia 
 
 
 
NCT Number:  
NCT05665387  
 
Date of the document: 
 08 AUG 2023 
 
 
 


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STATISTICAL ANALYSIS PLAN 
OPSIS Study 
 
 
 
Protocol Title: 
OPSIS: A Phase IIa, Randomized, Double-Masked, Placebo-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety of 
STN1013600 Ophthalmic Solution 0.1% and 0.3% Compared with Placebo in 
Subjects with Presbyopia 
 
 
Product: 
STN1013600 Ursodiol Ophthalmic Solution  
 
 
Protocol Number:  
101360002IN 
 
 
Sponsor: 
Santen Inc. 
 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608 
USA. 
 
 
Date:  
August 08, 2023 
 
 
Status:  
Version 1.0 
 
CONFIDENTIAL 
 
The information in this document is considered privileged and confidential by Santen Inc. and 
may not be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by Federal and State Laws.  Persons to 
whom this information is disclosed must be informed that this information is privileged and 
confidential and that it should not be further disclosed. 
 
 
 


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TABLE OF CONTENTS 
ABBREVIATIONS .........................................................................................................................7 
1. 
INTRODUCTION ........................................................................................................9 
2. 
OBJECTIVES AND ENDPOINTS ..............................................................................9 
2.1. 
Objectives .....................................................................................................................9 
2.1.1. 
Primary Objectives .......................................................................................................9 
2.1.2. 
Secondary Objectives ...................................................................................................9 
2.1.3. 
Safety Objective ............................................................................................................9 
2.1.4. 
Exploratory Objective ...................................................................................................9 
2.2. 
Endpoints ......................................................................................................................9 
2.2.1. 
Primary Efficacy Endpoint ...........................................................................................9 
2.2.2. 
Secondary Efficacy Endpoints ....................................................................................10 
2.2.3. 
Safety Endpoints .........................................................................................................10 
2.2.4. 
Exploratory Endpoints ................................................................................................10 
3. 
STUDY DESIGN .......................................................................................................10 
3.1. 
General Study Design .................................................................................................10 
3.2. 
Randomization and Masking ......................................................................................12 
3.3. 
Sample Size Determination ........................................................................................12 
3.4. 
Visits and Assessments ...............................................................................................12 
4. 
TIME-RELATED TERMS .........................................................................................16 
4.1. 
Baseline Visit ..............................................................................................................16 
4.2. 
Treatment Period, Treatment Start Date, and Treatment End Date ............................16 
4.3. 
Study Day and Analysis Visit .....................................................................................16 
4.4. 
Analysis Visit and Analysis Window .........................................................................16 
4.5. 
Extent of Exposure .....................................................................................................17 
5. 
GENERAL CONSIDERATIONS ..............................................................................18 
5.1. 
Adjustments for Covariates ........................................................................................18 
5.2. 
Handling of Missing Data ...........................................................................................18 
5.2.1. 
Efficacy Measures ......................................................................................................18 
5.2.2. 
Safety Measures ..........................................................................................................19 
5.2.3. 
Dates for Medical Events and Medications ................................................................19 
5.3. 
Multi-Center Studies ...................................................................................................20 


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5.4. 
Multiple Comparisons / Multiplicity ..........................................................................20 
5.5. 
Interim Analysis ..........................................................................................................20 
6. 
STUDY POPULATION .............................................................................................20 
6.1. 
Safety Population ........................................................................................................20 
6.2. 
Full Analysis Set .........................................................................................................20 
6.3. 
Per-Protocol Set ..........................................................................................................20 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................21 
7.1. 
Subject Disposition .....................................................................................................21 
7.2. 
Demographics and Baseline Characteristics ...............................................................21 
7.3. 
Medical and Surgical History .....................................................................................21 
7.4. 
Protocol Deviations ....................................................................................................22 
7.5. 
Impact of the COVID-19 Pandemic ...........................................................................22 
7.6. 
Prior and Concomitant Medications ...........................................................................22 
7.7. 
Treatment Compliance ................................................................................................23 
7.8. 
Exposure to Study Medication ....................................................................................23 
8. 
EFFICACY ANALYSES ...........................................................................................24 
8.1. 
Efficacy-Related Definitions ......................................................................................24 
8.1.1. 
Study Eye and Fellow Eye ..........................................................................................24 
8.1.2. 
Baseline Score ............................................................................................................24 
8.1.3. 
Change and Percent Change from Baseline ................................................................24 
8.1.4. 
Efficacy Measures ......................................................................................................24 
8.1.5. 
Visual Acuity Response Endpoints ............................................................................25 
8.1.6. 
Treatment Satisfactory Response Endpoints ..............................................................26 
8.1.7. 
Refractive Status and Manifest Refraction Spherical Equivalent Endpoint ...............26 
8.1.8. 
Lens and Corneal Elasticity ........................................................................................26 
8.1.9. 
Subjective Accommodative Amplitude (Defocus curve) ...........................................26 
8.2. 
Analyses of Primary Endpoint ....................................................................................27 
8.2.1. 
Historical Control Data ...............................................................................................27 
8.2.2. 
Primary Analyses ........................................................................................................27 
8.2.3. 
Sensitivity Analyses ....................................................................................................28 
8.3. 
Analyses of Secondary Efficacy Endpoints ................................................................28 
8.3.1. 
Analyses of Continuous Secondary Endpoints ...........................................................28 
8.3.2. 
Analyses of Binary Secondary Endpoints ..................................................................29 


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8.4. 
Subgroup Analyses .....................................................................................................29 
8.5. 
Exploratory Analyses ..................................................................................................29 
9. 
SAFETY ANALYSES ...............................................................................................30 
9.1. 
Safety-Related Definitions ..........................................................................................30 
9.1.1. 
Adverse Event .............................................................................................................30 
9.1.2. 
Safety Measures ..........................................................................................................31 
9.2. 
Adverse Events ...........................................................................................................32 
9.3. 
Intraocular Pressure (IOP) ..........................................................................................32 
9.4. 
Pupil Measurement .....................................................................................................32 
9.5. 
Best Corrected Distance Visual Acuity (BCDVA) ....................................................33 
9.6. 
Slit-lamp Biomicroscopy ............................................................................................33 
9.7. 
Ophthalmoscopy .........................................................................................................33 
10. 
SUMMARY OF CHANGES TO THE PROTOCOL ................................................33 
10.1. 
Secondary and Exploratory Endpoints .......................................................................33 
10.1.1. 
Secondary efficacy endpoints .....................................................................................33 
10.1.2. 
Safety endpoints ..........................................................................................................33 
10.1.3. 
Exploratory endpoints .................................................................................................34 
10.2. 
Primary Analysis ........................................................................................................34 
11. 
REFERENCE .............................................................................................................34 
12. 
APPENDIX.................................................................................................................35 
12.1. 
Conversion Table for Near Activity Visual Questionnaire (NAVQ) .........................35 
12.2. 
Details for Historical Control Data Borrowing ..........................................................35 
 
LIST OF TABLES 
Table 1: 
Abbreviations ................................................................................................................7 
Table 2: 
Assessment Schedule ..................................................................................................13 
Table 3: 
Definitions for Period Start and End Dates by Study Period ......................................16 
Table 4: 
Analysis Visit and Analysis Window .........................................................................17 
Table 5: 
Efficacy Measures ......................................................................................................24 
Table 6: 
Safety Assessments .....................................................................................................31 
Table 7: 
Bayesian Type I Error (False Positive Rate) ..............................................................37 


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Table 8: 
Power Calculation of the Primary Analysis ................................................................38 
 
LIST OF FIGURES 
Figure 1: 
Study Design Diagram ................................................................................................11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ABBREVIATIONS 
Table 1: 
Abbreviations 
Abbreviation 
Explanation 
ADR 
Adverse Drug Reaction 
AE(s) 
Adverse Event(s) 
ATC 
Anatomical-Therapeutic-Chemical 
BCDVA 
Best-Corrected Distance Visual Acuity 
BID 
bis in die (twice a day) 
CI 
Confidence Interval 
CM 
Concomitant Medications 
CSR 
Clinical Study Report 
D 
Diopter 
DCNVA 
Distance Corrected Near Visual Acuity 
eCRF 
Electronic Case Report Form 
ESI(s) 
Event(s) of Special Interest 
ET 
Early Termination 
FAS 
Full Analysis Set 
IOP 
Intraocular Pressure 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Medical History 
mmHg 
Millimeter of Mercury 
MMRM 
Mixed-effect Model for Repeated Measures 
MRSE 
Manifest Refraction Spherical Equivalent 
NAVQ 
Near Activity Visual Questionnaire 
OD 
Oculus Dexter (right eye) 
OS 
Oculus Sinister (left eye) 
OU 
Oculus Uterque (both eyes) 
PPS 
Per-Protocol Set 
PT 
Preferred Term 
 


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Table 1: 
Abbreviations (Continued) 
Abbreviation 
Explanation 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
US 
United States 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the statistical methods to be implemented for the 
analysis of data collected from the OPSIS study within the scope of Santen’s Protocol 
101360002IN, “OPSIS: A Phase IIa, Randomized, Double-Masked, Placebo-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety of STN1013600 
Ophthalmic Solution 0.1% and 0.3% Compared with Placebo in Subjects with Presbyopia”. It 
applies to the study protocol version Original, dated 23 September 2022, and provides detailed 
instructions as to how each analysis will be performed. 
Results obtained from the analyses specified in the final approved version of the SAP will 
become the basis of the clinical study report (CSR) for this study. Any deviations from the final 
approved version of the SAP must be substantiated by sound statistical reasoning and 
documented in the CSR. 
2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives 
To assess the efficacy of two concentrations of STN1013600 ophthalmic solution (0.1% and 
0.3%) twice daily dosing when compared to Placebo in subjects aged from 47 to 55 years with 
presbyopia. 
2.1.2. 
Secondary Objectives 
To assess the dose response of STN1013600 ophthalmic solution. 
2.1.3. 
Safety Objective 
To assess the safety of two concentrations of STN1013600 ophthalmic solution (0.1% and 0.3%) 
twice daily dosing when compared to Placebo in subjects aged from 47 to 55 years with 
presbyopia. 
2.1.4. 
Exploratory Objective 
To explore other efficacy outcome measures of two concentrations of STN1013600 ophthalmic 
solution (0.1% and 0.3%) twice daily when compared to Placebo in subjects aged 47 to 55 years 
with presbyopia. 
2.2. 
Endpoints 
2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean change from baseline in Binocular Distance Corrected 
Near Visual Acuity (DCNVA) at Month 2. 


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2.2.2. 
Secondary Efficacy Endpoints 
 Mean change from baseline in Study Eye DCNVA at all visits 
 Mean change from baseline in Binocular DCNVA at all visits 
 Proportion of subjects who improve 1/2/3-lines or more in Study Eye and Binocular 
DCNVA at each visit without loss of more than 1 line (5 letters) in Best Corrected 
Distance Visual Acuity (BCDVA) 
 Mean change from baseline in quality of life assessed with Near Activity Visual 
Questionnaire (NAVQ) at Month 2 and Month 3  
 Subject treatment satisfaction as assessed by Patient Global Rating of Treatment at 
Month 2 
2.2.3. 
Safety Endpoints 
The safety of STN1013600 ophthalmic solution will be evaluated by adverse events (AEs), Intra-
ocular Pressure (IOP), slit-lamp bio-microscopy, ophthalmoscopy, and laboratory tests (serum 
chemistry, hematology, and urinalysis). 
2.2.4. 
Exploratory Endpoints 
3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is a Phase IIa, randomized, double-masked, placebo-controlled, parallel-group study 
assessing the efficacy and safety of STN1013600 ophthalmic solution (0.1% and 0.3%) in 
subjects with Presbyopia. 
Subjects with Presbyopia who meet all eligibility criteria at Visit 1 (Screening) will be 
randomized at Visit 2 (Baseline) to receive treatment for 2 months. 


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Approximately 75 subjects who meet all eligibility criteria at Visit 1 (Screening) will be 
randomized at Visit 2 (Baseline) in a 2:2:1 ratio to one of the following three treatment arms: 
 0.1% STN1013600 ophthalmic solution BID (08:00 & 20:00 ± 60 min) 
 0.3% STN1013600 ophthalmic solution BID (08:00 & 20:00 ± 60 min) 
 Placebo (Vehicle) BID (08:00 & 20:00 ± 60 min) 
Subjects will be treated for 2 months, followed by a 1-month safety follow-up without treatment 
(Figure 1). 
Figure 1: 
Study Design Diagram 
 
* On Day 1, subject should administer 1 dose of assigned medication after study visit at 20:00 ± 60 min. BID dosing 
starts from Day 2 through Month 2. 
 
This study will consist of a Screening Period of up to 15 days, followed by a 2-month Treatment 
Period and subsequently a 1-month Treatment-free follow-up Period.  
At Visit 1 (Screening), subjects will be screened against the inclusion and exclusion criteria and 
if subject meets all eligibility criteria, subjects will proceed to Visit 2 (Baseline). 
Per study design, subjects who qualify per eligibility criteria will be treated bilaterally (both 
eyes). 
The study eye will be the eye that qualifies with the worse DCNVA per eligibility criteria at 
Visit 2. If both eyes have the same DCNVA, the right eye will be designated as the study eye. 
Treatment Period (2 months): 
At Visit 2 (Baseline), approximately 75 eligible subjects will be randomized to receive either 
0.1% STN1013600 ophthalmic solution BID or 0.3% STN1013600 ophthalmic solution BID or 
Placebo BID in a 2:2:1 ratio. Subjects will be treated for 2 months with scheduled assessment 
visits at Visit 2 (Baseline), Visit 3 (Day 7), Visit 4 (Day 14), Visit 5 (Month 1), and Visit 6 
(Month 2). 
At Visit 2 (Baseline), subjects will administer their first dose of study medication (study eye 
drops) as per their assigned/randomized study treatment at 20:00 (± 60 min). The next day  


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(Day 2), subjects will subsequently dose with their assigned study medication at 08:00 & 20:00  
(± 60 min) and continue dosing through Visit 6 (Month 2). 
Treatment-free Follow-up Period (1 month): 
After Treatment Period, subjects will be followed for 1 month with scheduled study assessment 
(including safety assessments) visits at Visit 7 (Month 3).  
3.2. 
Randomization and Masking 
A permuted-block randomization will be employed to randomize eligible subjects in a 2:2:1 ratio 
to either 0.1% STN1013600 ophthalmic solution or 0.3% STN1013600 ophthalmic solution or 
Placebo (vehicle). The randomization will be centralized and stratified by baseline binocular 
DCNVA (59 ETDRS letters or less; 60 ETDRS letters or more). 
The randomization schedule will be generated and implemented using central randomization via 
Interactive Response Technology (IRT). Each randomized subject will receive numbered study 
medication kits as assigned by IRT. 
This is a double-masked study. The packaging (kit cartons and bottles) will be identical. The 
subjects, investigators, Examiners, and Santen personnel involved in the conduct of the study 
will be masked to the study treatment. An authorized unmasked study staff member at the 
investigative site who is not the investigator or Examiner will dispense and collect study 
medication(s) and will query about dosing compliance. 
In case of a medical emergency, the Principal Investigator may reveal the treatment information 
by unmasking through IRT to know which treatment the subject has received. 
3.3. 
Sample Size Determination 
The sample size of this study is not based on any statistical power calculation due to the 
exploratory nature of the study and limited knowledge of the treatment effect of study 
medications. Based on the feasibility of conducting the trial, a total of approximately 75 subjects 
will be randomized into a 2:2:1 ratio to 0.1% STN1013600, 0.3% STN1013600, and placebo 
arm. That is, approximately 30 subjects and 15 subjects will be randomized into each of 
STN1013600 treatment arms and placebo arm, respectively. 
Assuming a difference in mean change in DCNVA at Month 2 of 0.08 logMAR, or 4 ETDRS 
letters between STN1013600 group and placebo group with a standard deviation of 0.12 
logMAR or 6 ETDRS letters based on literature data (Korenfeld et al., 2021), the primary 
analysis with 30 subjects in treatment arm and 15 subjects in control arm will achieve at least 
81.5% power to detect such difference. The power calculation for the primary analysis is 
described in detailed in Section 12.2. 
3.4. 
Visits and Assessments 
There are 7 scheduled visits for each enrolled subject.  Assessments at each visit and the 
time/visit window for each post-baseline assessment are specified in the Assessment Schedule 
(Table 2). For subjects whose study participation is terminated prior to Visit 7 (Month 3), to the 
extent possible, all assessments scheduled for Visit 7 (Month 3) will be performed at the Exit 
Visit. 


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Table 2: 
Assessment Schedule 
 
 
Treatment Period 
Follow Up 
Without 
Treatment 
Study Procedures 
Visit 1 / 
Screening  
Up to 15 days 
before Day 1 
Visit 2 
Baseline / 
Day 1 
Visit 3  
Day 7  
± 2 days 
Visit 4  
Day 14  
± 2 days 
Visit 5 
Month 1  
± 3 days 
Visit 6 
Month 2  
± 3 days 
Visit 7 Month 3  
± 3 days /  
Early 
Discontinuation 
Informed consenta 
X 
 
 
 
 
 
 
Inclusion and Exclusion criteria 
X 
X 
 
 
 
 
 
Symptom Assessment iN Dry Eye 
questionnaire (SANDE)b 
X 
 
 
 
 
 
 
Near Activity Visual Questionnaire (NAVQ)b 
 
X 
 
 
 
X 
X 
Demographics information 
X 
 
 
 
 
 
 
Ocular and systemic medical history 
X 
 
 
 
 
 
 
Vital signs (blood pressure, heart rate, 
temperature) 
X 
X 
X 
X 
X 
X 
X 
Height and weight 
X 
 
 
 
 
 
 
Previous and current concomitant ocular and 
systemic medications 
X 
X 
X 
X 
X 
X 
X 
Objective refraction test 
Xc 
X 
X 
X 
X 
X 
X 
Subjective refraction test 
X 
X 
X 
X 
X 
X 
X 
Distance Corrected Near Visual Acuity 
(DCNVA) testd  
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 


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Table 2: 
Assessment Schedule (Continued) 
 
 
Treatment Period 
Follow Up 
Without 
Treatment 
Study Procedures 
Visit 1 / 
Screening  
Up to 15 days 
before Day 1 
Visit 2 
Baseline / 
Day 1 
Visit 3  
Day 7  
± 2 days 
Visit 4  
Day 14  
± 2 days 
Visit 5 
Month 1  
± 3 days 
Visit 6 
Month 2  
± 3 days 
Visit 7 Month 3  
± 3 days /  
Early 
Discontinuation 
Best Corrected Distance Visual Acuity 
(BCDVA) testd 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Slit lamp biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
Pupil size 
X 
X 
X 
X 
X 
X 
X 
Tear film break-up time (TFBUT) 
X 
 
 
 
 
 
 
Corneal Fluorescein Staining (CFS) assessment 
(with Oxford Scale) 
X 
 
 
 
 
 
 
Intraocular pressure (IOP) 
X 
X 
X 
X 
X 
X 
X 
Ophthalmoscopy 
Xg 
X 
X 
X 
X 
X 
Xg 
Patient global rating of treatment 
 
 
 
 
 
X 
 
Post-study clinical trial experience survey 
 
 
 
 
 
 
X 
Urine pregnancy test (women of childbearing 
potential only)h 
X 
 
 
 
 
X 
X 
Blood chemistry and Hematology (CBC, CMP) 
X 
 
 
 
X 
X 
 
Hemoglobin A1c 
X 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
X 
X 
 
 


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Table 2: 
Assessment Schedule (Continued) 
 
 
Treatment Period 
Follow Up 
Without 
Treatment 
Study Procedures 
Visit 1 / 
Screening  
Up to 15 days 
before Day 1 
Visit 2 
Baseline / 
Day 1 
Visit 3  
Day 7  
± 2 days 
Visit 4  
Day 14  
± 2 days 
Visit 5 
Month 1  
± 3 days 
Visit 6 
Month 2  
± 3 days 
Visit 7 Month 3  
± 3 days /  
Early 
Discontinuation 
Adverse events (AEs) 
X 
X 
X 
X 
X 
X 
X 
Dispense study medication 
 
Xi 
 
 
X 
 
 
Medication compliance diaryj 
 
 
X 
X 
X 
X 
 
a Informed Consent Form must be signed and dated before study procedures are performed. 
b NAVQ and SANDE questionnaires are to be performed at the beginning of the study visit, in the order reflected on Schedule of Assessments Table. 
c During screening, cycloplegic refraction (objective refraction with dilation) should be performed; At visit 7 objective refraction can be performed with or 
without cycloplegia. 
d DCNVA, 
 and BCDVA assessments should be performed on OD, OS, and OU. 
e 
 
 
 
 
g Dilated ophthalmoscopy required at Screening and Exit visits. 
h Urine pregnancy test (women of childbearing potential only) may be repeated at each visit as per request of IRB/IECs or at the Investigator’s discretion. 
i Only patients fulfilling eligibility criteria will be enrolled and receive the study medication. 
j Dispense medication compliance diaries with when study medication is dispensed and instruct subjects on the proper completion of the diary. Collect paper 
diaries at specified visits and review for accuracy and completeness. Dosing for randomized subjects on Visit 2 (Day 1/Baseline) is after the study visit in the 
evening (20:00 ± 60 min), and Day 2 through Month 2 is daily BID (08:00 ± 60 min and 20:00 ± 60 min). Re-educate the subject on diary completion and/or 
medication instillation procedures as needed. 


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4. 
TIME-RELATED TERMS 
4.1. 
Baseline Visit 
The Baseline Visit is Visit 2 (Day 1) when the subject is randomized. 
4.2. 
Treatment Period, Treatment Start Date, and Treatment End Date 
This study has two study periods: Treatment Period and Treatment-free Follow-up Period. The 
start date and end date for each period are defined as follows in Table 3.  
Table 3: 
Definitions for Period Start and End Dates by Study Period 
Study Period 
Period Start Date 
Period End Date 
Treatment 
Period 
The date at which a 
randomized subject takes 
the first dose of study drug  
The date at which a subject takes the last dose of study 
drug. If the date of the last dose is missing,  
The day of the Visit 6 (Month 2) date will be 
considered as the end date 
The day before the Study Exit date will be used for 
subjects who prematurely discontinued the study 
before Visit 6 (Month 2). If the Study Exit date of a 
non-completer is not available, then the day of the last 
available visit date will be considered the treatment 
end date 
Treatment-free 
Follow-up 
Period 
The day after the Visit 6 
(Month 2) date.  
The date of Visit 7 (Month 3)  
 
Treatment start date and Treatment end date are the start date and the end date of the Treatment 
Period, defined in Table 3.  
4.3. 
Study Day and Analysis Visit 
The study day describes the relative day of an observation starting with the reference date 
designated as Study Day 1. In this study, the treatment start date is the reference date. Thus, the 
study day will be calculated as: 
 For a pre-baseline date, Study Day = Date – Treatment Start Date  
 For a post-baseline date, Study Day = Date – Treatment Start Date + 1 
4.4. 
Analysis Visit and Analysis Window 
Analysis visit is a timing variable to be used for analyses involving visits. For each analysis visit, 
an analysis window is set up to determine the analysis visit to which a measurement should be 
mapped (Table 4). The analysis visit of a measurement will be determined based on the study 
day of the measurement and specified analysis windows and is not necessarily the same as the 


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study visit at which the measurement was collected. For example, an out-of-window 
measurement collected at the Day 7 study visit will be mapped to the Day 14 analysis visit, if the 
study day of the measurement falls into the analysis window of Day 14. 
The following analysis windows will be applied to minimize the amount of missing data for 
analysis purposes: 
Table 4: 
Analysis Visit and Analysis Window 
Analysis 
Visit  
(Target 
Study 
Day) 
Protocol 
Visit 
Window 
Analysis Window 
Patient 
Global 
Rating of 
Treatment 
Blood 
Chemistry, 
Hematology, 
Urinalysis 
Other 
Parameters 
Baseline 
(Day 1) 
[1, 1] 
NA* 
[ - , 1] 
[ - , 1] 
Day 7 
(Day 7) 
[5, 9] 
NA* 
NA* 
[2, 11] 
Day 14 
(Day 14) 
[12, 16] 
NA* 
NA* 
[12, 23] 
Month 1 
(Day 30) 
[27, 33] 
NA* 
[2, 49] 
[24,  49] 
Month 2 
(Day 60) 
[57, 63] 
[2, -] 
[50, -] 
[50, day of 
Month 2 
Visit] 
Month 3 
(Day 90) 
[87, - ] 
NA* 
NA* 
[day of 
Month 2 
Visit + 1, - ] 
*Not collected at this visit. 
 
If there are two or more visits that fall into the same analysis window, then the visit closest to the 
target assessment day will be selected for that visit window. In the case that two visits are 
equidistant to the target assessment day, i.e., one is before and one is after the target assessment 
day, the latter will be selected for that visit. 
4.5. 
Extent of Exposure 
The extent of exposure to study medication will be assessed by duration of treatment exposure, 
derived as: 
Duration of treatment exposure = Treatment end date – Treatment start date + 1 


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5. 
GENERAL CONSIDERATIONS 
All measures will be summarized descriptively. Continuous variables will be summarized using 
descriptive statistics such as number of observations (n), mean, standard deviation, standard 
error, median, minimum, and maximum. Categorical variables will be tabulated using frequency 
(n) and percent (%). 
Unless otherwise specified, the following conventions will be followed in reporting the decimal 
places. 
Reporting Statistics 
Decimal places  
Range (Low Value, High Value) 
Recorded Decimal Places 
Mean, Median  
Recorded value + 1 Decimal Places 
Confidence Interval, Standard Deviation, Standard 
Error 
Recorded value + 2 Decimal Places 
p-Value 
4 Decimal Places (ex. 0.0021) 
 
The statistical testing will be conducted at a significance level of 0.10 (two-sided) and the  
90% confidence interval will be shown, unless specified otherwise.  No statistical testing will be 
conducted for safety measures. 
All data manipulations, descriptive summaries, and statistical hypothesis testing will be 
performed using Statistical Analysis System (SAS) Version 9.4 or later. Individual data, 
including relevant derived variables, will be listed. 
Additional analyses not specified in this SAP may be conducted if deemed necessary and will be 
documented in the CSR. 
5.1. 
Adjustments for Covariates 
Details in covariates to be included in the statistical model for each individual statistical analysis 
are provided Section 8. 
5.2. 
Handling of Missing Data 
5.2.1. 
Efficacy Measures 
The primary analysis of DCNVA will be based on observed cases; hence, missing data will not 
be imputed. As a sensitive analysis of the primary efficacy endpoint, an analysis using mixed-
effect model for repeated measures (MMRM) will be performed. The MMRM model will be 
applied using observed cases and no imputation will be needed. 
For continuous secondary endpoints where MMRM-based analysis will be performed, no 
imputation will be necessary. For binary secondary endpoints with response status, the analysis 
will be based on observed cases; hence, no imputation will be performed. 


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5.2.2. 
Safety Measures 
Descriptive summaries of safety measures will be based on observed data only. No imputation of 
missing scores will be implemented. 
5.2.3. 
Dates for Medical Events and Medications 
Completely or partially missing onset and resolution dates for AEs, Concomitant Medications 
(CM), and Medical History (MH) will be imputed in a conservative fashion as follows:   
Incomplete Adverse Event Onset Date 
1. Year imputation  
 If year is missing (or AE onset date is completely missing), then the onset date will 
not be imputed. 
2. Month imputation 
 If year is not missing but month is missing, then:  
 If year = year of first study dose date, then set the month and day to the day and 
month of first study dose 
 Else if year ≠ year of first study dose: set month to January 
3. Day imputation 
 If day is missing (month and year not missing), then: 
 If year = year and month = month of first study dose, then set day to day of first 
study dose 
 Else if year ≠ year and month ≠ month of first study dose, then set day to first day 
of the month in the year 
Incomplete Adverse Event Resolution Date 
 Do not impute if any resolution date is missing  
 If the duration of AE is needed, the following approach may be considered: 
 If year is missing (or AE resolution date is completely missing): do not impute 
 If year is not missing but month and day are missing: impute December 31st for 
missing month and day 
 If year and day are not missing but month is missing: impute December for 
missing month 
 If year and month are not missing but day is missing: impute last day of the month 
for missing day. 
 
 
 


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Incomplete CM or MH Onset Date  
1. If year is missing (or CM/MH onset date is completely missing): do not impute 
2. If year is not missing but month and day are missing: impute January 1st for missing 
month and day 
3. If year and day are not missing but month is missing: impute January for missing month 
4. If year and month are not missing but day is missing: impute 01 for missing day 
 
Incomplete CM or MH Resolution Date 
 Do not impute if any resolution date is missing. 
5.3. 
Multi-Center Studies 
This is a multi-center study enrolling subjects from 12 US sites. The number of subjects per site 
might be small. Therefore, there are no analyses adjusting for sites. 
5.4. 
Multiple Comparisons / Multiplicity 
This trial plans to have only one hypothesis testing, which is for the primary efficacy endpoint. 
Therefore, multiple comparisons do not apply and there is no need to adjust for multiplicity. 
5.5. 
Interim Analysis 
Following the Santen Steering Committee’ recommendation, no interim analysis is planned for 
this study. 
6. 
STUDY POPULATION 
6.1. 
Safety Population 
The Safety Population will include all subjects who signed informed consent, met the eligibility 
criteria at baseline (Visit 2, Day 1), and received at least one dose of the study medication. The 
safety analyses will be performed on the Safety Population. 
6.2. 
Full Analysis Set 
The Full Analysis Set (FAS) will include all Safety population who had at least one post-baseline 
DCNVA measurement. The efficacy analyses will be performed using the FAS or a subset of the 
FAS. 
6.3. 
Per-Protocol Set 
The Per-Protocol Set (PPS) is a subset of the FAS, restricted to the subjects who fulfill the 
protocol in the terms of eligibility, interventions, and other assessment. It will be the analysis 
population for some sensitivity analyses. 


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Before database lock, Santen’s study team will review all protocol deviations, identify subjects 
with any protocol deviation that could impact the efficacy outcome, and determine whether to 
exclude the subject from the PPS. 
7. 
SUMMARY OF STUDY POPULATION DATA 
7.1. 
Subject Disposition 
The disposition of all randomized subjects will be summarized by treatment and overall. The 
summary will include the number and percentage of subjects in the Safety population, FAS, and 
PPS. The disposition summary will also include the number and percentage of subjects who 
completed the treatment period, who completed all study visits, subjects who discontinued the 
study prematurely before the end of treatment period (Visit 6, Month 2), as well as the number 
and percentage of subjects who discontinued from the study prior to Month 3 Visit by the 
primary discontinuation reason separately. 
7.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be descriptively summarized for FAS. 
Specifically, for subject demographics, the following variables will be summarized: 
 Age at enrollment (continuous and categorical: 47-50 years or 51-55 years) 
 Sex (categorical: Male or Female) 
 Ethnicity (categorical: Hispanic/Latino or Not) 
 Race (categorical: American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, or Other) 
For baseline characteristics, the following variables will be summarized for both eyes (if 
applicable), study eye and fellow eye, separately: 
 Best corrected distance visual acuity 
 
 
 Distance corrected near visual acuity 
 Objective refraction (spherical/cylinder/axis) 
 Subjective refraction (spherical equivalent, spherical, cylinder, and axis) 
 Refractive status (categorical: Myopes/Emmetropes/Hyperopes) 
7.3. 
Medical and Surgical History 
For this study, medical and surgical history and adverse events will be coded using  
MedDRA 25.1, September 2022. Each medical event will be classified into a system organ class 
(SOC) and mapped to a Preferred Term (PT). 


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The medical and surgical history will be summarized for the FAS population. Subjects reporting 
any medical and surgical history at baseline will be tabulated by SOC and PT for each planned 
treatment and overall. 
7.4. 
Protocol Deviations 
In this study, protocol deviations are categorized as follows: 
 Informed Consent 
 Inclusion/Exclusion Criteria 
 Concomitant Treatment  
 Investigational Product  
 Procedures/Tests/Assessments 
 Laboratory  
 Time Window 
 Other 
A protocol deviation is considered significant if it may affect the subject’s rights, safety, or  
well-being, and/or the completeness, accuracy, or reliability of the study data. Santen’s study 
team will review all protocol deviations and determine the list of significant protocol deviations 
prior to database lock. All FAS subjects with any significant protocol deviation(s) will be 
tabulated by deviation category for each planned treatment and overall. In addition, two listings 
will be provided: (1) all significant protocol deviations and (2) subjects excluded from the per 
protocol population. 
7.5. 
Impact of the COVID-19 Pandemic 
The impact of the COVID-19 pandemic is defined as any disruption to the study and subject 
participation, such as changes in study visits, missed visits, subject discontinuations, etc. All 
Safety Population subjects who experienced any of such impact will be summarized and listed 
along with the description of how their participation was altered. 
7.6. 
Prior and Concomitant Medications 
Non-study medications will be categorized into prior medications and concomitant medications. 
Specifically, prior medication is defined as any non-study medication taken and ended prior to 
the study medication start date. Concomitant medication is defined as any non-study medication 
taken concurrently while receiving study medication, i.e., the period from first dose to last dose 
of a concomitant medication taken by a subject must overlap with the period from first dose to 
last dose of the study medication.  
For this study, non-study medications, including prior and concomitant medications, will be 
coded using World Health Organization (WHO) Drug Global, Version September 2018, format 
B3. Each non-study medication will be classified using the Anatomical-Therapeutic-Chemical 
(ATC) classification system and mapped to a WHO Drug preferred drug name. 


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Non-study medications will be summarized for the Safety population. Subjects taking any prior 
medications will be tabulated by ATC level 3, level 4, and preferred drug name. A subject will 
be counted at most once for each prior medication, even if the subject took the same prior 
medication on multiple occasions. Subjects taking any concomitant medications will be tabulated 
similarly. In addition, prior medications and concomitant medications will also be listed, 
separately. 
7.7. 
Treatment Compliance 
For compliance calculation, there will be three study intervals in the Treatment Period: 
 Baseline Visit to Day 7 
 Day 7 to Day 14 
 Day 14 to Month 1 
 Month 1 to Month 2 
The compliance rate for a subject will be calculated as follows for each study interval: 
Compliance Rate (%) = (2 x Duration – ∑Miss) / (2 x Duration) × 100 
Where 
Duration: The number of days subject should have administered study medication 
calculated as: 
Study Interval 
Equation for Duration Calculation 
Baseline to Day 7 
Day 7 Visit date – Date of first study drug dispensation 
Day 7 to Day 14 
Day 14 Visit date – Day 7 Visit date 
Day 14 to Month 1 
Month 1 Visit date – Day 14 Visit date 
Month 1 to Month 2 
Month 2 Visit date – Month 1 Visit date 
Miss: The number of missed doses since the last visit. 
A subject is fully compliant with the study treatment if his/her overall compliant rate is 100% 
over the Treatment Period (between Baseline and Month 2). The compliance rate of subjects in 
the FAS will be summarized by study intervals and over the Treatment Period for each planned 
treatment and overall. 
7.8. 
Exposure to Study Medication 
The duration of exposure to a study medication is measured by days on treatment as derived in 
Section 4.5. For subjects in the Safety Population, the duration of exposure will be summarized 
using descriptive statistics, and frequency and percentage of subjects will be tabulated by 
duration category (1-30 days, 31-60 days, or ≥ 61 days) for each actual treatment received. 


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8. 
EFFICACY ANALYSES 
8.1. 
Efficacy-Related Definitions 
8.1.1. 
Study Eye and Fellow Eye 
The study eye of a treated subject will be the eye that received the study medication and has a 
lower score of DCNVA as study eye at Visit 2 (Baseline, Day 1). If both eyes have the same 
score of DCNVA, the right eye will be designated as the study eye. The other eye will be the 
non-study eye, or fellow eye. 
8.1.2. 
Baseline Score 
The baseline score is the observed measurement at Visit 2 (Baseline, Day 1). If a baseline score 
is missing, the last observed measurement or derived score prior to the first dose of study 
medication will be used to impute the baseline score. 
8.1.3. 
Change and Percent Change from Baseline 
The change and the percent change from baseline in a measure at a post-baseline visit will be 
derived as: 
 Change = (Score at the Post-Baseline Visit) – (Baseline Score) 
 Percent Change from Baseline = 100 × Change / (Baseline Score) 
8.1.4. 
Efficacy Measures 
Table 5 lists all the efficacy measures that will be evaluated in this study. 
Table 5: 
Efficacy Measures 
Efficacy Measures 
Note 
Distance-corrected Near 
Visual Acuity (DCNVA) 
DCNVA will be measured in the right eye, left eye and both 
eyes at all visits using the distance manifest refraction. The total 
number of letters at 40 cm will be recorded. 
 
 
 
 
  
Near Activity Visual 
Questionnaire (NAVQ): 
Rasch score and overall 
satisfactory score 
Any N/A responses are scored according to the median overall 
score. The summated score from the main body of 10 questions 
is adjusted to a Rasch score from 0 to 100 using a conversion 
table (Section 12.1) such that 0 indicates no difficulty at all with 
any near tasks, and 100 indicates extreme difficulty with all near 
activities. 
 


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Table 5: 
Efficacy Measures (Continued) 
Efficacy Measures 
Note 
Patient Global Rating of 
Treatment 
At Visit 6 (month 2), patients will be asked to rate their overall 
satisfactory with the treatment on a 4-point Likert scale with 
responses including ‘Unsatisfactory’, ‘Not very satisfactory’, 
‘Satisfactory’, and ‘Very satisfactory’. 
 
 
 
 
 
 
 
 
 
 
 
Objective and Subjective 
Refraction 
Objective refraction will be performed as per standard of care 
using autorefractor available at clinical site at all study visits. 
Subjective refraction with “push plus” approach will be 
performed at all visits to determine the best correction for a 
subject to perform the visual acuity tests. 
 
8.1.5. 
Visual Acuity Response Endpoints 
Binocular DCNVA response endpoints are defined as follows: 
 Binocular DCNVA 1-line gain response: having an increase in DCNVA of 5 letters  
(1 line) or more from baseline and having no decrease in BCDVA of more than 5 letters 
(1 line). That is, change from baseline in DCNVA ≥ 5 letters and change from baseline in 
BCDVA ≥ -5 letters. 
 Binocular DCNVA 2-line gain response: having an increase in DCNVA of 10 letters  
(2 lines) or more from baseline and having no decrease in BCDVA of more than 5 letters 
(1 line). That is, change from baseline in DCNVA ≥ 10 letters and change from baseline 
in BCDVA ≥ -5 letters. 
 Binocular DCNVA 3-line gain response: having an increase in DCNVA of 15 letters  
(3 lines) or more from baseline and having no decrease in BCDVA of more than 5 letters 
(1 line). That is, change from baseline in DCNVA ≥ 15 letters and change from baseline 
in BCDVA ≥ -5 letters. 


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The three Study Eye DCNVA response endpoints are defined similarly. 
 
 
For a response endpoint, the response rate at a given post-baseline visit is calculated as the 
proportion of subjects who met the response criterion at that visit. 
8.1.6. 
Treatment Satisfactory Response Endpoints 
The treatment satisfactory response endpoint is defined as having the response of either 
‘Satisfactory’ or ‘Very Satisfactory’ when asked to rate the overall satisfactory with the 
treatment under Patient Global Rating of Treatment questionnaire. 
8.1.7. 
Refractive Status and Manifest Refraction Spherical Equivalent Endpoint 
Manifest refraction spherical equivalent (MRSE) is calculated by adding the spherical power 
with half of the cylindrical power, where spherical and cylindrical power are measured from the 
subjective refraction test. 
Based on the MRSE, a refractive status of an eye will be defined as follows: 
 Myopia: MRSE < -0.25D  
 Emmetropia: -0.25D ≤ MRSE ≤ +0.25D  
 Hyperopia: MRSE > +0.25D  
8.1.8. 
Lens and Corneal Elasticity 
Five parameters for lens elasticity are (1) width of the bottom plateau, (2) width of the top 
plateau, (3) height of the plateau, (4) slope of the anterior cortex, and (5) slope of the posterior 
cortex. Lens elasticity will be measured in triplicate on each eye at each visit. Measurement 
values across multiple scans of each parameter will be averaged and used for the analysis. Any 
unsuccess scans whose all 5 parameters are zeros will be excluded before the averaging 
calculation. 
Corneal elasticity will be measured in duplicate on each eye at Baseline and Month 2 visit. The 
average value of corneal elasticity across multiple scans will be used for analysis. 
 
 
 
 
 
 
 


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8.2. 
Analyses of Primary Endpoint 
8.2.1. 
Historical Control Data 
Searching the clinicaltrials.gov database for presbyopia clinical studies with pharmacological 
treatment with the exposure duration of 2 months or longer, the study team identified three 
studies with similar study populations and inclusion/exclusion criteria. Out of three studies, only 
one (NCT02516306) has reported the study results (Korenfeld, 2011) with the same endpoint as 
this study’s primary endpoint. Based on the historical data of 23 subjects in the control group, the 
estimated mean ± standard deviation of the change from baseline in binocular DCNVA at Month 
2 is reported as -0.085 ± 0.087 logMAR, or 4.25 ± 4.35 EDTRS letters read. 
A power prior with a power parameter 𝑤, presenting the prior knowledge learned from a study 
with 𝑛0 subjects, will be derived based on the estimated mean 𝜇0
̂, and standard deviation 𝑠0 as 
follows: 
𝜇∼N (𝜇0
̂,
𝑠0
2
𝑤⋅𝑛0
), 
where 𝜇 is the mean change from baseline in binocular DCNVA, N( ⋅ , ⋅ ) denotes the normal 
distribution with the first and second parameter indicating mean and variance, respectively. 
Hence, the effective sample size borrowing from the historical control data will be 𝑤⋅𝑛0. 
8.2.2. 
Primary Analyses 
The primary efficacy endpoint is the change from Baseline (Day 1) in binocular DCNVA at 
Month 2 (Visit 6).  
For comparison of 0.1% STN1013600 vs Placebo and of 0.3% STN1013600 vs Placebo, the 
primary endpoint will be evaluated under the Bayesian framework in accordance with the 
following null (versus alternative) hypothesis: 
H0: 𝜇𝑇≤𝜇𝐶  
versus 
HA: 𝜇𝑇> 𝜇𝐶 
where 𝜇𝑇 and 𝜇𝐶 is the mean value of change from baseline binocular DCNVA at Month 2 of the 
treatment group and the control group, respectively.  
For the primary analysis, a power prior with power parameter 𝑤
 will be used for the 
control group mean and a non-informative prior, 𝑝(𝜇𝑇) ∝1, for the treatment group mean. 
Based on the posterior means and variances for treatment and control groups, the probability of 
(Treatment mean – Control mean > 0) given the data i.e., 𝑃(𝜇𝑇−𝜇𝐶> 0 | Data) will be 
calculated. The null hypothesis H0 will be rejected and the efficacy of the treatment will be 
declared when 𝑃(𝜇𝑇−𝜇𝐶> 0 | Data) > 0.95. The details for historical data borrowing analysis 
are in Section 12.2 . 


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8.2.3. 
Sensitivity Analyses 
To assess the robustness of results from the primary analysis in the presence of prior-data 
conflict (i.e., the mean of historical data is different from the observed mean of the placebo arm), 
a mixed-effect model for repeated measures (MMRM) will be performed in observed cases up to 
Month 3 for the primary endpoint. The model will include treatment, analysis visit, and 
treatment-by-visit interaction as fixed effects, and baseline binocular DCNVA at baseline as a 
covariate, and subject as a random effect. The denominator degrees of freedom for fixed effects 
will be estimated using the Kenward-Roger approximation. An unstructured covariance matrix 
will be used to model the within-subject errors. 
If there are convergence issues, covariance matrix structures other than unstructured will be tried 
in the following order: (1) heterogeneous Toeplitz (TOEPH), (2) heterogeneous autoregressive of 
order 1 (ARH(1)), (3) heterogeneous compound symmetry (CSH), and (4) compound symmetry 
(CS). The first covariance structure that converges will be used for this sensitivity analysis. Least 
squares mean change from baseline at Month 2 and differences between least squares treatment 
arm means and associated 90% confidence intervals will be reported. 
In addition, the following sensitivity analyses will be performed to assess the robustness of the 
results from the primary analysis: 
 The primary analysis will be repeated on the PP Population. 
 
 
 
 
 
 
8.3. 
Analyses of Secondary Efficacy Endpoints 
8.3.1. 
Analyses of Continuous Secondary Endpoints 
The following secondary endpoints will be analyzed using MMRM on observed cases up to 
Month 3: 
 Mean change from baseline in Study Eye DCNVA at all visits 
 Mean change from baseline in Binocular DCNVA at all visits 
 Mean change from baseline in Rasch score at Month 2 and Month 3 as measured by 
Near Activity Visual Questionnaire (NAVQ) 
 Mean change from baseline in the NAVQ overall satisfactory rating of near vision at 
Month 2 and at Month 3 
For the analysis of the above secondary endpoints, the MMRM model will include treatment, 
visit, and treatment-by-visit as fixed effects, baseline as covariate and subject as random effect. 
The denominator degrees of freedom for fixed effects will be estimated using the Kenward-
Roger approximation. An unstructured covariance matrix will be used to model the within-
subject errors. When non-convergence issue arises, covariance structure in the following order 
will be tried: (1) heterogeneous Toeplitz (TOEPH), (2) heterogeneous autoregressive of order  


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1 (ARH(1)), (3) heterogeneous compound symmetry (CSH), and (4) compound symmetry (CS). 
The first covariance structure that converges will be used for the analysis.  
8.3.2. 
Analyses of Binary Secondary Endpoints 
The following binary secondary endpoints will be summarized descriptively:    
 Having Binocular DCNVA 1/2/3-line gain from baseline at each visit 
 Having Study Eye DCNVA 1/2/3-line gain from baseline at each visit 
 Proportion of subjects with treatment satisfactory assessed by Patient Global Rating 
of Treatment at Month 2 
The responder rates will be tabulated using frequencies and percentages based on observed cases. 
For exploratory purposes, comparison between 0.1% STN1013600 vs Placebo and between 0.3% 
STN1013600 vs Placebo in response rate will be performed using the Fisher’s Exact test for a 
2x2 contingency table. 
8.4. 
Subgroup Analyses 
The homogeneity of treatment effects among prospectively defined subgroups will be assessed 
via descriptive statistics of the change from baseline in Binocular DCNVA by analysis visit for 
the following subgroups: 
 Age (47-50 or 51-55 years) 
 Sex (males or females) 
 Race (White or non-White)  
 Baseline Binocular DCNVA (< 60 or ≥ 60 ETDRS letters) 
 Baseline refractive status of the Study Eye (Myopia or Emmetropia or Hyperopia) 
Other subgroup analyses may be performed as deemed necessary. 
8.5. 
Exploratory Analyses 
    
 
 
 
 
 
 
 
 
 
 


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 
 
 
 
 
 
 
 
 
 
 
9. 
SAFETY ANALYSES 
9.1. 
Safety-Related Definitions 
9.1.1. 
Adverse Event 
Under Protocol 101360002IN, an AE is defined as any on-study untoward medical occurrence 
(e.g., sign, symptom, disease, syndrome, intercurrent illness) that occurs in a study subject, 
regardless of the suspected cause and regardless of the timing of the study medication 
administration. An on-study AE can occur any time after the date of informed consent through 
the last study visit. An AE will be considered as treatment-emergent if the AE occurred on or 
after the treatment start date up to 8 days after treatment end date (or the last study visit).   
Treatment-emergent AEs (TEAEs) are a subset of on-study AEs. Both on-study and TEAEs will 
be collected, but only TEAEs will be tabulated. 
The severity of each AE will be graded by the Clinical Investigator as Mild, Moderate, or 
Severe. AEs will also be rated by the Investigator as to their causality/relationship to the study 
drug. 
Each AE will be classified into a system organ class (SOC) and coded to a preferred term (PT) 
using Medical Dictionary for Regulatory Activities (MedDRA), version 25.1 published in 
September 2022. 
9.1.1.1. 
Ocular Adverse Event 
An AE will be counted as an ocular AE if the Clinical Investigator selected “Ocular” under 
‘Event Location’ on the AE eCRF. 
9.1.1.2. 
Adverse Drug Reaction 
An AE will be counted as an adverse drug reaction (ADR) if the Clinical Investigator answered 
‘Related’ to the AE eCRF question “Relationship to Study Drug.” 
9.1.1.3. 
Serious Adverse Event 
An AE will be counted as a serious adverse event (SAE) if the Clinical Investigator selected 
“Yes” to the question ‘Is the adverse event serious?’ on the AE eCRF. Any AE is considered a 
SAE if it fulfills one or more of the following criteria: 
 Death (i.e., the AE caused or led to death) 


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 Life threatening (i.e., immediately life-threatening) 
 It required prolonged inpatient hospitalization. 
 It resulted in a persistent or significant disability/incapacity (i.e., the AE resulted in a 
substantial disruption of the subject’s ability to carry out normal life functions). 
 It resulted in a congenital anomaly/birth defect in the offspring of a study subject who 
was exposed to study therapy prior to conception or during pregnancy. 
 It is a medically significant event(s), which may include “sight-threatening events,” 
that may not meet any of the above serious criteria but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the outcomes listed above. 
9.1.1.4. 
Events of Special Interest 
For this study, events of special interest (ESI) are pregnancy and clinically significant study 
medication administration error. 
9.1.2. 
Safety Measures 
Table 6 lists the safety measures to be evaluated for this study. 
Table 6: 
Safety Assessments 
Safety Measures 
Note 
Intraocular pressure (IOP) 
The examiner will measure IOP using a Goldmann Applanation 
Tonometer in each eye at least two, and sometimes three, 
consecutive times. IOP will be the mean of 2 readings or median 
of 3 readings of the first 2 readings are 3 mmHg or more apart. 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy examinations (severity scores for  
12 parameters: anterior chamber cells, anterior chamber flare, lid 
hyperemia, lid edema, conjunctival hyperemia, conjunctival 
chemosis, corneal edema, corneal staining, keratic precipitates, 
lens, anterior synechiae of iris, posterior synechiae of iris) will 
be performed and graded at all visits.  Cataract severity will be 
assessed for subjects with phakic lens.  
Ophthalmoscopy 
The ophthalmoscopy (fundus) examination will be performed 
with dilation at Visit 1 (Screening) and Visit 7 (Month 3) and 
without dilation at other study visits. Variables from 
ophthalmoscopy are cup-to-disc ratio, and assessments of 
vitreous, retina, macula, choroid, and optic nerve.  
 


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Table 6: 
Safety Assessments (Continued) 
Safety Measures 
Note 
Pupil measurement 
Pupil measurement will be performed with ambient lighting 
conditions (10-12 lux) with an automated device. The same 
device should be used for all visits on a subject. 
Best Corrected Distance 
Visual Acuity (BCDVA) 
BCDVA will be recorded for right eye, left eye and both eyes at 
all visits using ETDRS charts. The total number of letters at  
4 meters and 1 meter will be recorded. If a subject’s visual 
acuity is so poor that he/she cannot read any chart letters when 
tested at 1 meter, then the subject’s ability to count fingers, 
detect hand motion, or have light perception should be 
evaluated. 
 
The safety-related measures collected in this study include AEs, slit-lamp biomicroscopy 
(severity scores for 12 parameters), ophthalmoscopy (cup-to-disc ratio, and assessments of 
vitreous, retina, macula, choroid, and optic nerve), intraocular pressure, pupil diameter, and 
BCDVA. The Safety population will be used for all summaries. 
All the safety-related measures will be summarized descriptively by actual treatment received. 
Except AEs and BCDVA, the descriptive summary of each ocular safety-related measure and the 
change from baseline in that measure will be performed for study eyes and fellow eyes 
separately.   
9.2. 
Adverse Events 
Subjects with any AE(s) will be tabulated by type of AE(s) for each actual treatment received 
and overall. Unless otherwise specified, any AE experienced by either eye or both eyes will be 
counted once for that AE. In addition to the overall AE summary, subjects with any AE(s) will 
be tabulated by SOC and preferred term. A subject who experienced multiple AEs within a SOC 
or preferred term will be counted only once for that SOC or preferred term. Ocular AEs, SAEs, 
ADRs, Serious ADRs, non-serious AEs (including number of events) will be tabulated similarly.  
AEs, AEs leading to death, AEs leading to discontinuation, SAEs, ADRs, serious ADRs, ocular 
AEs, and non-TEAEs, if any, will be listed separately.   
9.3. 
Intraocular Pressure (IOP) 
IOP (mmHg) and changes from baseline will be summarized by analysis visit for study eyes and 
fellow eyes, separately. In addition, any worsening of ≥ 10 mmHg from baseline will be listed. 
9.4. 
Pupil Measurement 
Pupil diameter (mm) and changes from baseline will be summarized by analysis visit for study 
eyes and fellow eyes, separately. Any clinically significant change from baseline in pupil 
diameter (more than 2.5 mm) will also be listed. 


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9.5. 
Best Corrected Distance Visual Acuity (BCDVA) 
BCVDA (ETDRS letters) and changes from baseline will be summarized by analysis visit for 
both eyes, study eyes, and fellow eyes, separately. In addition, any worsening of 10 letters (2 
lines) or more from baseline will be listed. 
9.6. 
Slit-lamp Biomicroscopy 
Twelve parameters for slip-lamp biomicroscopy are (1) anterior chamber cells, (2) anterior 
chamber flare, (3) lid hyperemia, (4) lid edema, (5) conjunctival hyperemia, (6) conjunctival 
chemosis, (7) corneal edema, (8) corneal staining, (9) keratic precipitates, (10) lens (cataract), 
(11) anterior synechiae of iris, (12) posterior synechiae of iris. Any additional findings from 
biomicroscopy examination will be combined into a “Other” category for summary purpose. For 
each biomicroscopy parameter, frequency and percentage of rating scores will be summarized by 
analysis visit for study eyes and fellow eyes, separately. The rating score of “Other” category of 
an eye at a visit will be the most severe rating of all findings within the category. In addition, any 
worsening (increase) of ≥ 2 units from baseline in severity for all parameters except anterior 
chamber cells and anterior chamber flare, and any worsening from baseline in severity for 
anterior chamber cells and anterior chamber flare will be listed.  
9.7. 
Ophthalmoscopy 
Cup-to-disc ratio will be summarized with n, mean, standard deviation, median, minimum, and 
maximum by analysis visit for study eyes and fellow eyes separately. In addition, subjects with 
at least 0.2 increase in cup/disc ratio from baseline will be listed. 
Retina, macula, choroid, vitreous, and optic nerve will be assessed as normal or abnormal. 
Frequency and percentage of rating will be summarized by analysis visit for study eyes and 
fellow eyes, separately. In addition, subjects with change from baseline from normal to abnormal 
in these parameters will be listed. 
10. 
SUMMARY OF CHANGES TO THE PROTOCOL 
10.1. 
Secondary and Exploratory Endpoints 
10.1.1. 
Secondary efficacy endpoints 
Based on the communication with regulatory agency, a clarification was added to the secondary 
efficacy endpoint “Proportion of subjects who improve 1/2/3-lines or more in Study Eye and 
Binocular DCNVA at each visit”. The new definition of this endpoint will be “Proportion of 
subjects who improve 1/2/3-lines or more in Study Eye and Binocular DCNVA at each visit 
without loss of more than 1 line (5 letters) in Best Corrected Distance Visual Acuity (BCDVA).” 
10.1.2. 
Safety endpoints 
Additional safety endpoints were added to further assess the safety of the study drug: pupil size 
and best corrected distance visual acuity. 


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10.1.3. 
Exploratory endpoints 
 
 
 
 
 
 
 
 
 
 
 
10.2. 
Primary Analysis 
In the protocol, the superior of the treatment arm over placebo arm would be establish of the 
probability of (Treatment mean – Placebo mean > 0) given the data is greater than 90%. In this 
SAP, the criterion was revised to be more stringent with 95% will be used to establish the 
superior of the treatment over the placebo. The new threshold of 95% will guarantee the 
(Bayesian) type I error to be lower than or equal to 0.10. 
Analysis will be based on observed cases instead of multiple imputation approached imputed 
values due to the following rationales:  
 In general, discrepancy in analysis results due to different imputation approaches are 
minimal when the amount of missing data is small. Based on masked review of 
subject disposition, few of than 5% of subjects with missing data due to missed visits 
and premature study discontinuation.  
11. 
REFERENCE 
1. 
Korenfeld, M. S., Robertson, S. M., Stein, J. M., Evans, D. G., Rauchman, S. H., Sall, K. 
N., Venkataraman, S., Chen, B. L., Wuttke, M., Burns, W. (2021) Topical lipoic acid 
choline ester eye drop for improvement of near visual acuity in subjects with presbyopia: 
a safety and preliminary efficacy trial. Eye (Lond). 


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12. 
APPENDIX 
12.1. 
Conversion Table for Near Activity Visual Questionnaire (NAVQ) 
The summated NAVQ score for the initial 10 questions can be converted to Rasch score using 
the following table: 
Non-adjusted score 
Rasch score 
Non-adjusted score 
Rasch score 
0 
0 
16 
56.89 
1 
10.72 
17 
58.89 
2 
18.13 
18 
60.84 
3 
23.07 
19 
62.77 
4 
26.96 
20 
64.68 
5 
30.30 
21 
66.81 
6 
33.3 
22 
68.58 
7 
36.08 
23 
70.62 
8 
38.70 
24 
72.77 
9 
41.22 
25 
75.09 
10 
43.65 
26 
77.68 
11 
46.02 
27 
80.72 
12 
48.32 
28 
84.59 
13 
50.56 
29 
90.55 
14 
52.73 
30 
100 
15 
54.84 
 
 
Any N/A responses are scored according to the median overall score for the subject. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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