Conditions: Primary Open-angle Glaucoma and Ocular Hypertension
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 98
Healthy volunteers: no

Brief summary:
This is a randomized, double-masked, parallel-group, multi-center study. Subjects diagnosed with POAG or OHT who meet eligibility criteria at Visit 1 (Screening) will wash out their current topical IOP lowering medication(s), if any. After completing the required washout period, subjects will return for Visit 2 (Baseline, Day 1). Subjects who meet all eligibility criteria at Visit 2 (Baseline, Day 1) will be randomized to receive study medication for up to 6 weeks.

Approximately 100 subjects with POAG or OHT will be randomized in a 1:1 ratio to either:

* DE-117 ophthalmic solution 0.002% QD (Once Daily)
* DE-117 ophthalmic solution 0.002% BID (Twice Daily)

This study will consist of a screening period of up to 35 days including a washout period of up to 28 days (+ 7 days window), and a 6-week double-masked treatment period.

Detailed description:

Arms:
arm 1: DE-117 Ophthalmic Solution QD (20:00) and Vehicle (8:00; no active DE-117 ingredient) QD arm 2: DE-117 Ophthalmic Solution BID Twice daily (20:00 and 8:00)

Interventions: intervention 1: DE-117 Ophthalmic Solution QD intervention 2: DE-117 Ophthalmic Solution BID
Intervention descriptions: intervention 1: DE-117 ophthalmic solution QD and Vehicle (no active DE-117 ingredient) QD add one drop in each eye intervention 2: DE-117 ophthalmic solution BID twice Daily (20:00 and 8:00) add one drop in each eye

Protocol document:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:   
A Randomized, Double-Masked, Parallel-Group, Multicenter Study 
Assessing the Safety and Efficacy of DE-117 Ophthalmic Solution 0.002% 
Once Daily and Twice Daily in Subjects with Primary Open-Angle 
Glaucoma or Ocular Hypertension-SPECTRUM 6 Study 
 
NCT Number:  
NCT03858894 
 
Date of the document: 
13 Nov 2018 
 
 
 


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DE-117 
Protocol 011712IN 
TITLE:  A Randomized, Double-Masked, Parallel-Group, Multicenter Study Assessing 
the Safety and Efficacy of DE-117 Ophthalmic Solution 0.002% Once Daily and Twice 
Daily in Subjects with Primary Open-Angle Glaucoma or Ocular Hypertension- 
SPECTRUM 6 Study  
PROTOCOL NUMBER: 011712IN 
COMPOUND NUMBER: DE-117  
STUDY PHASE: Phase II 
SPONSOR: SANTEN INCORPORATED 
LEGAL REGISTERED ADDRESS: 6401 Hollis Street, Suite 125, Emeryville, CA 94608  
REGULATORY AGENCY IDENTIFIER NUMBER(S): IND Number: 111,518 
APPROVAL DATE: V1.0 13NOV2018 
I have read the 011712IN 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 therein 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 Council for Harmonisation (ICH) 
guidelines, and the Declaration of Helsinki. 


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COMPANY/SPONSOR APPROVER 
Company/Sponsor Address 
Santen Incorporated 
6401 Hollis Street, Suite 125, Emeryville, CA 94608  
 
 
 


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Table 1: 
Contact Information 
Emergency Contact Information: 
Role in Study 
Name 
Address/Phone/Fax/Email 
 
 


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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ............................................................................................9 
1.1. 
Synopsis ........................................................................................................................9 
1.2. 
Schema ........................................................................................................................12 
1.3. 
Schedule of Activities (SoA) ......................................................................................12 
2. 
INTRODUCTION ......................................................................................................15 
2.1. 
Study Rationale ...........................................................................................................15 
2.2. 
Background .................................................................................................................15 
2.3. 
Benefit/Risk Assessment ............................................................................................16 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................17 
4. 
STUDY DESIGN .......................................................................................................18 
4.1. 
Overall Design ............................................................................................................18 
4.2. 
Scientific Rationale for Study Design ........................................................................19 
4.3. 
Justification for Dose ..................................................................................................20 
4.4. 
End of Study Definition ..............................................................................................20 
5. 
STUDY POPULATION .............................................................................................21 
5.1. 
Inclusion Criteria ........................................................................................................21 
5.2. 
Exclusion Criteria .......................................................................................................22 
5.3. 
Lifestyle Considerations .............................................................................................23 
5.3.1. 
Contraception Requirements ......................................................................................23 
5.4. 
Screen Failures ............................................................................................................24 
6. 
STUDY INTERVENTION ........................................................................................25 
6.1. 
Investigational Product Administered, Formulation, Packaging, and 
Labelling .....................................................................................................................25 
6.2. 
Investigational Product Preparation, Handling, Storage and Accountability .............26 
6.2.1. 
Study Medication Preparation ....................................................................................26 
6.2.2. 
Study Medication Administration...............................................................................26 
6.2.3. 
Study Medication Handling and Disposal ..................................................................26 
6.2.4. 
Study Medication Storage ...........................................................................................26 
6.2.5. 
Study Medication Accountability ...............................................................................26 
6.3. 
Measures to Minimize Bias: Randomization and Masking ........................................27 
6.4. 
Study Intervention Compliance ..................................................................................27 
6.5. 
Discontinue Use of All IOP-lowering Medications ....................................................28 


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6.6. 
Concomitant Medication/Therapy ..............................................................................29 
6.6.1. 
Prohibited Medications or Therapies ..........................................................................29 
6.7. 
Dose Modification ......................................................................................................30 
6.8. 
Intervention after the End of the Study .......................................................................30 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..................................................................31 
7.1. 
Discontinuation of Study Intervention........................................................................31 
7.2. 
Subject Discontinuation/Withdrawal from the Study .................................................31 
7.2.1. 
Subject Withdrawal Criteria .......................................................................................31 
7.3. 
Lost to Follow up ........................................................................................................32 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................33 
8.1. 
Visit Details ................................................................................................................33 
8.1.1. 
Visit 1 (Screening) ......................................................................................................33 
8.1.2. 
Visit 1a (Optional, Washout Period) ..........................................................................35 
8.1.3. 
Visit 2 (Baseline, Day 1) ............................................................................................35 
8.1.4. 
Visit 3 (Week 2, Day 15 ± 2) ......................................................................................36 
8.1.5. 
Visit 4 (Week 6, Day 43 ± 3) Study Exit/Early Termination .....................................37 
8.2. 
Procedures of Assessments .........................................................................................38 
8.2.1. 
Efficacy Assessments .................................................................................................38 
8.2.1.1. 
Intraocular Pressure ....................................................................................................38 
8.2.2. 
Safety Assessments .....................................................................................................40 
8.2.2.1. 
Demographics, Medication/Therapy and Medical History ........................................40 
8.2.2.2. 
Pregnancy Test ............................................................................................................41 
8.2.2.3. 
Refraction ...................................................................................................................41 
8.2.2.4. 
Best-Corrected Visual Acuity .....................................................................................41 
8.2.2.5. 
Slit-lamp Biomicroscopy ............................................................................................42 
8.2.2.6. 
Pachymetry (Central Corneal Thickness) ...................................................................45 
8.2.2.7. 
Gonioscopy .................................................................................................................45 
8.2.2.8. 
Visual Field .................................................................................................................45 
8.2.2.9. 
Ophthalmoscopy (Fundus) Examination ....................................................................45 
8.2.2.10. 
Events of Special Interest (ESIs) ................................................................................46 
8.2.3. 
Other Assessments ......................................................................................................47 
8.2.3.1. 
Blood Sample for Pharmacogenomics/genomics Study .............................................47 


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8.2.3.2. 
Pharmacodynamics .....................................................................................................47 
8.2.3.3. 
Biomarkers ..................................................................................................................47 
8.2.3.4. 
Pharmacokinetics ........................................................................................................47 
8.2.4. 
Study Supplies ............................................................................................................48 
8.3. 
Adverse Events and Serious Adverse Events .............................................................48 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................48 
8.3.2. 
Method of Detecting AEs and SAEs ..........................................................................48 
8.3.3. 
Follow-up of AEs and SAEs .......................................................................................48 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...........................................................49 
8.3.5. 
Pregnancy ...................................................................................................................49 
8.3.5.1. 
Female subjects who become pregnant ......................................................................49 
8.3.5.2. 
Male subjects with partners who become pregnant ....................................................50 
8.4. 
Treatment of Overdose ...............................................................................................50 
8.5. 
Health Economics/Medical Resource Utilization and Health Economics .................50 
9. 
STATISTICAL CONSIDERATIONS .......................................................................51 
9.1. 
Statistical Hypotheses .................................................................................................51 
9.2. 
Sample Size Determination ........................................................................................51 
9.3. 
Populations for Analyses ............................................................................................51 
9.3.1. 
Safety Population ........................................................................................................52 
9.3.2. 
Full Analysis Set .........................................................................................................52 
9.3.3. 
Per-Protocol Population ..............................................................................................52 
9.3.4. 
Statistical Analyses .....................................................................................................52 
9.3.5. 
Handling of Missing Values .......................................................................................52 
9.3.6. 
Efficacy Analyses .......................................................................................................52 
9.3.6.1. 
Analysis of Primary Endpoint ....................................................................................52 
9.3.6.2. 
Analysis of Secondary Efficacy Endpoints: ...............................................................53 
9.3.7. 
Safety Analyses ..........................................................................................................53 
9.4. 
Interim Analyses .........................................................................................................53 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................54 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................54 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................54 
10.1.2. 
Obligations of Investigators ........................................................................................54 


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10.1.3. 
Financial Disclosure ...................................................................................................55 
10.1.4. 
Informed Consent Process ..........................................................................................56 
10.1.4.1. 
Elements of Informed Consent ...................................................................................57 
10.1.5. 
Data Protection ...........................................................................................................58 
10.1.6. 
Data Quality Assurance ..............................................................................................58 
10.1.7. 
Source Data .................................................................................................................59 
10.1.8. 
Source Documents ......................................................................................................59 
10.1.9. 
Data Collection ...........................................................................................................60 
10.1.10. 
Sponsor’s Direct Access to Source Data/Documents and IRB/IEC Materials 
for Monitoring and Audit ............................................................................................60 
10.1.10.1. Study Monitoring ........................................................................................................60 
10.1.10.2. Audits and Inspections ................................................................................................61 
10.1.11. 
Study and Site Closure................................................................................................61 
10.1.12. 
Publication Policy .......................................................................................................62 
10.2. 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...........................................................................................62 
10.3. 
List of Abbreviations and Specialist Terms ................................................................68 
11. 
REFERENCES ...........................................................................................................71 
11.1. 
Literature .....................................................................................................................71 
11.2. 
Study Data ..................................................................................................................72 
 
LIST OF TABLES 
Table 1: 
Contact Information ......................................................................................................3 
Table 2: 
Study Objectives and Endpoints ...................................................................................9 
Table 3: 
Schedule of Activities .................................................................................................12 
Table 4: 
Study Objectives and Endpoints .................................................................................17 
Table 5: 
Study Drug Descriptions .............................................................................................25 
Table 6: 
LogMAR Scoring Grid for ETDRS Eye Chart...........................................................42 
Table 7: 
Definition of AE .........................................................................................................62 
Table 8: 
Definition of SAE .......................................................................................................64 
Table 9: 
Recording and Follow-Up of AE and/or SAE ............................................................65 
Table 10: Reporting of SAEs and ESIs.......................................................................................67 
Table 11: List of Abbreviations and Specialist Terms ................................................................68 


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LIST OF FIGURES 
Figure 1: 
Study Schema .............................................................................................................12 
 
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
A Randomized, Double-Masked, Parallel-Group, Multicenter Study Assessing the Safety and 
Efficacy of DE-117 Ophthalmic Solution 0.002% Once Daily and Twice Daily in Subjects with 
Primary Open-Angle Glaucoma or Ocular Hypertension- SPECTRUM 6 Study 
Rationale: 
This dose frequency study 011712IN (SPECTRUM 6) will assess the safety and efficacy of 
0.002% DE-117 ophthalmic solution once daily (QD) and twice daily (BID) in subjects with 
Primary Open-Angle glaucoma (POAG) or ocular hypertension (OHT). 
 
Table 2: 
Study Objectives and Endpoints 
Study Objectives 
Corresponding Study Endpoints 
Primary objective: 
To determine whether DE-117 
Ophthalmic Solution 0.002% given 
BID is superior to QD in reducing the 
intraocular pressure (IOP) after 6 
weeks of treatment in subjects with 
POAG or OHT. 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the IOP in the study eye 
measured at the specified time points: 08:00, 12:00 and 
16:00 at Week 2 (Visit 3) and Week 6 (Visit 4). 
Secondary Efficacy Endpoints: 
 
Mean diurnal IOP in the study eye at Week 6 (Visit 4) 
 
Absolute change and percent change from baseline in 
IOP  
 
Absolute change and percent change from baseline in 
mean diurnal IOP  
 
Having a mean diurnal IOP reduction ≥ 20%, ≥ 25%, or  
≥ 30% from Baseline (Visit 2) at each post-baseline visit 
 
Having a mean diurnal IOP ≤ 18 mmHg at each post-
baseline visit 
Safety objective: 
To determine the safety of DE-117 
ophthalmic solution 0.002% given 
BID as compared to QD in subjects 
with POAG or OHT. 
Safety Endpoints: 
Safety will be evaluated by the following parameters: 
 
Incidence of ocular and systemic adverse events (AEs) 
 
Best-corrected visual acuity (BCVA) 
 
Slit-lamp biomicroscopy findings: anterior chamber cells, 
anterior chamber flare, lid hyperemia, lid edema, 
conjunctival hyperemia, conjunctival chemosis, corneal 
edema, corneal staining, keratic precipitates, abnormal 
lens findings, anterior synechiae of iris, posterior 
synechiae of iris 
 
Ophthalmoscopy  
 


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Overall Design: 
This is a randomized, double-masked, parallel-group, multi-center study.  Subjects diagnosed 
with POAG or OHT who meet eligibility criteria at Visit 1 (Screening) will wash out their 
current topical IOP lowering medication(s), if any.  After completing the required washout 
period, subjects will return for Visit 2 (Baseline, Day 1).  Subjects who meet all eligibility 
criteria at Visit 2 (Baseline, Day 1) will be randomized to receive study medication for up to 6 
weeks.   
Approximately 100 subjects with POAG or OHT will be randomized in a 1:1 ratio to either: 
 DE-117 ophthalmic solution 0.002% QD (20:00) and Vehicle QD (08:00), or 
 DE-117 ophthalmic solution 0.002% BID (20:00 & 08:00) 
This study will consist of a screening period of up to 35 days including a washout period of up to 
28 days (+ 7 days window), and a 6-week double-masked treatment period. 
At the screening visit (Visit 1), subjects will be screened against the inclusion and exclusion 
criteria.  Eligible subjects will be instructed to discontinue use of all IOP-lowering medications, 
if any, as follows (up to +7 days is allowed):  
 Miotics: 7 days 
 Oral/topical Carbonic Anhydrase Inhibitors (CAIs): 7 days 
 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandins Analogs (PGA): 28 days 
 Rho kinase (ROCK) inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will be 
used. 
During the required washout period, subjects who discontinue their current treatment may, if the 
investigator deems necessary, be treated with a short-acting IOP lowering agent, topical CAI, 
e.g., brinzolamide or dorzolamide eye drops, one drop twice daily.  Topical CAI treatment must 
be stopped 1 week before the randomization at Visit 2 (Baseline, Day 1).  An interim safety visit 
during the washout period (mid-washout visit: Visit 1a) may be performed if, in the 
investigator’s opinion, a subject’s IOP may be of concern during the washout period.  If subjects 
are treated with a topical CAI during the washout period, a mid-washout visit (Visit 1a) is 
recommended. 
Final eligibility will be determined at Visit 2 (Baseline) after all necessary washout from prior 
IOP lowering medications have been completed.  Subjects who have not used any IOP lowering 
medications for the last 28 days, including treatment-naive subjects, must have ≥ 1 day between 
their screening visit and Visit 2 (Baseline). 


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At Visit 2, baseline IOP will be measured for both eyes at 8:00 (±60 min), 12:00 (±60 min) and 
16:00 (±60 min).  The study eye will be the eye that qualifies per eligibility criteria at Visit 2.  If 
both eyes meet the eligibility criteria, the eye with the higher diurnal IOP at Visit 2 will be 
designated as the study eye.  If both eyes meet the eligibility criteria and have the same mean 
diurnal IOP at Visit 2, the right eye will be designated as the study eye.  Both eyes should be 
treated with the study medication for the duration of the study even if only one eye is eligible per 
IOP inclusion criteria.   
Treatment Period (6 weeks):  
Approximately 100 eligible subjects will be randomized to either DE-117 0.002% QD in the 
evening and vehicle QD in the morning or DE-117 0.002% BID in a 1:1 ratio.  Subjects will be 
treated for 6 weeks with scheduled Visits 2, 3 and 4 (Baseline, Week 2 and Week 6). 
At Visit 2 (Baseline), subjects will be instructed to instill their first dose of study medication 
(study eye drops) as per their assigned/randomized study treatment at 20:00 (±60 minutes) that 
same evening.  The next day, subjects will subsequently dose their assigned study medication at 
08:00 (±60 minutes) and 20:00 (±60 minutes).  At each scheduled follow-up visit, subjects will 
instill their morning dose of study medication/eye drops following the 08:00 IOP measurement 
at the investigative site (the doctor’s office). 
IOP will be measured at 08:00, 12:00 and 16:00 (±60 minutes).  At these scheduled visits, 
BCVA and slit-lamp biomicroscopy will be performed just prior to the 08:00 IOP measurement.  
Ophthalmoscopy (fundus examination) will be performed after 16:00 IOP measurement.   
Pharmacogenomics/Genomics: 
Subjects who consent to the optional pharmacogenomics/genomics laboratory study will provide 
a blood sample for future testing.  The purpose of this exploratory research is to identify possible 
genetic markers associated with the study medication(s) and/or ocular conditions. 
Number of Subjects (Planned):  
Approximately 100 subjects (50 subjects in each treatment arm) with POAG or OHT in the 
United States will be enrolled in this study. 
Intervention Groups and Duration: 
Approximately 100 subjects with POAG or OHT will be randomized in a 1:1 ratio to either: 
 DE-117 ophthalmic solution 0.002% QD (20:00) and Vehicle QD (08:00), or 
 DE-117 ophthalmic solution 0.002% BID (20:00 & 08:00). 
The study duration for each individual subject includes up to a 5-week screening period and up 
to a 6-week double-masked treatment period.   
Data Monitoring Committee: 
An independent data monitoring committee (DMC) will not be used in this study. 
 


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1.2. 
Schema 
Figure 1 provides an overview of the study design. 
 
Figure 1: 
Study Schema 
 
1.3. 
Schedule of Activities (SoA) 
The schedule of activities (SoA) is provided in Table 3. 
Table 3: 
Schedule of Activities 
 
Washout Period 
Double-Masked Treatment Period 
Visit 1 
(Screening) 
Washout 
Period 
(up to 4 
weeks) 
Optional 
Visit 1ak 
Visit 2 
Eligibility/ 
Baseline 
(Day 1) 
Visit 3 
Week 2 
(Day 15±2) 
Visit 4 
Week 6 
(Day 43±3) 
Exit or Early 
Terminationl 
Informed Consent(s) including 
the consent for 
pharmacogenomics/ genomics 
laboratory research studya 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
Concomitant Medications / 
Therapies 
X 
X 
X 
X 
X 


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Table 3: 
Schedule of Activities (Continued) 
 
Washout Period 
Double-Masked Treatment Period 
Visit 1 
(Screening) 
Washout 
Period 
(up to 4 
weeks) 
Optional 
Visit 1ak 
Visit 2 
Eligibility/ 
Baseline 
(Day 1) 
Visit 3 
Week 2 
(Day 15±2) 
Visit 4 
Week 6 
(Day 43±3) 
Exit or Early 
Terminationl 
Dosing Compliance 
 
 
 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
Pregnancy Testb 
X 
 
X 
 
X 
Refractionc 
X 
 
 
 
 
BCVAc 
X 
X 
X 
(prior to 8:00 IOP 
meas.) 
X 
(prior to 8:00 IOP 
meas.) 
X 
(prior to 8:00 IOP 
meas.) 
Biomicroscopyd 
X 
X 
X 
(prior to 8:00 IOP 
meas.) 
X 
(prior to 8:00 IOP 
meas.) 
X 
(prior to 8:00 IOP 
meas.) 
IOPe 
X 
(any time) 
X 
(any time) 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
Pachymetryf 
X 
 
 
 
 
Instill study eye drop after 
08:00 IOP measurement 
 
 
 
X 
(after 8:00 IOP 
meas.) 
X 
(after 8:00 IOP 
meas.) 
Gonioscopyg 
X 
 
 
 
 
Visual Fieldh 
X 
 
 
 
 
Ophthalmoscopyi 
X 
(pupil dilation) 
 
X 
(after 16:00 IOP 
meas.) 
 
X 
(after 16:00 IOP 
meas., pupil 
dilation) 
Blood Sampling for 
Pharmacogenomics/genomicsj 
 
 
 
X 
Dispense Study Medication 
 
 
X 
 
 
Collect Study Medication 
 
 
 
 
X 
Phone call to remind subjects 
to take morning and evening 
dose on the day before each 
visit 
 
 
 
X 
X 
a. 
Informed Consent(s) including the consent for pharmacogenomics/ genomics laboratory research study  
Informed consent form (ICF) must be signed and dated before study procedures are performed.  Informed 
consent for the optional pharmacogenomics/genomics laboratory research study may be obtained at any visit 
prior to study exit. 
b. Pregnancy Test 
A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
c. 
Refraction and BCVA  
Refraction will be performed at the screening visit.  If more than 10 letters in BCVA were lost compared to the 
screening visit, then refraction should be performed again.  BCVA examination will be completed before IOP is 
measured at 08:00 (±60 min). 


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d. Biomicroscopy 
Biomicroscopy examination must be completed before IOP is measured at 08:00.  Aqueous flare and cell 
evaluation will be performed before fluorescein instillation.   
e. 
IOP 
IOP measurements will be performed at 08:00, 12:00 and 16:00 (±60 min) at all visits except for Visit 1 and 
optional Visit 1a (screening and mid-washout). 
f. 
Pachymetry 
Pachymetry will be performed after IOP measurement at Visit 1 (Screening). 
g. Gonioscopy 
If gonioscopy was performed within 3 months (90 days) prior to screening and was documented in the subject’s 
records, no additional screening gonioscopy examination is necessary. 
h. Visual Field 
If visual field test was performed within 3 months (90 days) prior to screening and was documented in the 
subject’s records, no additional screening visual field test is necessary.   
i. 
Ophthalmoscopy 
Ophthalmoscopy will be performed at Visits 1, 2 and 4 (i.e.  Screening, Baseline and Week 6) after the very last 
IOP measurement.  Ophthalmoscopy will be performed with pupil dilation at Visit 1 and Visit 4/ Study Exit or 
Early Termination.  Dilation of the pupil will be performed after the very last IOP measurement at Visit 1 and 
Visit 4/ Study Exit or Early Termination. 
j. 
Blood Sampling for Pharmacogenomics/genomics 
Blood sampling for the pharmacogenomics/genomics laboratory research study may be performed at any visit 
after pharmacogenomics/genomics informed consent is obtained, subject is randomized and study drug, DE-117 
ophthalmic solution 0.002%, dosing has begun. 
k. Optional Visit 1a  
An interim safety visit may be performed during the washout period Visit 1a (optional, mid-washout visit), if in 
the Investigator’s opinion a subject’s IOP may be of concern.  If subjects are treated with a topical CAI during 
the washout period. Visit 1a (optional, mid-washout visit) is recommended to be performed. 
l. 
Exit or Early Termination  
All listed procedures are required for early terminated subjects. 
 


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2. 
INTRODUCTION 
DE-117 is an ophthalmic topical formulation of omidenepag isopropyl for the reduction of 
elevated IOP in patients with Glaucoma and OHT.  DE-117 is a pro-drug of its 
pharmacologically active acid metabolite, UR-7276, omidenepag, a selective EP2 receptor 
agonist with non-prostaglandin structure. 
2.1. 
Study Rationale 
This dose frequency study (011712IN, SPECTRUM 6) will assess the safety and efficacy of 
0.002% DE-117 ophthalmic solution QD and BID in subjects with POAG or OHT.   
2.2. 
Background 
Glaucoma represents a group of related diseases frequently associated with elevated IOP.  When 
left untreated, glaucoma can lead to retinal ganglion cell death and optic nerve damage, resulting 
in progressive and irreversible loss of vision.  Glaucoma is the second leading cause of blindness 
worldwide.  In 2013, the global prevalence of glaucoma for population aged 40 to 80 years was 
3.54%.  The number of people (aged 40 to 80 years) with glaucoma worldwide was estimated to 
be 64.3 million, increasing to 76.0 million in 2020 and 111.8 million in 2040 (Tham et al., 2014).  
It affects one in two hundred people aged fifty or younger and one in ten over the age of eighty 
(Resnikoff et al., 2004).   
Although currently there is no cure for open-angle glaucoma (OAG), results from multiple 
studies, including the Advanced Glaucoma Intervention Study (AGIS) (AGIS_Investigators, 
2000), the Ocular Hypertension Treatment Study (OHTS) (Kass et al., 2002), and the Early 
Manifest Glaucoma Trial (EMGT) (Leske et al., 2003), and United Kingdom Glaucoma 
Treatment Study (UKGTS) (Garway-Heath et al., 2015) have demonstrated that treating elevated 
IOP with topical ocular hypotensive agents is effective in delaying or preventing disease 
progression.  The lowering of IOP is currently the only method for reducing the risk of 
glaucomatous visual field loss and remains the primary goal of therapy. 
Several classes of ocular hypotensive medications exist today and are differentiated by their 
mechanism of action at the cellular/molecular level.  These include miotics, β-adrenergic 
receptor antagonists (β-blockers), CAIs, -adrenergic receptor agonists (-agonists), 
prostaglandin analogues (PGAs) and rho kinase (ROCK) inhibitors.  The pharmacodynamic 
effect of these medications can differ substantially, as some affect aqueous humor production (β-
blockers, -agonists, and CAIs) while others affect the outflow pathway (miotics, PGs, ROCK 
inhibitors, and -agonists).  In general, PGAs are recommended as the first choice agent for most 
eyes with OHT and OAG.  However, as disease progresses and maintaining target IOP becomes 
difficult, more than one drug is needed to achieve optimum benefit and reach target IOP.  
Surgical interventions, including laser surgery, shunting of aqueous humor to an appropriate 
locale, and filtering surgery, are available options for treating insufficiently controlled IOP.  In 
such instances pharmacotherapy may be continued as well. 
While adequate IOP-lowering can be achieved by currently available pharmacotherapies in some 
patients, not all patients are adequately treated and additional IOP-lowering may provide for 
further slowing of disease progression.  In some patients, treatment with a single IOP-lowering 
compound is not sufficient to obtain optimal IOP control.  Adjunctive or combination therapy 


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using different classes of drugs is often employed in order to achieve additional IOP-lowering 
effects.  Moreover, consistent lowering of IOP over a 24-hour period has not yet been fully 
realized.  If achieved, this could also contribute to slowing of disease progression.  Therefore, 
new pharmacologic agents with new mechanism of action are needed. 
Santen has developed an ophthalmic topical formulation of omidenepag isopropyl (UR-7385) for 
the reduction of elevated IOP in patients with OHT or OAG.  DE-117 is a pro-drug of the 
pharmacologically active acid metabolite, UR-7276, a synthetic non-prostanoid agonist of 
prostaglandin E2 (PGE2) receptor, subtype 2 (EP2).  PGE2 has been shown to markedly reduce 
IOP when applied topically to human and animal eyes (Bito, 2001).  PGE2, its analogues and 
receptor agonists are thought to mediate the IOP-lowering effect by relaxing the ciliary muscle 
and increasing outflow of aqueous humor through the uveo-scleral pathway (Yamaji et al., 
2005).  Very recently, Fuwa et al., demonstrated that DE-117 lowers the IOP through a novel 
mechanism of action: that is, through both conventional and uveoscleral outflows (Fuwa et al., 
2017).Currently approved IOP- lowering medications such as latanoprost (latanoprost 
ophthalmic solution, 0.005%; NDA 20-597) lower IOP by enhancing uveoscleral outflow only, 
but do so through effects on a receptor for PGF2α.  Unlike latanoprost and other approved 
prostaglandin F receptor (FP) agonists that are synthetic prostanoid analogues, DE-117 is a non-
prostanoid chemical compound. 
To date, Santen has completed seven clinical studies including three clinical studies (33-001,  
33-002, 33-003) in the U.S.  and four clinical studies (01171502, 01171503, 01171504, 
01171506) in Japan with DE-117 in healthy adult subjects, or subjects with OAG or OHT to 
evaluate the safety and efficacy of DE-117.  DE-117 ophthalmic solution 0.002% once a day 
(QD) appeared to be well tolerated and efficacious in IOP lowering.  However, it is unclear 
whether DE-117 ophthalmic solution 0.002% twice a day (BID) will improve the efficacy of IOP 
lowering without compromising the safety.  This study is being performed to complete the dose 
exploration via assessing the safety and efficacy of DE-117 ophthalmic solution QD and BID in 
subjects with POAG or OHT.   
Additional information on DE-117 ophthalmic solution, including the results of nonclinical and 
clinical studies can be found in the Investigator’s Brochure. 
2.3. 
Benefit/Risk Assessment 
DE-117 ophthalmic solution 0.002% demonstrated clinically meaningful IOP reduction in 
subjects with OAG or OHT in both US and Japanese population.  In a phase III study in Japan, 
DE-117 0.002% was non-inferior to Latanoprost 0.005% in IOP lowering.  DE-117 was 
generally well-tolerated.  No serious suspected adverse reaction has been reported.  The severity 
and the frequency of the reported ocular adverse events were not unexpected for a topical 
ophthalmic medication.  Benefit-risk balance continued to be favorable.  DE-117 ophthalmic 
solution 0.002% once a day received the market authorization approval from Japanese Health 
Authority on 21 September 2018. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of DE-117 may be found in the Investigator’s Brochure. 


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3. 
OBJECTIVES AND ENDPOINTS 
Table 4: 
Study Objectives and Endpoints 
Study Objectives 
Corresponding Study Endpoints 
Primary objective:  
To determine whether DE-117 
Ophthalmic Solution 0.002% given 
BID is superior to QD in reducing the 
intraocular pressure (IOP) after 6 
weeks of treatment in subjects with 
POAG or OHT. 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the IOP in the study eye 
measured at the specified time points: 08:00, 12:00 and 
16:00 at Week 2 (Visit 3) and Week 6 (Visit 4). 
Secondary Efficacy Endpoints:  
 
Mean diurnal IOP in the study eye at Week 6 (Visit 4) 
 
Absolute change and percent change from baseline in 
IOP  
 
Absolute change and percent change from baseline in 
mean diurnal IOP  
 
Having a mean diurnal IOP reduction ≥ 20%, ≥ 25%, or  
≥ 30% from Baseline (Visit 2) at each post-baseline visit 
 
Having a mean diurnal IOP ≤ 18 mmHg at each post-
baseline visit 
Safety objective:  
To determine the safety of DE-117 
ophthalmic solution 0.002% given 
BID as compared to QD in subjects 
with POAG or OHT. 
Safety Endpoints: 
 
Safety will be evaluated by the following parameters: 
 
Incidence of ocular and systemic AEs 
 
BCVA 
 
Slit-lamp biomicroscopy findings: anterior chamber cells, 
anterior chamber flare, lid hyperemia, lid edema, 
conjunctival hyperemia, conjunctival chemosis, corneal 
edema, corneal staining, keratic precipitates, abnormal 
lens findings, anterior synechiae of iris, posterior 
synechiae of iris 
 
Ophthalmoscopy  


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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, double-masked, parallel-group, multi-center study.  Subjects diagnosed 
with POAG or OHT who meet eligibility criteria at Visit 1 (Screening) will wash out their 
current topical IOP lowering medication(s), if any.  After completing the required washout 
period, subjects will return for Visit 2 (Baseline, Day 1).  Subjects who meet all eligibility 
criteria at Visit 2 (Baseline, Day 1) will be randomized to receive study medication for up to 6 
weeks.   
Approximately 100 subjects with POAG or OHT will be randomized in a 1:1 ratio to either: 
 DE-117 ophthalmic solution 0.002% QD (20:00) and Vehicle QD (08:00), or 
 DE-117 ophthalmic solution 0.002% BID (20:00 & 08:00) 
This study will consist of a screening period of up to 35 days including a washout period of up to 
28 days (+ 7 days window), and a 6-week double-masked treatment period. 
At the screening visit (Visit 1), subjects will be screened against the inclusion and exclusion 
criteria.  Eligible subjects will be instructed to discontinue use of all IOP-lowering medications, 
if any, as follows (up to +7 days is allowed):  
 Miotics: 7 days 
 Oral/topical Carbonic Anhydrase Inhibitors (CAIs): 7 days 
 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandins Analogs (PGA): 28 days 
 Rho kinase (ROCK) inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will be 
used. 
During the required washout period, subjects who discontinue their current treatment may, if the 
investigator deems necessary, be treated with a short-acting IOP lowering agent, topical CAI, 
e.g., brinzolamide or dorzolamide eye drops, one drop twice daily.  Topical CAI treatment must 
be stopped 1 week before the randomization at Visit 2 (Baseline, Day 1).  An interim safety visit 
during the washout period (mid-washout visit: Visit 1a) may be performed if, in the 
investigator’s opinion, a subject’s IOP may be of concern during the washout period.  If subjects 
are treated with a topical CAI during the washout period, a mid-washout visit (Visit 1a) is 
recommended. 
Final eligibility will be determined at Visit 2 (Baseline) after all necessary washout from prior 
IOP lowering medications have been completed.  Subjects who have not used any IOP lowering 


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medications for the last 28 days, including treatment-naive subjects, must have ≥ 1 day between 
their screening visit and Visit 2 (Baseline).   
At Visit 2, baseline IOP will be measured for both eyes at 8:00 (±60 min), 12:00 (±60 min) and 
16:00 (±60 min).  The study eye will be the eye that qualifies per eligibility criteria at Visit 2.  If 
both eyes meet the eligibility criteria, the eye with the higher diurnal IOP at Visit 2 will be 
designated as the study eye.  If both eyes meet the eligibility criteria and have the same mean 
diurnal IOP at Visit 2, the right eye will be designated as the study eye.  Both eyes should be 
treated with the study medication for the duration of the study even if only one eye is eligible per 
IOP inclusion criteria.   
Treatment Period (6 weeks):  
Approximately 100 eligible subjects will be randomized to either DE-117 0.002% QD in the 
evening and vehicle QD in the morning or DE-117 0.002% BID in a 1:1 ratio.  Subjects will be 
treated for 6 weeks with scheduled Visits 2, 3 and 4 (Baseline, Week 2 and Week 6). 
At Visit 2 (Baseline), subjects will be instructed to instill their first dose of study medication 
(study eye drops) as per their assigned/randomized study treatment at 20:00 (±60 minutes) that 
same evening.  The next day, subjects will subsequently dose their assigned study medication at 
08:00 (±60 minutes) and 20:00 (±60 minutes).  At each scheduled follow-up visit, subjects will 
instill their morning dose of study medication/eye drops following the 08:00 IOP measurement 
at the investigative site (the doctor’s office). 
IOP will be measured at 08:00, 12:00 and 16:00 (±60 minutes).  At these scheduled visits, 
BCVA and slit-lamp biomicroscopy will be performed just prior to the 08:00 IOP measurement.  
Ophthalmoscopy (fundus examination) will be performed after 16:00 IOP measurement.   
Pharmacogenomics/Genomics: 
Subjects who consent to the optional pharmacogenomics/genomics laboratory study will provide 
a blood sample for future testing.  The purpose of this exploratory research is to identify possible 
genetic markers associated with the study medication(s) and/or ocular conditions. 
4.2. 
Scientific Rationale for Study Design 
This is a dose frequency comparison study, where QD and BID will be compared.   
Although currently there is no cure for open-angle glaucoma, many well controlled studies 
(AGIS_Investigators, 2000; Garway-Heath et al., 2015; Kass et al., 2002; Leske et al., 2003) 
have demonstrated that treating elevated IOP with topical ocular hypotensive agents are effective 
in delaying or preventing disease progression.  The lowering of IOP is currently the only method 
for reducing the risk of glaucomatous visual field loss and remains the primary goal of therapy. 
The primary endpoint is the IOP measured at the specified time points: 08:00, 12:00 and 16:00 
at Visits 3 and 4 (i.e., Week 2, and Week 6 visits).  Lowering IOP is the only approach to slow 
down the glaucoma progression.  The IOP is a surrogate endpoint in glaucoma trials, and this 
surrogate endpoint is well established and accepted by agencies. 
A 6-week treatment duration was designed with two considerations: 1) the DE-117 IOP lowering 
effect will be stabilized within 4 weeks, and 2) any potential carry-over effect of the previous 


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ocular hypotensive medications after up to 4 weeks of washout will be further eliminated.  
Therefore, 6 weeks treatment for this study is appropriate. 
4.3. 
Justification for Dose 
DE-117 concentrations ranging from 0.0003% to 0.03% were tested in four (4) dose-finding 
studies (33-001, 33-002, 33-003 in US and 01171503 Stage 1 in Japan).  DE-117 ophthalmic 
solution 0.002% QD appeared to be well tolerated and efficacious in IOP lowering.  The higher 
concentrations (0.0025% and 0.003%) did not reveal significantly better efficacy.  As a result, 
DE-117 0.002% was chosen as the optimal dose for further development. 
4.4. 
End of Study Definition 
A subject is considered to have completed the study if he/she has completed all visits of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities.  
The end of the study is defined as the date of the last visit of the last subject in the study. 


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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 
At Visit 1 (Screening), the subject must meet all of the following inclusion criteria: 
1. Provide signed written informed consent on the IRB/EC approved ICF. 
2. Be 18 years of age or older on the date of signing the ICF and able and willing to comply 
with all treatment and follow-up study procedures. 
3. If a subject is a female of childbearing potential (i.e., not post-menopausal [within 12 
months since the last menses] or not surgically sterile [less than 6 months]), she must 
have a negative urine pregnancy test and must use at least one of the following acceptable 
contraceptive methods during the study (as well as for 4 weeks following last dose in the 
study). 
 Abstinence 
 Hormonal contraceptive method (including oral or transdermal contraceptives, 
injectable progesterone, progestin subdermal implants, progesterone-releasing 
intrauterine devices [IUDs]) initiated at least 28 days prior 
 Placement of a copper-containing IUD 
 Condom with spermicidal foam/gel/film/cream/suppository 
 Vasectomized male partner (surgery at least 6 months prior)  
 
Male subjects capable of fathering children should use/ practice an acceptable 
contraceptive method, such as abstinence, condom or vasectomy (surgery at least 6 
months prior) or other contraceptive method deemed adequate by the investigator 
throughout the course of the study (as well as for 12 weeks following last dose in the 
study). 
4. Subjects must have a diagnosis of POAG or OHT in both eyes, or one eye with POAG 
and the other with OHT. 
5. BCVA of +0.60 logMAR (Snellen equivalent 20/80) or better in each eye. 
6. Central corneal thickness ≥ 480 m and ≤ 600 m in each eye. 
7. Anterior chamber angle grade ≥ 2 (Shaffer scale) in each eye. 
In addition to continuing to meet inclusion criterion 5 (BCVA), the subject must meet the 
following criteria at Visit 2 (Baseline, Day 1): 
8. Completed the required wait/washout period. 


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9. At all time points of IOP measurements (8:00, 12:00 and 16:00) at Visit 2 (Baseline,  
Day 1), have IOP of ≥ 22 mmHg in at least one eye (the same eye), and ≤ 34 mmHg in 
both eyes. 
5.2. 
Exclusion Criteria  
At Visit 1 (Screening) and Visit 2 (Baseline, Day 1), a subject with any of the following ocular 
conditions in either eye or with any of the following non-ocular conditions or characteristics are 
not eligible to participate in the study: 
General 
1. Females who are pregnant, nursing or planning a pregnancy.   
2. Subjects with known or suspected drug or alcohol abuse. 
3. Current or planned participation in any other clinical trial involving an investigational 
product or device within 4 weeks prior to Visit 1 (Screening) or at any time during this 
trial. 
4. Subjects who have been exposed to DE-117 prior to Visit 1 (Screening). 
Medications / Therapies 
5. Intended or current use of the following prohibited medications/therapies during the 
study: 
 All ocular medications other than sodium chloride/potassium chloride ophthalmic 
solution, cataract treatment agents (e.g., glutathione, pirenoxine), Vitamin B12 
formulation (e.g., cyanocobalamin), over-the-counter dry eye artificial tears/drops, 
and study medications. 
 All systemic medications for ocular hypotensive (e.g., oral or intravenous CAI, oral 
glycerol). 
 Any ocular, periocular, inhaled, nasal or systemic corticosteroids including the joint 
injection, etc. 
 Lacrimal/punctal occlusion via plug(s) or cautery, dry eye treatments or devices that 
require a prescription, such as TrueTear®.   
6. Subjects who cannot safely discontinue use of ocular hypotensive medications during the 
wait/washout period. 
7. Subjects who will be required to initiate or modify any systemic or topical medication 
known to affect IOP (e.g., β-adrenergic antagonists, α-adrenergic agonists, calcium 
channel blockers, angiotensin-converting enzyme [ACE] inhibitors, and angiotensin II 
receptor blockers [ARB]).  Subjects use the above medication must be on a stable dose 
use for at least 30 days prior to Visit 1 (Screening) and during the study duration. 
8. Use of contact lenses within 2-3 weeks prior to Visit 2 (Baseline, Day 1) until end of 
treatment in either eye (2 weeks for soft contact lens wearers, and 3 weeks for rigid 
contact lens wearers). 
9. Any ocular surgery or ocular laser treatment within 180 days prior to Visit 1 (Screening) 
and throughout the study in either eye. 


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10. History of ocular surgery specifically intended to lower IOP (e.g.  laser trabeculoplasty, 
filtering surgery, tube shunt, Minimally Invasive Glaucoma Surgery [MIGS], or 
trabeculotomy) in either eye. 
11. History of keratorefractive surgery (e.g., RK, PRK or LASIK) in either eye.   
12. Allergy, hypersensitivity or contraindications to EP2 receptor agonists, benzalkonium 
chloride (BAK) or any other components of the study medications, or other study related 
procedures/medications. 
Diseases 
13. Presence of secondary glaucoma including pigmentary glaucoma or pseudoexfoliative 
glaucoma, uveitic glaucoma, neovascular glaucoma, traumatic glaucoma, etc. in either 
eye. 
14. Presence of advanced glaucoma (e.g., visual field mean deviation worse than -12 dB) in 
either eye. 
15. Presence of any corneal abnormality or other conditions interfering with or preventing 
reliable Goldmann applanation tonometry (e.g., Fuch’s dystrophy or significant corneal 
surface abnormality) in either eye. 
16. Presence of any active severe external ocular disease, inflammation, or infection of the 
eye and/or eyelids in either eye. 
17. Presence or history of macular edema or known risk factors for macular edema in either 
eye. 
18. History of severe ocular trauma in either eye. 
19. History of iritis and/or uveitis in either eye. 
20. History of retinal detachment, proliferative diabetic retinopathy, or any retinal disease 
that may be progressive during the time course of the study in either eye. 
21. Presence or history of any disease or condition that in the opinion of the study 
investigator may put the subject at significant risk, may confound study results, or may 
interfere significantly with the subject’s participation in the study (e.g., recurrent corneal 
erosion syndrome, uncontrolled cardiovascular disease etc.). 
22. Any decision by the Investigator or Medical Monitor to terminate a subject in screening 
or declare any subject ineligible for any sound medical reason. 
5.3. 
Lifestyle Considerations 
5.3.1. 
Contraception Requirements 
There are no controlled data with the investigational product in human pregnancy.  It is required 
that females of childbearing potential and male subjects able to father children abstain from 
intercourse or agree to practice acceptable methods of contraception throughout the course of the 
study. 
If a subject is female of childbearing potential (i.e., not post-menopausal [within 12 months since 
the last menses] or not surgically sterile [less than 6 months from date of surgery]), subject must 


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use at least one of the following acceptable contraceptive methods during the study (as well as 
for 4 weeks following last dose in study). 
 Abstinence 
 Hormonal contraceptive method (including oral or transdermal contraceptives, 
injectable progesterone, progestin subdermal implants, progesterone-releasing 
intrauterine devices [IUDs]) initiated at least 28 days prior 
 Placement of a copper-containing IUD 
 Condom with spermicidal foam/gel/film/cream/suppository 
 Vasectomized male partner (surgery at least 6 months prior)  
Male subjects capable of fathering children should use or practice an acceptable contraceptive 
method, such as abstinence, condom or vasectomy (surgery at least 6 months prior) or other 
contraceptive method deemed adequate by the investigator throughout the course of the study (as 
well as for 12 weeks following last dose in study). 
5.4. 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
qualified per inclusion or exclusion criteria and will therefore not be randomized or receive study 
medication.  A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure subjects to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities.  
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse event (SAE). 


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6. 
STUDY INTERVENTION 
Study intervention is a general term that refers to any investigational intervention(s), marketed 
product(s), placebo, sham, or medical device(s) intended to be administered to a study subject 
according to a study protocol.  In this protocol, the term Investigational Product (IP) is generally 
used to refer to the study interventions. 
6.1. 
Investigational Product Administered, Formulation, Packaging, and 
Labelling 
Study Drug descriptions are provided in Table 5, including formulation, packaging and labelling. 
Table 5: 
Study Drug Descriptions 
Arm Name 
DE-117 QD and Vehicle QD 
DE-117 BID 
Intervention 
Name 
DE-117 and Vehicle 
DE-117 
Type  
Drug 
Drug 
Use 
Experimental 
Experimental 
Dose 
Formulation 
Ophthalmic solution 
Ophthalmic solution 
Unit Dose 
Strength 
DE-117: 0.002% 
Vehicle: N/A, does not contain the active 
ingredient, DE-117 
0.002% 
Dosage Level 
DE-117: One drop in each eye, Once daily  
Vehicle: One drop in each eye, Once daily 
One drop in each eye, Twice daily 
Route of 
Administration 
Topical, ophthalmic solution  
Topical, ophthalmic solution 
Sourcing 
Provided centrally by the Sponsor or 
designee 
Provided centrally by the Sponsor or 
designee 
Packaging and 
Labeling 
DE-117: 2.5 mL fill in a 5 mL white low-
density polyethylene bottle, with a tip and 
cap, placed in a carton.  Bottle and carton 
with “evening” label. 
Vehicle: 2.5 mL fill in a 5 mL white low-
density polyethylene bottle, with a tip and 
cap, placed in a carton.  Bottle and carton 
with “morning” label. 
Two DE-117 (“evening”) bottles/cartons 
and two Vehicle (“morning”) 
bottles/cartons will be placed in a kit 
carton. 
Labeling will include study number, kit 
number, and other country requirement. 
2.5 mL fill in a 5 mL white low-
density polyethylene bottle, with a tip 
and cap, placed in a carton.  Bottle 
and carton with “evening” or 
“morning” label.  Four DE-117 (two 
“morning” and two “evening”) 
bottles/cartons will be placed in a kit 
carton. 
Labeling will include study number, 
kit number, and other country 
requirement. 


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6.2. 
Investigational Product Preparation, Handling, Storage and 
Accountability 
6.2.1. 
Study Medication Preparation 
The study medications will arrive at the site prepared for instillation. 
6.2.2. 
Study Medication Administration 
Subjects will instill one drop of study medication in each eye at approximately 20:00 (±60 min) 
and 8:00 (±60 min) daily for a total of 6 weeks.   
Each subject will be instructed to instill one drop of study medication from bottle labeled 
“evening” in each eye at 20:00 and one drop of study medication from bottle labeled 
“morning” in each eye at 08:00, starting the evening of Visit 2 (Baseline, Day 1) through the 
morning before Visit 4 (Week 6).   
6.2.3. 
Study Medication Handling and Disposal 
The used study medication kits returned by the subject will be stored at room temperature and 
the unused study medication kits will be refrigerated until final study medication accountability 
has been completed by Santen (or designee).  Following final study medication accountability 
and reconciliation by Santen (or designee), all used and unused study medication will be returned 
to the assigned central drug depot. 
6.2.4. 
Study Medication Storage 
All study medication will be provided by Santen and will be stored in an appropriate secure area 
at the investigational site.   
Study medications should be stored under refrigeration at 2° to 8°C (36° to 46°F), protected from 
light and stored upright.  During the refrigeration storage, the Investigator (or his/her designee) 
will verify and record that the temperature was maintained at 2° to 8°C (36° to 46°F) using 
temperature recorder at least once every seven days at the investigational site, until the last 
subject has exited the study at the site.  In the event of a temperature excursion or any study 
medications damaged during storage, the Investigator (or his/her designee) will notify Santen  
(or designee) and will not dispense the study medications until obtaining authorization from 
Santen (or designee). 
Subjects will be reminded to store all dispensed eye drop bottles under refrigeration, protected 
from light and kept in unit cartons in an upright position.  Study medications should not be 
frozen. 
6.2.5. 
Study Medication Accountability 
The Principal Investigator is responsible for ensuring that an inventory is conducted upon receipt 
of the clinical supplies.  The temperature chart recorder from the shipment will be deactivated, 
and the Investigator (or his/her designee) will verify that the temperature was maintained at 2° to 
8°C (36° to 46°F) during transit.  In the event of a temperature excursion or any study 
medications damaged during transit, the Investigator (or his/her designee) will notify Santen (or 
designee) and will not dispense the study medications until obtaining authorization from Santen 


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(or designee).  The receipt of clinical supplies form should be completed, signed, dated, and 
returned as directed.  A copy must be maintained at the site for the Investigator’s records.   
The Investigator (or his/her designee) will keep a current record of the inventory, storage 
conditions and dispensing of all study medications.  This record will be made available to Santen 
(or designee) for the purpose of accounting for all clinical supplies.  Any significant discrepancy 
and/or deficiency must be recorded with an explanation. 
All supplies sent to the investigational site must be accounted for and in no case will study 
medications be used in any unauthorized situation.  It is the responsibility of the Investigator to 
ensure that any used and unused supplies are available to Santen (or designee) for accountability 
purposes throughout the study. 
6.3. 
Measures to Minimize Bias: Randomization and Masking 
A permuted-block randomization will be employed to randomize eligible subjects in a 1:1 ratio 
to either DE-117 QD/Vehicle QD arm or DE-117 BID arm.   
The randomization schedule will be generated and implemented using central randomization via 
Interactive Response Technology (Medidata Balance/RTSM).  Each randomized subject will 
receive a numbered study medication kit as assigned by Balance/RTSM. 
This study 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 treatment.  A study 
staff member at the investigative site will dispense and collect study medication(s) and query 
about dosing compliance.  The appearance of the bottles of DE-117 ophthalmic solution 0.002% 
and the vehicle will be identical.  All subjects will receive bottles labeled “morning” for the 
morning dose and bottles labeled “evening” for the evening dose.  Each eligible subject will be 
assigned to receive a numbered study medication kit as assigned by central randomization via 
Interactive Response Technology at Visit 2 (Baseline). 
In case of a medical emergency, the Principal Investigator may reveal the treatment information 
by unmasking through Medidata Balance/RTSM to know which treatment the subject has 
received.  The Principal Investigator (or his/her designee) should contact Santen, or Santen’s 
designee, before taking this measure, if there is sufficient time.  Santen, or Santen’s designee, 
must be informed of all instances where the code is broken and of the reasons for such instances. 
Additionally, the AE or SAE for which study treatment was unmasked should be reported to 
Santen Pharmacovigilance. 
6.4. 
Study Intervention Compliance 
To obtain reliable safety and efficacy data, the following precautions will be taken to ensure 
compliance with the treatment regimen 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 will be reminded at study visits to consistently dose in each eye at the same 
time of the day. 


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 Twice daily at 20:00 and 8:00 [±60 min] through Visit 2 to 4.   
 Subjects will be reminded of the morning and evening instillation of the study drug 
on the day prior to Visit 3 (Week 2) and Visit 4 (Week 6)/Early Termination 
respectably. 
 Subjects will be reminded that the morning instillation of the study drug at Visit 3 
(Week 2) and Visit 4 (Week 6)/Early Termination will be done at the clinic. 
 Since subjects must have a diagnosis of POAG or OHT in both eyes, both eyes should 
be treated for the duration of the study, even if only one eye is eligible per IOP 
inclusion criteria. 
 Subjects will be queried regarding compliance with the protocol’s dosing regimen at 
Visit 3 (Week 2) and Visit 4 (Week 6)/Early Termination.   
 Subjects will be counseled on proper dosing procedures and dosing schedule if the 
subject’s compliance is not 100%.  If a subject deviates from the prescribed dosage 
regimen, the specific dates of the missed doses should be recorded.   
 A subject’s dosing compliance for a specific period is determined by the total number 
of days that subject followed the proper dosing procedures and dosing schedule.  
Stoppage of study medication use, overdosing of study medication, incorrect time 
(outside of protocol-specified time point ±60 min) of study medication 
administration, will be noted as non-compliance.  The subject’s dosing compliance 
will be recorded in the subject’s source documents and on the eCRF at Visit 3  
(Week 2) and Visit 4 (Week 6)/Early Termination.   
 Subjects may be discontinued from the study at the discretion of the Investigator if 
the subject cannot be brought into compliance. 
6.5. 
Discontinue Use of All IOP-lowering Medications  
At the screening visit (Visit 1), subjects will be screened against the inclusion and exclusion 
criteria.  Eligible subjects will be instructed to discontinue use of all IOP-lowering medications, 
if any, as follows (up to +7 days is allowed):  
 Miotics: 7 days 
 Oral/topical Carbonic Anhydrase Inhibitors (CAIs): 7 days 
 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandins Analogs (PGA): 28 days 
 Rho kinase (ROCK) inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will be 
used. 


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During the required washout period, subjects who discontinue their current treatment may, if the 
investigator deems necessary, be treated with a short-acting IOP lowering agent, topical CAI, 
e.g., brinzolamide or dorzolamide eye drops, one drop twice daily.  Topical CAI treatment must 
be stopped 1 week before the randomization at Visit 2 (Baseline, Day 1).  An interim safety visit 
during the washout period (mid-washout visit: Visit 1a) may be performed if, in the 
investigator’s opinion, a subject’s IOP may be of concern during the washout period.  If subjects 
are treated with a topical CAI during the washout period, a mid-washout visit (Visit 1a) is 
recommended. 
6.6. 
Concomitant Medication/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. 
 Concomitant therapy: name of therapy, treated eye(s) (if applicable), indication, start 
date and stop date. 
6.6.1. 
Prohibited Medications or Therapies 
 All ocular medications other than sodium chloride/potassium chloride ophthalmic 
solution, cataract treatment agents (e.g., glutathione, pirenoxine), Vitamin B12 
formulation (e.g., cyanocobalamin), over-the-counter dry eye artificial tears/drops, 
and study medications during the study duration. 
 If artificial sodium chloride/potassium chloride ophthalmic solution, cataract 
treatment agents, Vitamin B12 formulation, over-the-counter dry eye artificial 
tears/drops are concomitantly used, there must be an interval of at least 5 
minutes between use of these ocular medications and use of the study medication. 
 All systemic medications that are ocular hypotensive agents (e.g., oral or intravenous 
CAI, oral glycerol) during the study duration. 
 Any ocular, periocular, inhaled, nasal or systemic corticosteroids including joint 
injection, etc.  during the study duration. 
 Lacrimal/punctal occlusion via plug (s) or cautery, dry eye treatments or devices that 
require a prescription such as, TrueTear®, during the study duration.   
 Initiate or modify any systemic or topical medication known to affect IOP  
(e.g., β-adrenergic antagonists, α-adrenergic agonists, calcium channel blockers, ACE 
inhibitors, and ARB) within the first 30 days prior to Visit 1 (Screening) and during 
the study duration. 


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 Contact lenses within 2-3 weeks prior to Visit 2 (Baseline, Day 1) until end of 
treatment in either eye. 
 Any ocular surgery or ocular laser treatment within 180 days prior to Visit 1 
(Screening) and throughout the study in either eye. 
 Participation in any other clinical trial involving an investigational product or device 
within 4 weeks prior to Visit 1 (Screening) and during the study. 
The decision to administer a prohibited medication or therapy should be made with the safety of 
the subject as the primary consideration.  Whenever possible, Medical Monitor should be 
notified before any prohibited medication or therapy is administered.  There may be additional 
prohibited therapies not mentioned above.  Medical Monitor should be contacted if the 
permissibility of a specific medication or therapy is in question. 
6.7. 
Dose Modification 
In this study, the study drug dose (DE-117 ophthalmic solution 0.002%) regimen (QD vs.  BID) 
is assigned by randomization.  Dose modification is not allowed. 
6.8. 
Intervention after the End of the Study 
No subsequent intervention is currently planned for subjects after completing 6-week treatment 
period.   


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
Subjects may be discontinued from study drug administration for adverse events, 
non-compliance with study treatment, protocol deviation, lack of efficacy, withdrawal by 
subject, lost to follow-up, study termination, or other reasons.  The investigator or Santen 
medical monitor may discontinue a subject from further study drug administration for reasons 
related to the best interest of the subject.   
Subjects should be encouraged to continue participating in all remaining follow-up study 
visits/procedures on an observational basis when study drug administration is discontinued prior 
to the last scheduled visit (Visit 4). 
If subjects agree to continue the study participation, then to the extent possible, all procedures for 
Early Termination will be performed on the day of early drug discontinuation or at the earliest 
opportunity. 
7.2. 
Subject Discontinuation/Withdrawal from the Study 
Subjects 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.  At the time of discontinuing from the 
study, if possible, an early termination visit will be conducted to collect the data as shown in the 
SoA (Table 3); the subject will be permanently discontinued both from the study intervention 
and from the study at that time. 
If the subject withdraws consent for disclosure of future information, Santen may retain and 
continue to use any data collected before such a withdrawal of consent.  If a subject 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. 
7.2.1. 
Subject Withdrawal Criteria 
An early termination occurs when a subject who provides written informed consent ceases 
participation in the study after enrollment (Visit 2 Baseline [Day 1]), regardless of 
circumstances, and before the completion of the study.  Subjects may be voluntarily discontinued 
from study medication or withdrawn from the study at any time for any reason.  In addition, the 
Principal Investigator or Medical Monitor may discontinue the study drug administration or 
terminate a subject’s study participation due to any of the following reasons: 
 AE (e.g., not compatible with study continuation) 
 Non-compliance with study drug 
 Lack of efficacy (e.g., IOP exceeds 34 mmHg in either eye after enrollment) 
 Progressive disease 
 Protocol deviation (e.g., not fulfilling eligibility criteria) 


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 Pregnancy 
 Voluntary withdrawal by subject at any time for any reason 
 Lost to follow-up (e.g., no contact is possible) 
 Death 
 Other 
Subjects who are terminated from the study early will not be replaced. 
7.3. 
Lost to Follow up 
A subject 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 
subject fails to return to the clinic for a required study visit: 
 The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
 Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the subject’s 
medical record. 
 Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or discontinuation of the study is handled as indicated in 
Section 10.1.11. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Table 3).  Protocol waivers or 
exemptions are not allowed. 
Immediate safety concerns should be discussed with Santen immediately upon occurrence or 
awareness to determine if the subject 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 subjects 
meet all eligibility criteria.  The investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable. 
Procedures conducted as part of the subject’s routine clinical management 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 
(Table 3) and Procedures of Assessments (Section 8.2). 
The amount of blood collected from each subject over the duration of the study, including any 
extra assessments that may be required around is 10 mL for subjects who consent to the optional 
pharmacogenomics/genomics laboratory study.  Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples. 
8.1. 
Visit Details 
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 
pharmacogenomics/genomics laboratory research study may be obtained at any visit 
prior to blood sampling.  Ensure the subject understands that if he/she does not wish 
to provide a blood sample for the pharmacogenomics/genomics laboratory research 
study that their decision will have no influence on their participation in the main 
study. 
 Prepare the list of screening/registration of subjects. 
 Obtain demographics. 
 Obtain medications, procedures/therapies and medical history including all lifetime 
ocular medical history to the extent possible, non-ocular medical history within  
5 years, diagnosis, ocular surgical history, current ocular and systemic conditions. 
 Obtain urine and perform urine pregnancy test, if the subject is a female of child-
bearing potential. 
 As per the SoA (Table 3) and Procedures of Assessments (Section 8.2), perform the 
following procedures or assessments (all ophthalmic procedures to be performed in 
both eyes): 
 


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 Refraction 
 BCVA (prior to IOP measurement) 
 Gonioscopy  
 Visual field  
 Biomicroscopy (prior to IOP measurement) 
 IOP 
 Pachymetry (after IOP measurement)  
 Ophthalmoscopy with pupil dilation (after IOP measurement) 
 Determine if the subject meets eligibility criteria. 
 Eligible subjects will be instructed to discontinue use of all IOP-lowering 
medications, if any, as follows (up to +7 days is allowed): 
 Miotics: 7 days 
 Oral/topical CAIs: 7 days 
 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandins Analogs (PGA): 28 days 
 Rho kinase (ROCK) inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will 
be used. 
 During the required washout period, subjects who discontinue their current treatment 
may, if the Investigator deems necessary for safety, be treated with a short-acting IOP 
lowing agent, topical CAI, e.g., brinzolamide or dorzolamide eye drops, one drop 
twice daily.  Topical CAI treatment must be stopped 1 week before the randomization 
at Visit 2 (Baseline, Day 1). 
 An interim safety visit during the washout period (mid-washout visit: Visit 1a) may 
be performed if, in the investigator’s opinion, a subject’s IOP may be of concern 
during the washout period.  If subjects are treated with a topical CAI during the 
washout period, a mid-washout visit (Visit 1a) is recommended. 
 The eligibility visit (Visit 2) will be scheduled at the end of the washout period for 
those subjects on prior IOP-lowering medications. 
 Subjects who have not used an IOP-lowering medication for the last 28 days, 
including treatment-naive subjects, will need a wait period of ≥ 1 day before their 
Visit 2 (Baseline, Day 1). 


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 If a subject does not require washout from an IOP-lowering medication, but they 
use contact lenses in either eye, they will need a wait period of ≥ 2-3 weeks  
(2 weeks for soft contact lens wearers, and 3 weeks for rigid contact lens wearers) 
with no contact use before their Visit 2 (Baseline, Day 1). 
 Schedule the eligible subject to return for Visit 2 (Baseline, Day 1) after the required 
wait/washout period. 
 A subject who does not meet eligibility criteria or will not otherwise continue in the 
study is considered a screen failure. 
8.1.2. 
Visit 1a (Optional, Washout Period) 
 Visit 1a is an interim safety visit (referred to as mid-washout visit) that may be 
performed during the washout period if, in the Investigator’s opinion, a subject’s IOP 
causes any safety concern during washout period. 
 Update concomitant medications and procedures/therapies. 
 Query the subject regarding AEs. 
 As per the SoA (Table 3) and Procedures of Assessments (Section 8.2), perform the 
following procedures or assessments (all ophthalmic procedures to be performed in 
both eyes): 
 BCVA (prior to IOP measurement) 
 Biomicroscopy (prior to IOP measurement) 
 IOP 
8.1.3. 
Visit 2 (Baseline, Day 1) 
 Update concomitant medications and procedures/therapies. 
 Confirm the subject has complied with the required wait/washout period for ocular 
hypotensive medication(s), or contact lenses use, if required. 
 Query the subject regarding AEs. 
 Obtain urine and perform urine pregnancy test, if the subject is a female of child-
bearing potential. 
 As per the SoA (Table 3) and Procedures of Assessments (Section 8.2), perform the 
following procedures or assessments immediately before the 08:00 IOP measurement 
(all ophthalmic procedures to be performed in both eyes): 
 BCVA (prior to the 08:00 IOP measurement) 
 If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Biomicroscopy (prior to the 08:00 IOP measurement) 
 Perform IOP measurement at 08:00 (±60 min). 


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 If subject meets the 08:00 IOP eligibility requirements, schedule additional IOP 
measurements at 12:00. 
 Perform IOP measurement at 12:00 (±60 min). 
 If subject meets the 08:00 and 12:00 IOP eligibility requirements, schedule 
additional IOP measurements at 16:00 
 Perform IOP measurement at 16:00 (±60 min). 
 Perform ophthalmoscopy in both eyes after the 16:00 IOP measurement. 
 Perform final review of eligibility criteria after the 16:00 IOP measurement and 
ophthalmoscopy.  The subject will then be randomized, via Interactive Response 
Technology (Medidata Balance/RTSM). 
 A subject who does not meet eligibility criteria or will not otherwise continue in the 
study is considered a screen failure. 
 After the subject has been randomized to a treatment arm, and assigned a treatment 
kit by Balance/RTSM, a study staff member must: 
 Dispense the assigned kit to the subject which will contain the following;  
 Two (2) bottle of study drug labeled “morning” 
 Two (2) bottle of study drug labeled “evening” 
 Give the subject verbal and written instructions for proper instillation of the study 
medication, the dosing schedule and regimen, and study medication storage. 
 Instruct the subject to instill the study medicine daily, starting from this evening 
(“evening” dose) (20:00). 
 Schedule the subject to return on Day 15 ± 2 for Visit 3 (Week 2). 
 Inform the subjects they will be reminded of the morning and evening instillation of 
the study medication by phone call a few days before Visit 3. 
 Remind the subjects that the morning dose of Visit 3 will be done at the clinic. 
 Remind the subject to bring all used and unused study medication at Visit 3.   
8.1.4. 
Visit 3 (Week 2, Day 15 ± 2) 
 Update concomitant medications and procedures/therapies. 
 A study staff member should query the subject regarding dosing compliance and 
ensure subject has sufficient study medication to complete dosing through Visit 4.   
 Subjects will be counseled on proper dosing procedures and dosing schedule if the 
subject’s compliance is not 100%.  If a subject deviates from the prescribed 
dosage regimen, the specific dates of the missed doses should be recorded. 
 Query the subject regarding AEs. 


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 As per the SoA (Table 3) and Procedures of Assessments (Section 8.2), perform the 
following procedures or assessments immediately before the 08:00 IOP measurement 
(all ophthalmic procedures to be performed in both eyes): 
 BCVA (prior to the 08:00 IOP measurement) 
 If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Biomicroscopy (prior to the 08:00 IOP measurement) 
 Perform IOP measurement at 08:00 (±60 min). 
 Instill study medication/eye drop after the 08:00 IOP measurement in both eyes.  A 
study staff should make sure the instillation is performed. 
 Perform IOP measurement at 12:00 and 16:00 (±60 min). 
 If the subject provided written consent to provide a blood sample for a future 
pharmacogenomics/genomics laboratory research study, collect the sample at this 
visit or subsequent visit prior to exit from the study. 
 Note: If a blood sample cannot be collected at this visit, it may be collected at 
Visit 4 or unscheduled or early termination visit. 
 Schedule the subject to return on Day 43±3 for Visit 4 (Week 6). 
 Remind the subject to continue dosing according to the written instructions. 
 Inform the subjects they will be reminded of the morning and evening instillation of 
the study medication by phone call a few days before Visit 4. 
 Remind the subjects that the morning dose of Visit 4 will be done at the clinic. 
 Remind the subject to bring all used and unused study medication at Visit 4. 
8.1.5. 
Visit 4 (Week 6, Day 43 ± 3) Study Exit/Early Termination 
 Update concomitant medications and procedures/therapies. 
 A study staff member should query the subject regarding dosing compliance. 
 If a subject deviates from the prescribed dosage regimen, the specific dates of the 
missed doses should be recorded.   
 A study staff member must collect all used bottles of study medication. 
 Query the subject regarding AEs. 
 Obtain urine and perform urine pregnancy test, if the subject is a female of  
child-bearing potential. 
 As per the SoA (Table 3) and Procedures of Assessments (Section 8.2), perform the 
following procedures or assessments immediately before the 08:00 IOP measurement 
(all ophthalmic procedures to be performed in both eyes): 
 BCVA (prior to the 08:00 IOP measurement) 


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 If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Biomicroscopy (prior to the 08:00 IOP measurement) 
 Perform IOP measurement at 08:00 (±60 min). 
 Instill study medication/eye drop after the 08:00 IOP measurement in both eyes.  A 
study staff should make sure the instillation is performed. 
 Perform IOP measurement at 12:00, and 16:00 (±60 min). 
 Perform pupil dilation in both eyes after the 16:00 IOP measurement. 
 Perform ophthalmoscopy with pupil dilation in both eyes after the 16:00 IOP 
measurement. 
 If the subject provided written consent to provide a blood sample for a future 
pharmacogenomics/genomics laboratory research study, the sample must be collected 
at this visit, if not collected at the previous visits. 
 Exit the subject from the study. 
Note: If a subject’s study participation is terminated prior to Visit 4, then, to the extent 
possible, all scheduled Visit 4 procedures will be performed at the earliest visit or on the 
day of early termination. 
Note: If subject requires an unscheduled visit, procedures and assessments will be 
performed as needed. 
8.2. 
Procedures of Assessments 
8.2.1. 
Efficacy Assessments 
8.2.1.1. 
Intraocular Pressure 
IOP will be performed at each visit.  At Visit 1 (Screening) and Visit 1a (optional, mid-washout 
visit), IOP can be measured at any time.  For Visit 2 to Visit 4 Study Exit/Early Termination, 
IOP measurements will be scheduled for 08:00 (±60 min), 12:00 (±60 min) and 16:00 (±60 min). 
IOP will be measured using calibrated manual Goldmann applanation tonometer.  Measurement 
will be performed preferably by the same Investigator (operator) and the same authorized study 
staff member (recorder) throughout the study.  Investigator (operator) who performs the IOP 
measurement must have at least 2 years of experience in IOP measurement. 
The right eye is always tested first.  At least two, and sometimes three, consecutive 
measurements are made to obtain a determination of IOP.  Each IOP measurement and the clock 
time of IOP measurement will be recorded in the subject’s source document. 
A single measurement is made as follows: 
 The Investigator adjusts the force on the tonometer dial to an initial setting 
corresponding to 10 mmHg.  The slit-lamp magnification is set at 10X.  The light 


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source is positioned at an angle of approximately 45º, and the aperture is maximally 
opened.  A cobalt blue filter is employed. 
 After instillation of a topical anesthetic, a fluorescein paper strip is placed near the 
lateral canthus in the lower conjunctival sac.  Once the lacrimal fluid is sufficiently 
colored, the paper strip is removed.  Alternatively, one drop of premixed fluorescein 
and anesthetic (Fluress, Barnes Hind) may be instilled.  The Investigator should use 
the same technique each time, be it a paper strip or a pre-mixed eye drop. 
 The subject and slit-lamp are adjusted so that the subject’s head is firmly positioned 
on the chin rest and against the forehead rest without leaning forward or straining.  
Tight-fitting neckwear is loosened.  The subject is asked to look straight ahead at a 
distant object or fixation target.  If it is necessary to hold the eyelids open, the 
Investigator holds the eyelids against the orbit rim, taking care not to apply any 
pressure to the globe.  The subject is cautioned not to hold his breath. 
 The Investigator looks through the slit-lamp and gently brings the tip of the prism into 
contact with the center of the cornea.  The mires are well-focused, centered 
horizontally, and positioned vertically so that they are of equal circumference above 
and below the horizontal dividing line.  If the mires are narrower than approximately 
1/10 their diameter, additional fluorescein is instilled. 
 The Investigator adjusts the measuring drum until the inner borders of the two mires 
just touch each other or, if pulsation is present, until the mires separate a given 
distance during systole and overlap the same distance during diastole. 
 The Investigator removes the tip from the cornea, and the authorized study staff 
(recorder) records the reading on the dial, rounded to the next highest integer.  For 
example, if the measurement indicated is between 16 and 17, then 17 is recorded as 
the measurement in the subject’s source document. 
 The Investigator may also be the recorder instead of an authorized study staff 
member, if a study staff member was not assigned. 
 If corneal astigmatism is greater than 3.0 D, the prism is rotated so that the red line 
corresponds to the orientation of the longer axis of the elliptical applanated area. 
The above procedure is then repeated for the same eye, and that second measurement is also 
recorded in the subject’s source document. 
 If the two measurements differ by less than 3 mmHg, then the average of the two 
measurements becomes the recorded IOP.  For example, if the two measurements are 
22 and 23, then 22.5 is the final recorded IOP. 
 However, if the two measurements differ by 3 mmHg or more, then a third 
measurement is made, and the median of the three measurements becomes the 
recorded IOP (the median is the middle measurement after ordering the 
measurements from low to high).  For example, if the three measurements are 15, 19, 
and 16, then 16 is the final recorded IOP. 
The IOP in the left eye is then measured using the same technique. 


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8.2.1.1.1. Goldmann Applanation Tonometer Calibration 
It is mandatory for every tonometer used in the study to be calibrated for accuracy before the 
first subject undergoes screening.  Thereafter, the calibration must be checked monthly until the 
last subject has exited the study.  For calibration checks, the manufacturer’s instructions should 
be followed.  If the variation is within ±2 mmHg, the tonometer is considered adequately 
calibrated.  However, if the variation exceeds this amount, the tonometer should be sent for 
repair and a different, adequately calibrated instrument should be used for IOP measurement.  
The date of each calibration, along with the name and signature (or initials) of the person who 
performed the calibration, will be documented.  The tonometer calibration record will be retained 
as a part of the study record. 
8.2.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 3). 
8.2.2.1. 
Demographics, Medication/Therapy and Medical History 
Demographics, Medication/Therapy and Medical History will be obtained through subject 
interviews at Visit 1 (Screening) to determine if the subject meets eligibility criteria. 
Demographics 
Demographics include age, sex, race, prostaglandin analogs naïve status, and ethnicity.  They 
must be confirmed and recorded in the source documents. 
Medical and Surgical History  
Followings must be confirmed. 
 Non-ocular medical history including diagnosis and relevant treatments within 5 
years before the date of Visit 1 
 All lifetime ocular medical history including diagnosis and relevant treatments 
 All current ocular and systemic conditions 
Following details must be recorded in the source documents. 
 Diagnosis and treatment(s), affected eye(s) (if applicable), start date and resolved 
date. 
Medications 
Following must be confirmed. 
 Prior medications that have been used for POAG or OHT within 28 days before the 
date of Visit 1 (Screening) 
 All concomitant medications (including over-the-counter) 
Following details must be recorded in the source documents. 
 Name of medication, route of administration, treated eye(s) (if applicable), dose, 
frequency, indication, start date and stop date 
 


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Therapies 
Following must be confirmed. 
 Prior therapies that have been used for POAG or OHT within 28 days before the date 
of Visit 1 (Screening) 
 All concomitant therapies 
Following details must be recorded in the source documents. 
 Name of therapy, treated eye(s) (if applicable), indication, start date and stop date 
Surgical procedures occurring during the study 
Following details must be recorded in the source documents. 
 Name of surgical procedure, treated eye(s) (if applicable), indication, start date and 
stop date 
8.2.2.2. 
Pregnancy Test 
A urine pregnancy test will be conducted using a commercially available test kit at Visit 1 
(Screening), Visit 2 (Baseline, Day 1), and Visit 4 Study Exit/Early Termination for all females 
of childbearing potential.  A female is considered of childbearing potential unless she is post-
menopausal (at least 12 months since last menses occurred), is without a uterus or without both 
ovaries, or has had a bilateral tubal ligation.  To perform the pregnancy test, follow instructions 
provided by the manufacturer of the urine pregnancy test kit. 
8.2.2.3. 
Refraction 
Refraction will be performed for each eye at Visit 1 (Screening).  At Visits 2 to 4, if more than 
10 letters in BCVA were lost compared to the screening visit, then refraction should be 
performed again. 
8.2.2.4. 
Best-Corrected Visual Acuity 
Best-Corrected Visual Acuity (BCVA) will be measured for each eye prior to the 08:00 (±60 
min) IOP measurement at all visits except for Visit 1 (Screening) and Visit 1a (optional,  
mid-washout visit).  For Visit 1 (Screening) and Visit 1a (optional, mid-washout visit), BCVA 
will be performed prior to IOP measurement.  BCVA will be measured under normal room 
illumination using visual acuity chart (ETDRS chart) and the logMAR scoring will be recorded 
in the subject’s source document.  The following procedure should be followed using ETDRS 
chart for BCVA testing. 
8.2.2.4.1. ETDRS Visual Acuity Scoring 
The Examiner records each letter identified correctly by circling the corresponding letter on an 
appropriate visual acuity worksheet.  The Examiner records a letter read incorrectly, or a letter 
for which the subject made no guess, by crossing the letter out with an “x” or a line.  Each letter 
read incorrectly is scored as one point.  The last line in which a letter is read correctly will be 
taken as the Base logMAR line. 


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The total number of letters that have an “x” or a line through them (letters read incorrectly or not 
at all) down to and including the Base logMAR line, and multiply the total number by 0.02.  Add 
this value to the Base logMAR value to obtain the logMAR score. 
Example: 
Subject correctly reads 4 of 5 letters on the +0.2 line, and 2 of 5 letters on the +0.1 line, and 
zero letters on the 0.0 line 
Base logMAR value = +0.1 (last line in which a letter was read correctly) 
Total number of letters missed = 4 (number of letters missed on the +0.2 line plus the number 
missed on the +0.1 line) 
LogMAR score = +0.1 + (4 x 0.02) = 0.18 
Table 6: 
LogMAR Scoring Grid for ETDRS Eye Chart 
 
Total Number of Letters Missed 
Snellen 
Base 
LogMAR 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
20/200 
+1.0 
1.00 
1.02 
1.04 
1.06 
1.08 
--- 
--- 
--- 
--- 
--- 
--- 
20/160 
+0.9 
0.90 
0.92 
0.94 
0.96 
0.98 
1.00 
1.02 
1.04 
1.06 
1.08 
1.10 
20/125 
+0.8 
0.80 
0.82 
0.84 
0.86 
0.88 
0.90 
0.92 
0.94 
0.96 
0.98 
1.00 
20/100 
+0.7 
0.70 
0.72 
0.74 
0.76 
0.78 
0.80 
0.82 
0.84 
0.86 
0.88 
0.90 
20/80 
+0.6 
0.60 
0.62 
0.64 
0.66 
0.68 
0.70 
0.72 
0.74 
0.76 
0.78 
0.80 
20/63 
+0.5 
0.50 
0.52 
0.54 
0.56 
0.58 
0.60 
0.62 
0.64 
0.66 
0.68 
0.70 
20/50 
+0.4 
0.40 
0.42 
0.44 
0.46 
0.48 
0.50 
0.52 
0.54 
0.56 
0.58 
0.60 
20/40 
+0.3 
0.30 
0.32 
0.34 
0.36 
0.38 
0.40 
0.42 
0.44 
0.46 
0.48 
0.50 
20/32 
+0.2 
0.20 
0.22 
0.24 
0.26 
0.28 
0.30 
0.32 
0.34 
0.36 
0.38 
0.40 
20/25 
+0.1 
0.10 
0.12 
0.14 
0.16 
0.18 
0.20 
0.22 
0.24 
0.26 
0.28 
0.30 
20/20 
0.0 
0.00 
0.02 
0.04 
0.06 
0.08 
0.10 
0.12 
0.14 
0.16 
0.18 
0.20 
20/16 
-0.1 
-0.10 
-0.08 
-0.06 
-0.04 
-0.02 
0.00 
0.02 
0.04 
0.06 
0.08 
0.10 
20/12.5 
-0.2 
-0.20 
-0.18 
-0.16 
-0.14 
-0.12 
-0.10 
-0.08 
-0.06 
-0.04 
-0.02 
0.00 
20/10 
-0.3 
-0.30 
-0.28 
-0.26 
-0.24 
-0.22 
-0.20 
-0.18 
-0.16 
-0.14 
-0.12 
-0.10 
8.2.2.5. 
Slit-lamp Biomicroscopy 
As described below, slit-lamp biomicroscopy examinations will be performed and graded 
immediately prior to the 08:00 (±60 min) IOP measurement at all visits except for Visit 1 
(Screening) and Visit 1a (optional, mid-washout visit).  For Visit 1 (Screening) and Visit1a 
(optional, mid-washout visit), the biomicroscopy examinations should be performed prior to IOP 
measurement.  Some exception can be applied, if pupil dilation is required for evaluation.  For 
example, the possible tear(s) in the posterior lens capsule.  The slit-lamp exam for posterior lens 
capsule can be performed after the pupil dilation, that is at 16:00 after IOP measurement.   


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Anterior chamber cells and flare will be observed and graded using the Standardization of 
Uveitis Nomenclature (SUN) scale, before fluorescein instillation. 
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) 
 
The lid, conjunctiva, cornea, lens, and iris will be observed and graded on a 4-point scale (0-3 
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 


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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 
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 
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 Synechiae of Iris 
None 
(0) = No anterior synechiae of iris is found 


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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 
8.2.2.6. 
Pachymetry (Central Corneal Thickness) 
The central corneal thickness (µm) of each eye using any pachymeter including optical 
pachymeter, ultrasound pachymeter, OCT (optical coherence tomography) etc.  will be measured 
and recorded after IOP measurement at Visit 1 (Screening).  Pachymetry should be performed 
after IOP measurement.  The same pachymeter should be used during the course of the study. 
8.2.2.7. 
Gonioscopy 
Gonioscopy will be performed to examine the angle of the anterior chamber after IOP 
measurement at Visit 1 (Screening), if it has not been performed within 3 months (90 days).  The 
Shaffer scale will be used to rate the degree of angle closure. 
(0) = approximately 5 degrees or less, complete or partial closure 
(1) = approximately 10 degrees 
(2) = approximately 20 degrees 
(3) = approximately 30 degrees 
(4) = approximately 40 degrees or more 
8.2.2.8. 
Visual Field 
Visual field examinations will be performed using a static or dynamic perimeter (Humphrey or 
Octopus) without pupil dilation at Visit 1 (Screening), if this has not been performed within  
3 months (90 days) or the previous visual field test(s) indicates low subject reliability (e.g., due 
to fixation losses, false positive errors, or false negative errors).  Glaucomatous visual field loss 
will be evaluated by the Investigator as presence or absence (mean deviation, pattern SD, 
glaucoma hemifield test, and type of glaucomatous visual field loss). 
Visual field tests that, in the Investigator's opinion, indicate low subject reliability (e.g., due to 
fixation losses, false positive errors, or false negative errors) should be excluded.  A copy of the 
computer printout from the visual field test(s) will be attached to the subject’s source documents. 
8.2.2.9. 
Ophthalmoscopy (Fundus) Examination 
The ophthalmoscopy (fundus) examination will be performed for each eye at Visit 1 (Screening), 
Visit 2 (Baseline, Day 1), and Visit 4 Study Exit/Early Termination, and graded as described 


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below.  Ophthalmoscopy will be performed under dilation at Visit 1 (Screening) and Visit 4 
Study Exit/Early Termination.  Pupil dilation must be performed after all other ocular procedures 
have been completed.  Cup to disc ratio and abnormality in retina, macula, choroid, and vitreous 
will also be evaluated. 
Glaucomatous Optic Nerve Findings 
The optic nerve will be evaluated using a 4-point scale (0-3 scale). 
None 
(0) = No damage 
Mild 
(1) = Optic nerve damage, secondary to glaucoma including any rim loss 
(sloping or thinning) 
Moderate (2) = Optic nerve damage, including cupping to disc margin at one or more 
points 
Severe 
(3) = Optic nerve damage, nearly total cupping, only nasal rim or less present 
8.2.2.10. Events of Special Interest (ESIs) 
Events of Special Interest (ESIs) are medical events both anticipated and unanticipated that may 
have particular impact on the benefit/risk profile of DE-117 and therefore may require more 
detailed characterization.  The DE-117 ESIs are as follows: 
 Pregnancy: 
 There are no controlled data with the investigational product in human pregnancy.  
It is required that females of childbearing potential use effective contraception 
during the study and recommended for 4 weeks for female subjects of 
childbearing potential and 12 weeks for male subjects capable of fathering 
children after the completion of the study.  Any pregnancy occurring during study 
treatment should be reported and the subject will be discontinued from the study.  
The subject should be followed until the end of pregnancy or until the end of the 
study, whichever is longer. 
 Medication administration errors 
 Study medication administration errors determined to be significant by the 
Investigator will be reported and evaluated as ESIs.  Examples of study 
medication administration errors may include, but are not limited to: incorrect 
dose of study medication and administration of study medication from an 
incorrect kit.  An AE does not necessarily need to have occurred to count as a 
study medication administration error.  A medication administration error is an 
unintended failure in the process of treatment with a medicinal product that leads 
to, or has the potential to lead to harm of the subject. 
 Macular edema (including cystoid macular edema): 
 Macular edema has been reported in some patients during the DE-117 clinical 
trials.  Any cases of macular edema (including cystoid macular edema) should be 
reported in the ESI form in eCRF, or in case the Electronic Data Capture (EDC) 
system is down, in the manual ESI form.  Any cases of macular edema (including 


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cystoid macular edema) will need to be followed until the event is determined to 
be resolved, irreversible, chronic, stable, the subject withdraws consent, or no 
further information can be reasonably obtained as per Section 8.3.3. 
Most ESIs are AEs, some ESIs may also be SAEs, and some ESIs may not be AEs (e.g., an IP 
administration error may not be an AE; pregnancies are not AEs).  However, all ESIs should be reported 
within 24 hours of knowledge of the event using applicable eCRFs and recording as much information as 
available.  ESIs should be followed by the investigator to the same extent as SAEs, that is, until the event 
is determined to be resolved, irreversible, chronic, stable, the subject withdraws consent, or no further 
information can be reasonably obtained.  Monitoring for pregnancy and follow-up of pregnancy is 
described in Section 8.3.5. 
8.2.3. 
Other Assessments 
8.2.3.1. 
Blood Sample for Pharmacogenomics/genomics Study 
For sites which elect to participate and for subjects who agree to provide a blood sample, an 
exploratory biomarker laboratory research study will be performed to evaluate the association of 
possible genetic biomarkers with the study drug(s) and/or ophthalmologic conditions.  
Approximately 10 mL of blood will be collected for genetic analysis from the subject and stored 
until shipment.  Please refer to the separate procedure manual for sample handling, storage, and 
shipment.  The samples will be coded to protect the subjects’ private information.  Nucleic acids 
will be extracted from blood sample and stored in the repository for future 
pharmacogenomics/genomics studies performed by appropriate assay platforms such as PCR 
(Polymerase Chain Reaction), hybridization, and sequencing on the genes involved in the study 
drug(s) and/or ophthalmologic conditions.  Individual subjects’ results from the research testing 
on their samples will not be communicated to them. 
Samples collected and stored, and relevant documents (the list of screening/registration of 
subjects only for documents to be retained by the medical institution) will be retained for the 
period agreed in the ICF.  Upon completion of analyses or the retention period, they will be 
anonymized and discarded.  If the subject withdraws the consent, samples will be immediately 
disposed, and the applicable subject will be informed in writing. 
For any other matters not specified in the protocol, a written procedure will be defined 
separately. 
8.2.3.2. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.2.3.3. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.2.3.4. 
Pharmacokinetics 
PK parameters are not evaluated in this study. 


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8.2.4. 
Study Supplies 
Commercial urine pregnancy test kits and customized blood sample collection kits for the 
pharmacogenomics/genomics will be provided by Santen (or designee). 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Section 10.2. 
AE 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, SAE or ESI and remain responsible for 
following up AEs that are serious, considered related to the study intervention or study 
procedures, or that caused the subject to discontinue the study intervention (see Section 7).   
8.3.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the ICF until the subject withdrawals or 
completes the scheduled exit visit.   
All AEs will be collected from the signing of the ICF until the subject withdrawals or completes 
the scheduled exit visit.   
All SAEs and ESIs will be recorded and reported to Santen or designee immediately and under 
no circumstance should this exceed 24 hours, as indicated in Section 10.2.  The investigator will 
submit any updated SAE or ESI data to Santen 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 
a subject 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 
Santen. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE, SAE and ESI and the 
procedures for completing and transmitting SAE reports are provided in Section 10.2. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of AEs and SAEs 
All reported AEs should be followed by the investigator until resolution or until the subject’s 
participation in the study ends. 
More extensive follow-up is required for (1) SAEs, (2) ESIs and (3) IP related AEs that lead to 
or cause early withdrawal of a subject from the study.  All of these types of events should be 
followed by the investigator until the event is determined to be resolved, irreversible, chronic, 
stable, the subject withdraws consent, or no further information can be reasonably obtained.  In 


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addition to the above, Santen (or designee) may request, on a case-by-case basis, follow up of 
events/subjects beyond the scheduled exit visit. 
Prior to database lock, follow-up information on an individual SAE or AE (or ESI) will be 
entered into the eCRF.  When database lock has already been completed, or if information 
requested by Santen is not part of the eCRF, the site’s response to follow-up requests should be 
emailed or documented on paper and faxed to Santen Global Pharmacovigilance  
(see Table 1). 
8.3.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to Santen of a SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects and the safety of a study intervention 
under clinical investigation are met. 
Santen 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.  Santen will comply 
with country-specific regulatory requirements relating to safety reporting to the regulatory 
authority, IRB/IEC and investigators. 
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 Santen 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 
8.3.5.1. 
Female subjects who become pregnant 
The investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study.  Information will be recorded in eCRF and on the 
appropriate manual form and submitted to Santen within 24 hours of learning of a subject's 
pregnancy.  The subject will be followed to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to Santen.  Generally, follow-up will not be required for longer 
than 6 to 8 weeks beyond the estimated delivery date.  Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure.  While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an Event of Special 
Interest (ESI).  Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as such.   
Any post-study pregnancy-related SAE considered reasonably related to the IP by the 
investigator will be reported to Santen.  While the investigator is not obligated to actively seek 
this information in former study subjects, he or she may learn of an SAE through spontaneous 


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reporting.  Any female subject who becomes pregnant while participating in the study will 
discontinue IP and be withdrawn from the study. 
8.3.5.2. 
Male subjects with partners who become pregnant 
The investigator will attempt to collect pregnancy information on any male subject’s female 
partner who becomes pregnant while the male subject is in this study.  After obtaining the 
necessary signed informed consent from the pregnant female partner directly, the investigator 
will record pregnancy information on the appropriate form and submit it to Santen within 24 
hours of learning of the partner’s pregnancy. 
8.4. 
Treatment of Overdose 
Overdose is unlikely to occur after ocular administration.  If overdose occurs, treatment should 
be symptomatic. 
Decisions regarding dose interruptions will be made by the investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the subject. 
8.5. 
Health Economics/Medical Resource Utilization and Health 
Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 


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9. 
STATISTICAL CONSIDERATIONS 
This section outlines 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). 
Unless specified otherwise, efficacy measures will be summarized by planned (i.e., randomized) 
treatment and based on the FAS population, and safety measures will be summarized by actual 
treatment received and based on the Safety population.  All AEs will be analyzed at the subject 
level.  Other safety assessments that pertain to the eye may be analyzed by the study eye and 
fellow eye separately.   
Continuous variables will be summarized using descriptive statistics such as number of 
observations (n), mean, standard deviation, medium, minimum, and maximum.  Categorical 
variables will be tabulated using frequency (n) and percent (%).   
All data manipulations, descriptive summaries, and statistical hypothesis testing will be 
performed using Statistical Analysis System (SAS) Version 9.4 or later.  Food and Drug 
Administration (FDA) guidance regarding case report tabulations (annotated eCRFs, SAS 
datasets, metadata, and SAS programs) in electronic submissions will be followed.  Data 
definition tables will be created for Study Data Tabulation Model (SDTM) and Analysis Data 
Model (ADaM) datasets separately. 
9.1. 
Statistical Hypotheses 
The primary efficacy endpoint is the IOP at each scheduled time point (08:00, 12:00 and 16:00) 
in the study eye at Week 2 and 6 (Visit 3 and 4).  The comparison between DE-117 BID arm and 
QD arm will be performed with the following hypotheses: 
H0i: µBi = µQi 
versus 
H1i: µBi ≠ µQi 
where µB and µQ denote the mean values of the primary endpoint in DE-117 BID arm and QD 
arm at i =1,2, …6 timepoints, with i = 1, 2, 3 represent 08:00, 12:00 and 16:00 at Week 2 and  
i = 4, 5, 6 represent 08:00, 12:00 and 16:00 at Week 6, respectively.   
9.2. 
Sample Size Determination 
The sample size calculation does not take into account of multiplicity from multiple time points.  
Assuming a two-sided type I error rate of 5% and a standard deviation of 3.5 mmHg, 50 patients 
per treatment arm (100 in total) will have 80% power to detect a 2.0 mmHg between-treatment 
difference. 
9.3. 
Populations for Analyses 
The following analysis populations for study analyses are defined: Safety, Full Analysis and Per-
Protocol (PP). 


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9.3.1. 
Safety Population 
The Safety Population will include all randomized subjects who received at least one dose of the 
study medication.  The safety analysis will be performed on the Safety Population and will use 
actual treatment received. 
9.3.2. 
Full Analysis Set 
The Full Analysis Set (FAS) will consist of all randomized subjects who received at least one 
dose of study medication and provided at least one post-baseline IOP measurement.  The 
efficacy analysis will be performed on the FAS and will use treatment as randomized.   
9.3.3. 
Per-Protocol Population 
The Per-Protocol (PP) Population is a subset of the FAS.  It will be the analysis population for 
sensitivity analyses and will use treatment as randomized.  Any subject affected by a significant 
protocol deviation will be excluded from the PP population.  PP Population will be identified 
before the unmasking of treatment assignments. 
9.3.4. 
Statistical Analyses 
Details of statistical analyses will be described in the SAP, which will be developed and finalized 
before database lock.  This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints. 
9.3.5. 
Handling of Missing Values  
In the analysis of IOP, subjects with missing IOP value at any timepoint at Week2 or Week6 
may be imputed using the last-observation-carried-forward (LOCF) approach for sensitivity 
analyses. 
For medical events including AEs, completely or partially missing onset and resolution dates will 
be imputed in a conservative fashion to be detailed in SAP.  The same rules will be followed to 
impute completely or partially missing start and end dates of non-study medications. 
Unless otherwise specified, descriptive summaries will be based on observed cases.  Additional 
details on handling of missing data will be provided in the SAP.   
9.3.6. 
Efficacy Analyses 
Unless specified otherwise, the efficacy analyses will be performed on the FAS, where subjects 
are classified by planned treatment, irrespective of the actual treatment received. 
9.3.6.1. 
Analysis of Primary Endpoint 
The primary efficacy endpoint is IOP in the study eye at each specified timepoint (08:00, 12:00 
and 16:00) at Week 2 (Visit 3) and Week 6 (Visit 4).  For the primary analysis, a mixed-effect 
model for repeated measures (MMRM) will be carried out and least squares mean of the 
endpoint will be reported.  The model will include treatment, visit, and treatment-by-visit 
interaction as fixed effects, baseline IOP as a covariate, and subject as a random effect.  
Treatment differences between the DE-117 BID arm and QD arm will be reported for each time 
point along with p-values and 95% confidence intervals.   


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Analysis of covariance (ANCOVA) with missing data imputed by an LOCF approach will be 
used as sensitivity analyses.   
In addition, plots of IOP measures versus analysis time/analysis visit will be provided. 
9.3.6.2. 
Analysis of Secondary Efficacy Endpoints:  
 Mean diurnal IOP in the study eye at Week 6 (Visit 4) 
 Absolute change and percent change from baseline in IOP  
 Absolute change and percent change from baseline in mean diurnal IOP  
 Having a mean diurnal IOP reduction ≥ 20%, ≥ 25%, or ≥ 30% from Baseline  
(Visit 2) at each post-baseline visit 
 Having a mean diurnal IOP ≤ 18 mmHg at each post-baseline visit 
Continuous secondary efficacy endpoints will be analyzed by a mixed-effects model for repeated 
measures (MMRM) using observed cases or analysis of covariance (ANCOVA) with missing 
data imputed by an LOCF approach.  Binary secondary efficacy endpoints will be analyzed using 
Pearson’s Chi-square test.   
9.3.7. 
Safety Analyses 
All safety analyses will be performed on the Safety Population by each actual treatment received.   
Safety of DE-117 will be primarily assessed by AEs, BCVA and evaluation with slit-lamp 
biomicroscopy and indirect ophthalmoscopy. 
Besides the overall summary of AEs, subjects with any AE(s) will be tabulated by system organ 
class (SOC) and preferred term specified in MedDRA dictionary.  They will also be tabulated by 
SOC, preferred term, and maximum severity.  For AE tables, a subject who experienced multiple 
AEs within a SOC or preferred term will be counted only once at the maximum severity for that 
SOC or preferred term.  SAEs will be tabulated similarly.  Separate summaries for ocular AEs 
and non-ocular AEs will also be performed. 
AEs leading to death, SAEs, and AEs leading to discontinuation, if any, will be listed separately.  
Events of special interest will be listed by type of event.  For other safety assessments, 
descriptive summaries of observed score, change from baseline, whichever applicable, will be 
performed. 
9.4. 
Interim Analyses  
There is no planned interim analysis for this study.   


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
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-GCP Guidelines 
 Applicable laws and regulations 
10.1.2. 
Obligations of Investigators 
In summary, the clinical investigator has agreed to the following obligations: 
 Obtaining signed and dated informed consent from every subject prior to the subject’s 
participation in any study related activity and maintaining records of consent as part 
of the study records. 
 Obtaining approval from the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) and ensuring a copy of the letter indicating IRB/IEC approval 
is available at the investigational site before involving any subject in any study 
related activity; submitting verification of the approval to Santen.  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.  Submitting the final report to IRB/IEC and to Santen. 
 Approving the protocol and conducting the study according to the protocol and 
applicable regulations; informing Santen of all deviations from the protocol. 
 Informing the IRB/IEC of all protocol amendments/modifications and obtaining 
approval for the amendment/modification from the IRB/IEC in accordance with local 
requirements before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study subjects; sending Santen 
a copy of the letter from the IRB/IEC approving the amendment/modification. 
 Reporting to Santen and the IRB/IEC any SAEs or other significant safety findings 
that occur in the course of the investigation. 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, and all other applicable local 
regulations. 
 Keeping careful and accurate records of all clinical study data (study records must be 
considerably more exact and complete than those kept in ordinary medical practice); 
maintaining records of all materials submitted to the IRB/IEC including the subject 


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consent form and recruitment materials; maintaining records of all actions by the 
IRB/IEC regarding the study. 
 Making study records available for inspection by the Sponsor (Santen) and 
representatives of the FDA and other regulatory agencies; keeping records until 
notified by the Sponsor that they may be destroyed. 
 Maintaining proper control and documentation of all test and control articles. 
 Submitting the following records and reporting to the Sponsor: 
I.  Prior to the Beginning of the Study 
 A signed Form FDA-1572, Statement of Investigator. 
 A current curriculum vitae (CV) if not submitted to Santen previously or if updated. 
 CVs for all sub-investigators listed on the FDA-1572. 
 A letter from the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) indicating that the protocol was approved, including the name and address 
of the IRB/IEC. 
 A copy of the consent form approved by IRB/IEC. 
 A list of current members of the IRB/IEC. 
 Financial disclosure (Section 10.1.3). 
II.  While the Study is in Progress 
 Acknowledgment of receipt of the test and control articles; documentation of 
disposition of all test and control articles. 
 Original Case Report Forms for each subject enrolled in the study. 
 Information regarding all deviations from the protocol. 
 Information regarding all adverse events occurring to a subject while enrolled in the 
study. 
 Annual progress report (if study is ongoing for more than one year).  Letter from the 
IRB/IEC indicating approval of the annual progress report. 
III.  Once the Study Is Completed 
 Disposition of all used and/or unused test and control articles, as well as 
documentation of all drug accountability. 
 A final study report. 
10.1.3. 
Financial Disclosure 
Investigators and sub-investigators will provide Santen with sufficient, accurate financial 
information as requested to allow Santen to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities.  Investigators are responsible 


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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 
subject or his/her legally authorized representative and answer all questions regarding 
the study.  Each subject should be allowed time to consider the information provided.   
 Subjects must be informed that their participation is voluntary and that they are free 
to discontinue from the study at any time.  Subjects 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 Informed Consent Form must be approved by the governing IRB or IEC. 
 The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained.  The subject’s signed and dated informed consent must be obtained 
before any protocol-directed procedures are performed. 
 The subjects signature must be witnessed by the authorized person obtaining the 
informed consent.  If the investigator obtains informed consent, then the subjects 
signature must be witnessed by another individual (e.g., member of the site staff).   
 The investigator or authorized person obtaining the informed consent must also sign 
and date the IRB-approved Informed Consent Form where designated. 
 Subjects must be re-consented to the most current version of the IRB-approved ICF(s) 
during their participation in the study.   
 The Principal Investigator(s) must maintain the original, signed Informed Consent 
Form with the study records.  A copy of the ICF(s) must be provided to the subject or 
the subject’s legally authorized representative.   
 The ICF will contain a separate section that addresses blood samples collected and 
stored for subsequent pharmacogenomics/genomics analysis by Santen.  The 
investigator or authorized designee will explain to each subject the objectives of this 
exploratory research.  Subjects 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 storage 
period.  A separate signature will be required to document a subject's consent to 
participate in the pharmacogenomics/genomics blood sampling and allow collected 
sample to be used for exploratory research.  Subjects who decline to participate in this 
optional research will not provide this separate signature. 
See Section 10.1.4.1 for further details on the content of informed consent. 
 


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10.1.4.1. Elements of Informed Consent 
I. 
Elements of Informed Consent 
The following information must be provided to each subject in obtaining informed consent.  If 
written consent is being obtained, the subject (or subject’s legal representative) should be 
provided with a copy of the signed written Informed Consent Form.   
1. State that the study involves RESEARCH. 
A. 
Explain the PURPOSE of the research. 
B. 
State the expected DURATION of the subject’s participation. 
C. 
Describe the PROCEDURES to be followed. 
D. 
Identify any EXPERIMENTAL procedures. 
2. Describe any reasonably foreseeable RISKS OR DISCOMFORTS to the subject. 
3. Describe any BENEFITS to the subject or to others that may reasonably be expected 
from the research.   
4. Note appropriate ALTERNATIVE procedures or courses of treatment, if any, that might 
be advantageous to the subject. 
5. Describe the extent, if any, to which CONFIDENTIALITY of records identifying the 
subject will be maintained.  Note that regulatory agencies MAY INSPECT the records. 
6. For research involving more than minimal risk, explain if any COMPENSATION or 
medical treatments are available should injury occur.  If so, explain what they consist of, 
OR where further information may be obtained. 
7. Tell whom to contact for ANSWERS to pertinent questions about the research, and 
research subjects’ rights and whom to contact in the event of a research-related INJURY 
to the subject. 
8. State that participation is VOLUNTARY, refusal to participate will involve NO 
PENALTY or loss of benefits to which the subject is otherwise entitled, and the subject 
MAY DISCONTINUE participation at any time without penalty or loss of benefits to 
which the subject is otherwise entitled. 
II. 
Additional Elements of Informed Consent 
When appropriate, one or more of the following elements of information shall also be provided 
to each subject:  
1. A statement that particular treatment or procedure may involve risks to the subject (or to 
the embryo or fetus, if the subject is or may become pregnant) which are currently 
unforeseeable. 
2. Anticipated circumstances under which the subject’s participation may be terminated by 
the investigator without regard to the subject’s consent. 
3. Any additional costs to the subject that may result from participation in the research. 


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4. The consequences of a subject’s decision to withdraw from the research and procedures 
for orderly termination of participation by the subject. 
5. A statement that significant new findings developed during the course of the research, 
which may relate to the subject’s willingness to continue participation, will be provided 
to the subject. 
6. The approximate number of subjects involved in the study. 
The informed consent requirements in this protocol are not intended to preempt any applicable 
Federal, State, or local laws which require additional information to be disclosed for informed 
consent to be legally effective. 
Nothing in this protocol is intended to limit the authority of a physician to provide emergency 
medical care to the extent the physician is permitted to do so under applicable Federal, State, or 
local law. 
REFERENCE: 21 CFR Part 50.25 – PROTECTION OF HUMAN SUBJECTS, Elements of 
Informed Consent. 
10.1.5. 
Data Protection 
 Subjects will be assigned a unique identifier by Santen.  Any subject records or 
datasets that are transferred to Santen will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.   
 The subject must be informed that his/her personal study-related data will be used by 
Santen in accordance with local data protection law.  The level of disclosure must 
also be explained to the subject.   
 The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by 
Santen, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.6. 
Data Quality Assurance 
 All subject data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to Santen 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. 


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 Santen or designee is responsible for the data management of this study including 
quality checking of the data.   
 Santen 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 subjects 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 for 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.   
10.1.7. 
Source Data 
Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data should be accurate, legible, 
contemporaneous, original, attributable, complete and consistent.  Source data is documented in 
source documents which may be both electronic and on paper. 
The Investigator(s) should be aware about the location of the source data and consistent in 
recording them.  The intended location should be clearly defined prior to subject enrollment.  
One way of achieving this is to generate a source data location list.  The source data location list 
will be prepared by the site and will be signed and dated by the Principal Investigator.  The list 
will be filed in the Investigator’s trial master file. 
10.1.8. 
Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected.  Source documents are filed at the investigator’s site. 
The investigator must maintain detailed source documents on all study subjects who are enrolled 
in the study or who undergo screening.  Definition of what constitutes source data can be found 
in the Source Data Agreement.  Source documents include subject medical records, hospital 
charts, clinic charts, investigator subject study files, as well as the results of diagnostic tests  
(e.g., visual field test printouts).  Data for enrolled subjects will be transcribed on to eCRFs 
provided by Santen.  All data should be transcribed completely, promptly, and legibly on the 
eCRFs.  Data transcribed from source documents must be consistent with the source documents 
or the discrepancies must be explained.  Exit forms are to be completed for all enrolled subjects, 
regardless if they did or did not complete the study (e.g., subject discontinuation, study 
termination). 


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The investigator may need to request previous medical records or transfer records, depending on 
the study.  Also, current medical records must be available.  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 
 Evidence that required procedures and/or evaluations were completed 
 Use of any concurrent medications 
 Documentation of study drug accountability 
 Occurrence and status of any AEs 
 The date the subject exited the study, and a notation as to whether the subject 
completed the study or was discontinued, including the reason for discontinuation 
10.1.9. 
Data Collection 
The Principal Investigator must maintain detailed records on all subjects who provide informed 
consent.  Data for screened subjects will be entered into eCRFs.  eCRFs should be completed 
within 3 business days of each subject visit as much as possible.  Review of the eCRFs will be 
completed remotely by Santen (or designee).  At designated intervals, a study monitor will 
perform Source Data Verification on site.  During those visits, Santen (or designee) will monitor 
the subject data recorded in the eCRF against source documents at the study site.  Santen  
(or designee) will review and evaluate eCRF data and use standard system edits, and may use 
centralized monitoring evaluations, to detect errors in data collection.  At the end of the study, a 
copy of the completed eCRFs will be sent to the site to be maintained as study records. 
10.1.10. 
Sponsor’s Direct Access to Source Data/Documents and IRB/IEC Materials for 
Monitoring and Audit 
10.1.10.1. Study Monitoring 
Santen or Santen’s designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study.  The investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct. 
Before an investigational site can enter a patient into the study, a representative of Santen will 
visit the investigational study site to: 
 Determine the adequacy of the facilities, and 


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 Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of Santen or its representatives.  This 
will be documented in a Clinical Study Agreement between Santen or its designee 
and the investigator. 
During the study, a monitor from Santen or representative will have regular contacts with the 
investigational site, for the following: 
 Provide information and support to the investigator(s) 
 Confirm that facilities remain acceptable 
 Confirm that the investigational team is adhering to the protocol and ICH-GCP, that 
data are being accurately recorded in the case report forms, and that investigational 
product accountability checks are being performed 
 Perform source data verification.  This includes a comparison of the data in the case 
report forms with the subject’s medical records at the hospital or practice, and other 
records relevant to the study.  This will require direct access to all original records for 
each subject (e.g., clinic charts). 
 Record and report any protocol deviations not previously sent to Santen. 
 Confirm non-serious AEs and SAEs have been properly documented on eCRFs and 
confirm any safety information requiring expedited reporting to Santen global PV 
(including SAEs, ESIs and Pregnancies) have been forwarded to Santen and those 
SAEs that met criteria for reporting have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff need information 
or advice. 
10.1.10.2. Audits and Inspections 
Authorized representatives of Santen, a regulatory authority (national or foreign), an Independent 
Ethics Committee or an Institutional Review Board may visit the site to perform audits or 
inspections, including source data verification.  The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, ICH-GCP, and any applicable regulatory 
requirements.  The investigator should contact Santen immediately if contacted by a regulatory 
agency about an inspection. 
10.1.11. 
Study and Site Closure 
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 Santen.  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. 


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Reasons for the early closure of a study site by Santen 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 intervention development 
10.1.12. 
Publication Policy 
The existence of this clinical study is confidential, and it should not be discussed with persons 
outside of the study.  Additionally, the information in this document and regarding this study 
contains trade secrets and commercially sensitive information that is confidential and may not be 
disclosed unless such disclosure is required by federal or state law or regulations.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who 
have a need to know, but all such persons must be instructed not to further disseminate this 
information to others.  These restrictions of disclosure will apply equally to all future 
information supplied that is indicated as confidential.  Information pertaining to this study will 
be published on www.clinicaltrials.gov. 
The data generated by this clinical study are the property of Santen and should not be disclosed 
without the prior written permission of Santen.  These data may be used by Santen now and in 
the future for presentation or publication at Santen’s discretion or for submission to 
governmental regulatory agencies.  Santen reserves the right of prior review of any publication 
or presentation of data from this study. 
This study will be registered at ClinicalTrials.gov, and results information from this study will be 
submitted to ClinicalTrials.gov. 
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. 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
 
Table 7: 
Definition of AE 
AE Definition 
 
An AE is any untoward medical occurrence in a patient or clinical study subject, temporally 
associated with the use of study intervention, whether or not it is 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. 


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Table 7: 
Definition of AE (Continued) 
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 (and not related to progression of underlying disease [glaucoma or ocular 
hypertension], unless judged by the investigator to be more severe than expected for the subject's 
condition). 
 
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. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an 
AE or SAE.  Such instances will be captured in the efficacy assessments.  However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if 
they fulfill the definition of 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 subject’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 subject’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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Table 8: 
Definition of SAE 
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 subject 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 subject 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: 
 
Sight threatening event: A sight-threatening event is any event that places the subject at immediate 
risk of permanently losing vision in either eye as a direct result of the event.   
 
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 subject 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. 


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Table 9: 
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. 
 
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 subject’s medical records to 
Santen in lieu of completion of the Santen AE/SAE CRF page. 
 
There may be instances when copies of medical records for certain cases are requested by Santen.  
In this case, all subject identifiers, with the exception of the subject 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. 
 
Death and hospitalization are outcomes of events.  The event leading to death or hospitalization 
should be recorded as the SAE.  Death or hospitalization should only be recorded as the primary 
event if all reasonable attempts to arrive at a diagnosis are unsuccessful.   
 
Indicate the outcome of the AE and provide resolution date or date of death.  For intermittent 
events (e.g., intermittent headache), the date should reflect when the last occurrence resolved or 
stopped.  For example, if a subject has an intermittent headache from 12/14/2010 until 12/21/2010 
and each individual headache lasts 3 hours a day, then the date of resolution is 12/21/2010 (NOT 
12/14/2010). 
If treatment was initiated, then include the treatment and duration in the comments section  
(e.g., subject took acetaminophen for headache on 12/14/2010, 12/17/2010 and 12/20/2010). 
Assessment of Severity 
The investigator will assess severity 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 subject, 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 severity 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. 
For intermittent events, record the maximum severity of the individual events.  For example, if a 
subject complains of intermittent headaches for one week and the severity of each headache ranges 
from mild to moderate, then the severity would be moderate.  Record that the severity of the headaches 
ranged from mild to moderate in the comment section of the form. 
 
 
 


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Table 9: 
Recording and Follow-Up of AE and/or SAE (Continued) 
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 following criteria can be used to make a causality judgment: 
 
Related (possibly or probably) 
o There is a clinically plausible time sequence between onset of the AE and study drug 
administration; and/or  
o There is a biologically plausible mechanism for study drug causing or contributing to 
the AE; and 
o The AE may or may not be attributed to concurrent/underlying illness, other drugs, or 
protocol procedures. 
 
Not Related 
o A clinically plausible temporal sequence is inconsistent with the onset of the AE and 
study drug administration/protocol procedure; and/or 
o A causal relationship is considered biologically implausible.  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 records 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 assess 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 
requirements. 
 
 
 


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Table 9: 
Recording and Follow-Up of AE and/or SAE (Continued) 
Procedures for 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 subject 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. 
 
Table 10: 
Reporting of SAEs and ESIs 
SAE/ESI Reporting to Santen via an Electronic Data Collection Tool 
 
The primary mechanism for reporting SAEs 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 subject 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 Santen Global 
Pharmacovigilance (Table 1). 
 
Contacts for SAE reporting can be found in Table 1. 
 
For SAE supporting information (i.e.  X-ray reports, hospital summaries, etc.) that are not 
included in the EDC format, follow a procedure analogous to the manual SAE reporting process 
(see next section).   
 
All ESIs should be reported within 24 hours of knowledge of the event using applicable eCRFs 
and recording as much information as available. 
Pregnancy information will be recorded in eCRF and on the appropriate manual paper form and 
submitted to Santen within 24 hours of learning of a subject's pregnancy. 
 
ESIs should be followed by the investigator to the same extent as SAEs, that is, until the event is 
determined to be resolved, irreversible, chronic, stable, the subject withdraws consent, or no 
further information can be reasonably obtained. 


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Table 10: 
Reporting of SAEs and ESIs (Continued) 
SAE/ESI Reporting to Santen via Paper CRF (If Electronic Data Collection Tool is Unavailable) 
 
Complete the paper AE, SAE, or ESI Forms as applicable (located in your site regulatory binder) 
 
Attach a Fax Cover Sheet with your contact information and fax to Santen Global 
Pharmacovigilance (Table 1). 
 
In the rare circumstance of the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the paper AE, SAE or ESI forms 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 or ESI CRF pages within the designated reporting time frames. 
 
Contacts for SAE/ESI reporting can be found in Table 1. 
10.3. 
List of Abbreviations and Specialist Terms 
The following abbreviations and specialist terms are used in this study protocol. 
Table 11: 
List of Abbreviations and Specialist Terms 
Abbreviation or 
Specialist Term 
Explanation 
ACE 
Angiotensin-Converting Enzyme 
ADaM 
Analysis Data Model  
AE 
Adverse Event 
AGIS 
The Advanced Glaucoma Intervention Study 
ANCOVA 
Analysis of Covariance 
ARB 
Angiotensin II Receptor Blockers 
BAK 
Benzalkonium Chloride 
BCVA 
Best-corrected Visual Acuity 
BID 
Twice Daily 
CAI 
Carbonic Anhydrase Inhibitors 
CIOMS 
Council for International Organizations of Medical Sciences 
CONSORT 
the Consolidated Standards of Reporting Trials 
CV 
Curriculum Vitae 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form  
EDC 
Electronic Data Capture 
EMGT 
the Early Manifest Glaucoma Trial 
EP2 
Prostaglandin E Receptor Subtype 2 


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Table 11: 
List of Abbreviations and Specialist Terms (Continued) 
Abbreviation or 
Specialist Term 
Explanation 
ESI 
Events of Special Interest 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FP 
Prostaglandin F receptor 
GCP 
Good Clinical Practices 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
LASIK 
Laser-Assisted-in-Situ Keratomileusis 
LOCF 
Last-observation-carried-forward 
MIGS 
Minimally Invasive Glaucoma Surgery 
MMRM 
Mixed-effect Model for Repeated Measures 
NDA 
New Drug Application 
OAG 
Open-angle Glaucoma 
OCT 
Optical Coherence Tomography 
OHT 
Ocular Hypertension 
OHTS 
the Ocular Hypertension Treatment Study 
PCR 
Polymerase Chain Reaction 
PGA 
Prostaglandins Analogs 
PGE2 
Prostaglandin E2 
POAG 
Primary Open-Angle glaucoma 
PP 
Per-Protocol 
PRK 
Photo-Refractive Keratectomy 
QD 
Once Daily 


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Table 11: 
List of Abbreviations and Specialist Terms (Continued) 
Abbreviation or 
Specialist Term 
Explanation 
RK 
Radial Keratotomy 
ROCK 
Rho Kinase 
RTSM 
Randomization and Trial Supply Management 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SDTM 
Study Data Tabulation Model  
SoA 
Schedule of Activities 
SUN 
Standardization of Uveitis Nomenclature 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
UKGTS 
United Kingdom Glaucoma Treatment Study 
 


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11. 
REFERENCES 
11.1. 
Literature 
 
1. 
AGIS_Investigators.  (2000).  The Advanced Glaucoma Intervention Study (AGIS): 7.  The 
Relationship Between Control of Intraocular Pressure and Visual Field Deterioration.  American 
Journal of Ophthalmology.  130(4):429-40. 
2. 
Bito, L.  (2001).  A New Approach to the Medical Management of Glaucoma, from the Bench to 
the Clinic, and Beyond.  Investigative Ophthalmology & Visual Science.  42(6):1126-33. 
3. 
Fuwa, M., Toris, C.  B., Fan, S., Taniguchi, T., Ichikawa, M., Odani-Kawabata, N., Iwamura, R., 
Yoneda, K., Matsugi, T., Shams, N.  K., Zhang, J.-Z.  (2017).  ABSTRACT: ARVO 2018: 
Effects of a Novel Selective EP2 Receptor Agonist, Omidenepag Isopropyl, on Aqueous Humor 
Dynamics in Laser-induced Ocular Hypertensive Monkeys.2. 
4. 
Garway-Heath, D., Crabb, D., Bunce, C., Lascaratos, G., Amalfitano, F., Anand, N., Azuara-
Blanco, A., Bourne, R., Broadway, D., Cunlifee, I., Diamond, J., Fraser, S., Ho, T., Martin, K., 
McNaught, A., Negi, A., Patel, K., Russell, R., Shah, A., Spry, P., Katsuyoshi, S., White, E., 
Wormald, R., Xing, W., Zeyen, T.  (2015).  Latanoprost for open-angle glaucoma (UKGTS):a 
randomised, multicentre, placebo-controlled trial.  The Lancet.1-12. 
5. 
Kass, M., Heuer, D., Higginbotham, E., Johnson, C., Keltner, J., Miller, J., Parrish, R., Wilson, 
M., Gordon, M.  (2002).  The Ocular Hypertension Treatment Study: A Randomized Trial 
Determines That Topical Ocular Hypotensive Medication Delays or Prevents the Onset of 
Primary Open-Angle Glaucoma.  Arch Ophthalmol.  120:701-13. 
6. 
Leske, M., Heijl, A., Hussein, M., Bengtsson, B., Hyman, L., Komaroff, E.  (2003).  Factors for 
Glaucoma Progression and the Effect of Treatment: The Early Manifest Glaucoma Trial.  Arch 
Ophthalmol.  121(1):48-56. 
7. 
Resnikoff, S., Pascolini, D., Etya ale, D., Kocur, I., Pararajasegaram, R., Pokharel, G., Mariotti, 
S.  (2004).  Global data on visual impairment in the year 2002.  Bulletin of the World Health 
Organization.  82(11):844-52. 
8. 
Tham, Y., Li, X., Wong, T., Quigley, H., Aung, T., Cheng, C.  (2014).  Global Prevalence of 
Glaucoma and Projections of Glaucoma Burden through 2040.  Ophthalmology.  121(11):2081-
90. 
9. 
Yamaji, K., Yoshitomi, T., Ishikawa, H., Usui, S.  (2005).  Prostaglandins E 1  and E 2 , but not F 
2  α  or Latanoprost, Inhibit Monkey Ciliary Muscle Contraction.  Current Eye Research.  30:661-
5. 
 
 


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11.2. 
Study Data 
1. Data on File: Santen Study 33-001.  A Phase I/II, Randomized, Observer-masked, 
Placebo-and-active-controlled, Parallel-group, Multi-center Study Assessing the Safety 
and Efficacy of DE-117 Ophthalmic Solution in Subjects with Primary Open-angle 
Glaucoma or Ocular Hypertension 
2. Data on File: Santen Study 33-002.  A Phase II, Randomized, Observer-masked,  
Placebo-and Active-controlled, Parallel-group, Multi-center Study Assessing the Safety 
and Efficacy of DE-117 Ophthalmic Solution Compared with Latanoprost and Placebo in 
Subjects with Primary Open-angle Glaucoma or Ocular Hypertension  
3. Data on File: Santen Study 33-003.  A Phase IIb, Randomized, Observer-masked,  
Active-controlled, Parallel-group, Multicenter Study Assessing the Safety and Efficacy of  
DE-117 Ophthalmic Solution Compared with Latanoprost Ophthalmic Solution, 0.005% 
in Subjects with Primary Open-angle Glaucoma or Ocular Hypertension – SEE Study 
4. Data on File: Santen Study 01171502.  A Pharmacokinetic Study of DE-117 Ophthalmic 
Solution in Healthy Adult Male Subjects - Phase I Study - 
5. Data on File: Santen Study 01171503.  A Study Assessing the Efficacy and Safety of  
DE-117 Ophthalmic Solution in Subjects With Primary Open Angle Glaucoma or Ocular 
Hypertension -AYAME Study- 
6. Data on File: Santen Study 01171504.  A Long-term Study of DE-117 Ophthalmic 
Solution Monotherapy and Concomitant Use of DE-117 Ophthalmic Solution With 
Timolol Ophthalmic Solution in Patients With OAG or OH: RENGE Study 
7. Data on File: Santen Study 01171506.  A Study Assessing the Safety and Efficacy of  
DE-117 in Subjects With POAG or OH Who Are Non-/Low-responders to Latanoprost: 
FUJI Study 


This is a representation of an electronic record that was signed electronically
and this page is the manifestation of the electronic signature.

SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:   
A Randomized, Double-Masked, Parallel-Group, Multicenter Study 
Assessing the Safety and Efficacy of DE-117 Ophthalmic Solution 0.002% 
Once Daily and Twice Daily in Subjects with Primary Open-Angle 
Glaucoma or Ocular Hypertension - SPECTRUM 6 Study 
 
NCT Number:  
NCT03858894 
 
Date of the document: 
11 Jul 2019  
 
 
 


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STATISTICAL ANALYSIS PLAN 
DE-117 SPECTRUM 6 Study 
 
 
 
Protocol 
Title: 
A Randomized, Double-Masked, Parallel-Group, Multicenter Study Assessing 
the Safety and Efficacy of DE-117 Ophthalmic Solution 0.002% Once Daily 
and Twice Daily in Subjects with Primary Open-Angle Glaucoma or Ocular 
Hypertension - SPECTRUM 6 Study 
 
 
Product: 
0.002% DE-117 ophthalmic solution 
 
 
Protocol 
Number:  
011712IN 
 
 
Sponsor: 
Santen Inc. 
 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608 
USA 
 
 
Date:  
July 11, 2019 
 
 
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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APPROVAL SIGN-OFF SHEET 
A Randomized, Double-Masked, Parallel-Group, Multicenter Study Assessing the Safety 
and Efficacy of DE-117 Ophthalmic Solution 0.002% Once Daily and Twice Daily in 
Subjects with Primary Open-Angle Glaucoma or Ocular Hypertension - SPECTRUM 6 
Study 
DE-117 SPECTRUM 6 Study 
 
 
 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
ABBREVIATIONS .........................................................................................................................7 
1. 
INTRODUCTION ........................................................................................................8 
2. 
OBJECTIVE(S) AND ENDPOINTS ...........................................................................8 
3. 
STUDY DESIGN .........................................................................................................9 
3.1. 
General Study Design ...................................................................................................9 
3.2. 
Randomization and Masking ......................................................................................10 
3.3. 
Sample Size Planning .................................................................................................11 
3.4. 
Visits and Assessments ...............................................................................................11 
4. 
DEFINTIONS .............................................................................................................14 
4.1. 
Time-Related Terms ...................................................................................................14 
4.1.1. 
Baseline Visit ..............................................................................................................14 
4.1.2. 
Treatment Start and End Dates ...................................................................................14 
4.1.3. 
Study Day ...................................................................................................................14 
4.1.4. 
Out-of-Window Measurements, Analysis Visit, and Analysis Window ....................14 
4.1.5. 
Out-of-Time-Window Measurements, Analysis Timepoint and Analysis 
Timepoint Window .....................................................................................................15 
4.2. 
Efficacy-Related Definitions ......................................................................................16 
4.2.1. 
Study Eye and Fellow Eye ..........................................................................................16 
4.2.2. 
Efficacy Measure ........................................................................................................16 
4.2.3. 
Baseline Score ............................................................................................................16 
4.2.4. 
Change and Percent Change from Baseline ................................................................16 
4.2.5. 
IOP Response Endpoints and Response Rate .............................................................16 
4.3. 
Safety-Related Definitions ..........................................................................................17 
4.3.1. 
Adverse Event .............................................................................................................17 
4.3.1.1. 
Serious Adverse Event ................................................................................................17 
4.3.1.2. 
Ocular Adverse Event .................................................................................................17 
4.3.1.3. 
Suspected Adverse Reaction .......................................................................................17 
4.3.1.4. 
Events of Special Interest ...........................................................................................17 
4.3.2. 
Safety Measures ..........................................................................................................18 


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4.4. 
Other Definitions ........................................................................................................18 
4.4.1. 
Prior and Concomitant Medications ...........................................................................18 
5. 
STUDY POPULATION .............................................................................................19 
5.1. 
Intent-to-Treat Population ..........................................................................................19 
5.2. 
Safety Population ........................................................................................................19 
5.3. 
Full Analysis Set .........................................................................................................19 
5.4. 
Per-Protocol Set ..........................................................................................................19 
6. 
GENERAL CONSIDERATIONS ..............................................................................19 
6.1. 
Adjustments for Covariates ........................................................................................19 
6.2. 
Handling of Missing Data ...........................................................................................20 
6.2.1. 
Efficacy Measure ........................................................................................................20 
6.2.2. 
Safety Measures ..........................................................................................................20 
6.2.3. 
Dates for Medical Events and Medications ................................................................20 
6.3. 
Multi-Center Studies ...................................................................................................21 
6.4. 
Multiple Comparisons / Multiplicity ..........................................................................21 
6.5. 
Interim Analysis ..........................................................................................................21 
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 .....................................................................................22 
7.4. 
Protocol Deviations ....................................................................................................22 
7.5. 
Prior and Concomitant Medications ...........................................................................22 
7.6. 
Treatment Compliance ................................................................................................23 
7.7. 
Exposure to Study Medication ....................................................................................23 
8. 
EFFICACY ANALYSES ...........................................................................................24 
8.1. 
Analyses of Primary Endpoint ....................................................................................24 
8.1.1. 
Primary Analyses ........................................................................................................24 
8.1.2. 
Sensitivity Analyses ....................................................................................................24 
8.2. 
Analyses of Secondary Endpoints ..............................................................................24 
8.3. 
Subgroup Analyses .....................................................................................................25 
9. 
SAFETY ANALYSES ...............................................................................................25 
9.1. 
Adverse Event .............................................................................................................25 
9.2. 
Slit-lamp Biomicroscopy ............................................................................................25 


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9.3. 
Ophthalmoscopy .........................................................................................................25 
9.4. 
Best Corrected Visual Acuity .....................................................................................26 
10. 
ANALYSES OF OTHER MEASURES .....................................................................26 
11. 
REFERENCES ...........................................................................................................26 
12. 
APPENDICES ............................................................................................................27 
12.1. 
PROC MIXED for MMRM ........................................................................................27 


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LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints ...................................................................................8 
Table 2: 
Assessment Schedule ..................................................................................................12 
Table 3: 
Analysis Visit and Analysis Window .........................................................................15 
Table 4: 
Analysis Timepoint and Analysis Timepoint Window ..............................................15 
Table 5: 
Safety Assessments .....................................................................................................18 
Table 6: 
Handling of Missing Date for Medical Events and Medications ...............................20 
 
 
LIST OF FIGURES  
Figure 1: 
Study Schema .............................................................................................................10 
 
 
 


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ABBREVIATIONS 
AE 
adverse event 
ATC 
Anatomical-Therapeutic-Chemical  
BCVA 
Best-corrected visual acuity 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CSR 
Clinical Study Report 
eCRF 
electronic Case Report Form 
ESI 
event of special interest 
ET 
early termination 
FAS 
full analysis set 
IOP 
intraocular pressure 
LOCF 
last-observation-carried-forward 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeter of mercury 
OHT 
ocular hypertension 
OD 
oculus dexter (right eye) 
OS 
oculus sinister (left eye) 
OU 
oculus uterque (both eyes) 
POAG 
primary open-angle glaucoma 
PPS 
per-protocol set 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
suspected adverse reaction 
SAS 
Statistical Analysis System 
SOC 
system organ class 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 
 


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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 SPECTRUM 6 study within the scope of Santen’s Protocol 
011712IN, “A Randomized, Double-Masked, Parallel-Group, Multicenter Study Assessing the 
Safety and Efficacy of DE-117 Ophthalmic Solution 0.002% Once Daily and Twice Daily in 
Subjects with Primary Open-Angle Glaucoma or Ocular Hypertension - SPECTRUM 6 Study”.  
It applies to the study protocol dated 13 Nov 2018 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. 
OBJECTIVE(S) AND ENDPOINTS 
Table 1: 
Study Objectives and Endpoints 
Study Objectives 
Corresponding Study Endpoints 
Primary Objective: 
To determine whether DE-117 Ophthalmic 
Solution 0.002% given BID is superior to QD in 
reducing the intraocular pressure (IOP) after  
6 weeks of treatment in subjects with POAG or 
OHT. 
Primary Efficacy Endpoint: 
The primary efficacy endpoint is the IOP in the 
study eye measured at the specified time points: 
08:00, 12:00 and 16:00 at Week 2 (Visit 3) and 
Week 6 (Visit 4). 
Secondary Efficacy Endpoints: 
 
Mean diurnal IOP in the study eye at 
Week 6 (Visit 4) 
 
Absolute change and percent change from 
baseline in IOP 
 
Absolute change and percent change from 
baseline in mean diurnal IOP 
 
Having a mean diurnal IOP reduction  
≥ 20%, ≥ 25%, or ≥ 30% from Baseline 
(Visit 2) at each post-baseline visit 
 
Having a mean diurnal IOP ≤ 18 mmHg 
at each post-baseline visit 
 
 


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Table 1: 
Study Objectives and Endpoints (Continued) 
Study Objectives 
Corresponding Study Endpoints 
Safety Objective: 
To determine the safety of DE-117 ophthalmic 
solution 0.002% given BID as compared to QD in 
subjects with POAG or OHT. 
Safety Endpoints: 
Safety will be evaluated by the following 
parameters: 
 
Incidence of ocular and systemic AEs 
 
Best-corrected visual acuity (BCVA) 
 
Slit-lamp biomicroscopy findings: 
anterior chamber cells, anterior chamber 
flare, lid hyperemia, lid edema, 
conjunctival hyperemia, conjunctival 
chemosis, corneal edema, corneal 
staining, keratin precipitates, abnormal 
lens findings, anterior synechiae of iris, 
posterior synechiae of iris 
 
Ophthalmoscopy 
3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is a randomized, double-masked, parallel-group, multi-center study.  Subjects diagnosed 
with POAG or OHT who meet eligibility criteria at Visit 1 (Screening) will wash out their 
current topical IOP lowering medication(s), if any.  After completing the required washout 
period, subjects will return for Visit 2 (Baseline, Day 1).  Subjects who meet all eligibility 
criteria at Visit 2 will be randomized to receive study medication for up to 6 weeks. 
Approximately 100 subjects with POAG or OHT will be randomized in a 1:1 ratio to either: 
 DE-117 ophthalmic solution 0.002% QD (20:00) and Vehicle QD (08:00), or 
 DE-117 ophthalmic solution 0.002% BID (20:00 & 08:00) 
As shown in the Study Schema (Figure 1), this study will consist of a screening period of up to 
35 days including a washout period of up to 28 days (+ 7 days window), and a 6-week double-
masked treatment period. 
 
 
 
 
 


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Figure 1: 
Study Schema 
 
At Screening (Visit 1), subjects who provide written informed consent and meet all eligibility 
criteria are required to wash out any IOP-lowering medication(s) they are using, or wait at least 
one day if they have not used an IOP-lowering medication for the last 28 days, before returning 
for further eligibility assessments at baseline (Visit 2; Day 1).  Subjects who meet all eligibility 
criteria at baseline will be randomized in a 1:1 ratio to receive either DE-117 0.002% QD in the 
evening and vehicle QD in the morning or DE-117 0.002% BID for 6 weeks with scheduled 
Visits 2, 3 and 4 (Baseline, Week 2 and Week 6).  Post-baseline safety and efficacy measures 
will be collected at scheduled visits and Study Exit/Early Termination (ET) according to the 
Assessment Schedule (Table 2). 
3.2. 
Randomization and Masking 
A permuted-block randomization will be employed to randomize eligible subjects in a 1:1 ratio 
to either DE-117 QD/Vehicle QD arm or DE-117 BID arm.  The randomization schedule will be 
generated and implemented using central randomization via Interactive Response Technology 
(Medidata Balance/RTSM).  
Treatment assignments will be masked to Santen, study subjects, and Clinical Investigator.  The 
appearance of the bottles of DE-117 ophthalmic solution 0.002% and the vehicle will be 
identical.  All subjects will receive bottles labeled “morning” for the morning dose and bottles 
labeled “evening” for the evening dose. Each eligible subject will be assigned to receive a 
numbered study medication kit as assigned by central randomization via Interactive Response 
Technology at Visit 2 (Baseline).  In case of a medical emergency, the Principal Investigator 
may reveal the treatment information by unmasking through Medidata Balance/RTSM to know 
which treatment the subject has received. 


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3.3. 
Sample Size Planning 
The sample size calculation does not consider multiplicity from multiple time points.  Assuming 
a two-sided type I error rate of 5% and a standard deviation of 3.5 mmHg, approximately  
50 subjects per treatment arm (100 in total) will have about 80% power to detect a 2.0 mmHg 
between-treatment difference. 
3.4. 
Visits and Assessments 
There are 4 scheduled visits for each 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 Week 6 (Visit 4, Day 43 ± 3), to the 
extent possible, all assessments scheduled for Visit 4 will be performed at the Early Termination 
(ET) visit. 
 
 


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Table 2: 
Assessment Schedule 
 
Washout Period 
Double-Masked Treatment Period 
Visit 1 
(Screening) 
Washout 
Period (up to 
4 weeks) 
Optional 
Visit 1k 
Visit 2 
Eligibility/ 
Baseline 
(Day 1) 
Visit 3 Week 
2 (Day 15±2) 
Visit 4 Week 
6 (Day 43±3) 
Exit or Early 
Terminationl 
 
Informed Consent(s) including 
the consent for 
pharmacogenomics/ genomics 
laboratory research studya 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
Concomitant Medications / 
Therapies 
X 
X 
X 
X 
X 
Dosing Compliance 
 
 
 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
Pregnancy Testb 
X 
 
X 
 
X 
Refractionc 
X 
 
 
 
 
BCVAc 
X 
X 
X 
(prior to 8:00 
IOP meas.) 
X 
(prior to 8:00 
IOP meas.) 
X 
(prior to 8:00 
IOP meas.) 
Biomicroscopyd 
X 
X 
X 
(prior to 8:00 
IOP meas.) 
X 
(prior to 8:00 
IOP meas.) 
X 
(prior to 8:00 
IOP meas.) 
IOPe 
X 
(any time) 
X 
(any time) 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
Pachymetryf 
X 
 
 
 
 
Instill study eye drop after 
08:00 IOP measurement 
 
 
 
X 
(after to 8:00 
IOP meas.) 
X 
(after to 8:00 
IOP meas.) 
Gonioscopyg 
X 
 
 
 
 
Visual Fieldh 
X 
 
 
 
 
Ophthalmoscopyi 
X 
(pupil 
dilation) 
 
X 
(after 16:00 
IOP meas.) 
 
X 
(after 16:00 
IOP meas., 
pupil 
dilation) 
Blood Sampling for 
Pharmacogenomics/genomicsj 
 
 
 
X 
Dispense Study Medication 
 
 
X 
 
 
Collect Study Medication 
 
 
 
 
X 
 
 
 


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Table 2: 
Assessment Schedule (Continued) 
 
Washout Period 
Double-Masked Treatment Period 
 
Visit 1 
(Screening) 
Washout 
Period (up to 
4 weeks) 
Optional 
Visit 1k 
Visit 2 
Eligibility/ 
Baseline 
(Day 1) 
Visit 3 Week 
2 (Day 15±2) 
Visit 4 Week 
6 (Day 43±3) 
Exit or Early 
Terminationl 
 
Phone call to remind subjects 
to take morning and evening 
dose on the day before each 
visit 
 
 
 
X 
X 
a Informed Consent(s) including the consent for pharmacogenomics/ genomics laboratory research study 
Informed consent form (ICF) must be signed and dated before study procedures are performed. Informed consent 
for the optional pharmacogenomics/genomics laboratory research study may be obtained at any visit prior to study 
exit. 
b Pregnancy Test 
A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
c Refraction and BCVA 
Refraction will be performed at the screening visit. If more than 10 letters in BCVA were lost compared to the 
screening visit, then refraction should be performed again. BCVA examination will be completed before IOP is 
measured at 08:00 (±60 min). 
d Biomicroscopy 
Biomicroscopy examination must be completed before IOP is measured at 08:00. Aqueous flare and cell evaluation 
will be performed before fluorescein instillation. 
e IOP 
IOP measurements will be performed at 08:00, 12:00 and 16:00 (±60 min) at all visits except for Visit 1 and 
optional Visit 1a (screening and mid-washout). 
f Pachymetry 
Pachymetry will be performed after IOP measurement at Visit 1 (Screening). 
g Gonioscopy 
If gonioscopy was performed within 3 months (90 days) prior to screening and was documented in the subject’s 
records, no additional screening gonioscopy examination is necessary. 
h Visual Field 
If visual field test was performed within 3 months (90 days) prior to screening and was documented in the subject’s 
records, no additional screening visual field test is necessary. 
i Ophthalmoscopy 
Ophthalmoscopy will be performed at Visits 1, 2 and 4 (i.e. Screening, Baseline and Week 6) after the very last 
IOP measurement. Ophthalmoscopy will be performed with pupil dilation at Visit 1 and Visit 4/ Study Exit or 
Early Termination. Dilation of the pupil will be performed after the very last IOP measurement at Visit 1 and Visit 
4/Study Exit or Early Termination. 
j Blood Sampling for Pharmacogenomics/genomics 
Blood sampling for the pharmacogenomics/genomics laboratory research study may be performed at any visit after 
pharmacogenomics/genomics informed consent is obtained, subject is randomized and study drug, DE-117 
ophthalmic solution 0.002%, dosing has begun. 
k Optional Visit 1a 
An interim safety visit may be performed during the washout period Visit 1a (optional, mid-washout visit), if in the 
Investigator’s opinion a subject’s IOP may be of concern. If subjects are treated with a topical CAI during the 
washout period. Visit 1a (optional, mid-washout visit) is recommended to be performed. 
l Exit or Early Termination 
All listed procedures are required for early terminated subjects. 
 


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4. 
DEFINTIONS 
4.1. 
Time-Related Terms 
4.1.1. 
Baseline Visit 
The Baseline visit is Visit 2 (Day 1) when the subject is randomized. 
4.1.2. 
Treatment Start and End Dates 
Treatment start date is the date at which a randomized subject takes the first dose of the study 
medication. 
Treatment end date is the date at which a randomized subject takes the last dose of the study 
medication.  If the date of the last dose is missing, then 
 The day before the Visit 4 (Week 6) will be considered the treatment end date for 
subjects who completed the study, and 
 The day before the Exit Visit date will be used for subjects who prematurely 
discontinued from the study.  If the Exit Visit date of a non-completer is not 
available, then the day before the last available visit date will be considered the 
treatment end date. 
4.1.3. 
Study Day  
The study day describes the relative day of an observation starting with the reference date 
designated as Study day 1. In this study, the Visit 2 (Baseline) date is the reference date. Thus, 
the study day will be calculated as: 
 For days prior to the Visit 2 (Baseline) date, Study Day = Date – Visit 2 (Baseline) 
Date  
 For days on/after the Visit 2 (Baseline) date, Study Day = Date – Visit 2 (Baseline) 
Date + 1 
4.1.4. 
Out-of-Window Measurements, 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 3). 
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 study visit at 
which the measurement was collected.  For example, an out-of-window measurement collected 
at the Week 2 study visit will be mapped to the Week 6 analysis visit, if the study day of the 
measurement falls into the analysis window of Week 6.  
 


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Table 3: 
Analysis Visit and Analysis Window 
Analysis Visit (Target Assessment Date) 
Protocol Visit Window 
Analysis Window 
Baseline (Day 1) 
[1, 1] 
- 1] 
Week 2 (Day 15) 
[13, 17] 
[2, 28] 
Week 6 (Day 43) 
[40, 46] 
[29, 57] 
In case that 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 later one will be selected for that visit. 
For analyses of IOP involving post-baseline visits, if there are two or more visits that fall into the 
same analysis window of a post-baseline visit, then the visit in which IOP are measured at all the 
scheduled timepoints (8:00, 12:00, and 16:00) will be selected for that analysis visit first, before 
applying the above rule.  
Furthermore, if applying this analysis window results in missing IOP data, then the nominal visit 
will be used.   
4.1.5. 
Out-of-Time-Window Measurements, Analysis Timepoint and Analysis 
Timepoint Window 
Analysis timepoint is a timing variable to be used for analyses involving timepoints.  In general, 
the analysis timepoint is the scheduled timepoint per protocol.  For this study, the pre-specified 
IOP measurements time window in the protocol is (8:00±60 mins, 12:00 ±60 mins, 16:00 ±60 
mins).  
For each analysis timepoint, an analysis timepoint window is set up to determine the allowable 
range (Table 4). 
Table 4: 
Analysis Timepoint and Analysis Timepoint Window 
Analysis Timepoint 
Timepoint Window 
Analysis Timepoint Window 
8:00 
[7:00, 9:00] 
- 9:59] 
12:00 
[11:00, 13:00] 
[10:00, 13:59] 
16:00 
[15:00, 17:00] 
[14:00 - 
If there are two or more measurements that fall into the same analysis timepoint window, the 
measurement closest to the target assessment time will be selected for that timepoint.  In the case 
that two measurements are closest and equidistant to the target assessment time, i.e., one is 
before and one is after the target assessment time, the later one will be selected for that 
timepoint. 
Furthermore, if applying this analysis timepoint window results in missing IOP data, then the 
nominal timepoint will be used for that visit.  
 
 


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4.2. 
Efficacy-Related Definitions 
4.2.1. 
Study Eye and Fellow Eye 
The study eye will be the eye that qualifies per eligibility criteria at Visit 2.  If both eyes meet the 
eligibility criteria, the eye with the higher mean diurnal IOP at Visit 2 will be designated as the 
study eye.  If both eyes meet the eligibility criteria and have the same mean diurnal IOP, the right 
eye will be designated as the study eye.  The other eye will be the non-study eye, or fellow eye. 
4.2.2. 
Efficacy Measure 
IOP (measured in mmHg) is the efficacy measure for this study.  For the IOP at each timepoint 
of measurement, a mean of two consecutive measurements using the Goldmann applanation 
tonometer will be used.  If the two measurements differ by 2 mmHg or more, then a third 
measurement will be made, and the median of the three consecutive measurements will be used. 
For the mean diurnal IOP, the mean of the three scheduled timepoints (8:00, 12:00, and 16:00) 
will be used.   
4.2.3. 
Baseline Score 
The baseline score is the observed measurement at Visit 2 (Baseline).  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. 
4.2.4. 
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) 
4.2.5. 
IOP Response Endpoints and Response Rate 
At each post-baseline visit (Week 2 or Week 6), the following response endpoints are defined: 
 ≥ 20% Reduction Response: the percent reduction from baseline in mean diurnal IOP in 
the study eye is at least 20%. 
 ≥ 25% Reduction Response: the percent reduction from baseline in mean diurnal IOP in 
the study eye is at least 25%. 
 ≥ 30% Reduction Response: the percent reduction from baseline in mean diurnal IOP in 
the study eye is at least 30%. 
 ≤ 18 mmHg Response: the mean diurnal IOP in study eye is equal or below 18 mmHg. 


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4.3. 
Safety-Related Definitions 
4.3.1. 
Adverse Event 
Under Protocol 011712IN, an AE is defined as any 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 timing of 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 the 
2 days after treatment end date.  Treatment-emergent AEs are a subset of on-study AEs.  Both 
on-study and treatment-emergent AEs will be recorded, but only treatment-emergent AEs will be 
tabulated. 
The severity of each AE will be graded by the Clinical Investigator as Mild, Moderate, or 
Severe.  
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 21.1 published in 2018.   
4.3.1.1. 
Serious Adverse Event 
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) 
 Life threatening (i.e., immediately life-threatening) 
 Inpatient hospitalization and/or prolonged hospitalization 
 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) 
 A congenital anomaly/birth defect in the offspring of a study subject who was exposed to 
study therapy prior to conception or during pregnancy 
 Sight threatening event 
 Other medically important event (e.g., requires medical or surgical intervention to 
prevent one or more of the listed above) 
4.3.1.2. 
Ocular Adverse Event 
An AE will be counted as an ocular AE if the Clinical Investigator selected “OD”, “OS”, or 
“OU” on the AE eCRF.  
4.3.1.3. 
Suspected Adverse Reaction 
An AE will be counted as a suspected adverse reaction (SAR) if the Clinical Investigator 
selected answered ‘Related’ to the AE eCRF question ‘Relationship to Study Drug’ 
4.3.1.4. 
Events of Special Interest 
Events of special interest (ESI) in this study is defined as pregnancy, study medication 
administration error, or macular edema. 


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4.3.2. 
Safety Measures  
Table 5 lists the safety measures to be evaluated for this study. 
Table 5: 
Safety Assessments 
Safety Measures 
Note 
Slit-lamp biomicroscopy: 
anterior chamber cells 
anterior chamber flare 
lid hyperemia 
lid edema  
conjunctival (palpebral and bulbar) 
hyperemia  
conjunctival chemosis 
corneal edema 
corneal staining (with fluorescein) 
keratic precipitate  
anterior synechiae of iris  
posterior synechiae of iris  
Anterior Chamber Cells will be graded as 0 = No cells, 
0.5 = 1-5cells, 1 = 6-15 cells, 2 = 16-25 cells, 3 = 26-50 
cells, or 4 = > 50 cells. 
 
Anterior Chamber Flare will be graded as 0 = None,  
1 = Faint, 2 = Moderate, 3 = Marked, or 4 = Intense. 
 
The other biomicroscopy parameters will be graded as  
0 = None, 1 = Mild, 2 = Moderate, or 3 = Severe. 
Ophthalmoscopy 
glaucomatous optic nerve 
cup to disc ratio 
retina 
macula 
choroid 
vitreous 
Damage to optic nerve will be graded as 0 = None 
1 = Mild, 2 = Moderate, 3 = Severe. 
 
Cup/disc ratio will be recorded with two decimal points 
(e.g., 0.80). 
 
Retina, macula, choroid, and vitreous will graded as 0 = 
Normal, 1 = Abnormal. 
Best Corrected visual acuity 
Best corrected visual acuity score measures the 
acuteness or clearness of corrected vision, with a range 
of [-0.30, 1.10] in logarithm of the minimum angle of 
resolution (logMAR) scale. 
A decrease in logMAR score indicates improvements in 
corrected visual acuity. 
4.4. 
Other Definitions 
4.4.1. 
Prior and Concomitant Medications 
Non-study medications will be categorized into prior medications and concomitant medications.  
Specifically, the prior medication is defined as any non-study medication taken and ended prior 
to the treatment start date.  The concomitant medication is defined as any non-study medication 
taken concurrently while on the study medication, i.e., the treatment period of a concomitant 
medication taken by a subject’s needs to overlap with his/her treatment period of the study 
medication. 


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5. 
STUDY POPULATION  
5.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will include all randomized subjects.   
5.2. 
Safety Population 
The Safety population will include all randomized subjects who received at least one dose of the 
study medication.  Safety analyses will be performed using the Safety Population and 
summarized by actual treatment received. 
5.3. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all randomized subjects who received at least one dose of 
the study medication and had at least one post-baseline IOP measurement of the study eye during 
the study.  This will be the population used for efficacy analyses.  Efficacy analyses will be 
performed using the FAS and summarized by treatment as randomized. 
5.4. 
Per-Protocol Set 
The Per-Protocol Set (PPS) is a subset of the FAS. It will be the analysis population for 
sensitivity analyses and will be summarized using treatment as randomized.  Any subject 
affected by a significant protocol deviation that might affect the primary efficacy analysis will be 
excluded from the PPS.  The PPS will be identified before the unmasking of treatment 
assignments. 
Before the unmasking of treatment assignment, Santen’s study team will review all protocol 
deviations, identify subjects with any protocol deviation that could impact the efficacy outcome, 
and determine whether or not to exclude the subject from the PPS.  
6. 
GENERAL CONSIDERATIONS 
All measures will be summarized by treatment (planned or actually received) descriptively.  
Continuous variables will be summarized using descriptive statistics such as number of 
observations (n), mean, standard deviation, median, minimum, and maximum.  Categorical 
variables will be tabulated using frequency (n) and percent (%).   
Analysis treatment groups are defined as DE-117 QD/Vehicle QD or DE-117 BID. 
The statistical testing will be conducted at a significance level of 0.05 (2-sided) 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. 
6.1. 
Adjustments for Covariates 
In general, baseline IOP score will be adjusted in the inferential analysis of each IOP endpoint.  
Detailed information on covariate adjustment is provided in Section 8.1. 


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6.2. 
Handling of Missing Data 
6.2.1. 
Efficacy Measure 
For subjects with the use of any non-study IOP lowering therapy to lower IOP, unless otherwise 
specified, the IOP data collected after the non-study IOP lowering therapy will be censored 
(treated as missing) in efficacy analyses. 
For each IOP endpoint, no imputation is needed for the analysis on observed cases using the 
mixed-effects model for repeated measures (MMRM). 
6.2.2. 
Safety Measures 
Descriptive summaries of safety measures will be based on observed data only.  No imputation 
of missing scores will be implemented. 
6.2.3. 
Dates for Medical Events and Medications 
Completely or partially missing onset and resolution dates of medical history (MH), AEs and 
concomitant medications (CM) will be imputed as follows: 
Table 6: 
Handling of Missing Date for Medical Events and Medications 
Date 
Type of Missing Date 
Handling of Missing Date 
Event onset date  
(e.g., YYYY-MM-DD) 
Completely missing 
No imputation will be applied. 
For AE, the event will be considered 
treatment-emergent. 
For CM, the event will be considered 
concomitant. 
For MH, the event will be considered to 
occur prior to Inform Consent date. 
Only YYYY is available 
Use the first day of YYYY to impute the 
missing month and date parts of the onset 
date 
YYYY and MM are 
available, but DD is missing 
Use the first day of MM to impute the 
missing date part of the onset date 
Event resolution date 
(e.g., YYYY-MM-DD) 
Completely missing 
No imputation will be applied.  The event 
will be considered ongoing (i.e., not 
resolved) at the last visit date.  
Only YYYY is available 
Use the last day of YYYY to impute the 
missing month and date parts of the 
resolution date  
YYYY and MM are 
available, but DD is missing 
Use the last day of MM to impute the 
missing date part of the resolution date 
Same rules will be followed to impute the completely or partially missing start and end dates of 
non-study medications. 


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6.3. 
Multi-Center Studies 
Sites will not be pooled for any inferential analysis or descriptive summary in this study. 
6.4. 
Multiple Comparisons / Multiplicity 
No multiplicity adjustment will be applied in this study.  Treatment differences in IOP between 
DE-117 QD arm and DE-117 BID arm for each timepoint will be considered statistically 
significant if the 𝑝-value of the corresponding treatment comparison is smaller than 0.05. 
Superiority of DE-117 BID to DE-117 QD is achieved if the treatment differences are 
significantly greater than 0 at all six time points.  
6.5. 
Interim Analysis 
No interim analysis is planned for this study.  
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 of subjects in the FAS population and the numbers and 
percentages of subjects in the other study populations including the Safety population, and the 
PPS population.  The disposition summary will also include the number and percentage of 
completers and non-completers at Week 6 (Visit 4), respectively, as well as the number and 
percentage of non-completers at Week 6 (Visit 4) by the primary discontinuation reason from the 
study drug and from the study.  
7.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be descriptively summarized for the FAS 
population by planned treatment, Safety population by actual treatment, and overall.  
Specifically, for subject demographics, the following variables will be summarized:  
 Age at randomization (continuous and categorical: < 65 years or ≥ 65 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 study eye: 
 Primary ocular diagnosis (categorical: POAG, or OHT)  
 Prior use of Prostaglandin analogs (Yes or No) 
 Baseline mean diurnal IOP score and baseline IOP score at each scheduled timepoint 
(08:00, 12:00, and 16:00) 


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 Visual acuity 
 Glaucomatous optic nerve findings (categorical: none, mild, moderate, or severe) 
7.3. 
Medical and Surgical History 
For this study, medical and surgical history will be coded using MedDRA 21.1, 2018.  Each 
medical event will be classified into a SOC and mapped to a PT.   
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  
 Safety Reporting  
 Time Window 
 Withdrawal Criteria  
 Other deviations  
A protocol deviation is considered major if it may affect the subject’s rights, safety, or well-
being and/or the completeness, accuracy, and reliability of the study data.  Santen’s study team 
will review all protocol deviations and determine the list of major protocol deviations prior to 
database lock.  All randomized subjects with any major protocol deviation(s) will be tabulated by 
deviation category for each planned treatment and overall.  In addition, protocol deviations will 
also be listed. 
7.5. 
Prior and Concomitant Medications 
For this study, non-study medications, including prior and concomitant medications, will be 
coded using World Health Organization Drug Dictionary Enhanced (WHO-DDE) (March 2017).  
Each non-study medication will be classified using the Anatomical-Therapeutic-Chemical (ATC) 
classification system and mapped to a WHO-DDE preferred drug name.   
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 for each actual 
treatment received and overall.  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 


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taking any concomitant medications will be tabulated similarly.  In addition, prior medications 
and concomitant medications will also be listed, separately.  
7.6. 
Treatment Compliance 
A subject will be considered fully compliant to treatment if the he/she responded “0” at all post-
baseline visits to the eCRF question “How many doses were missed since the previous visit?”   
The treatment compliance rate for a subject at a visit will be as following:  
 Compliance Rate (%) = (2*Duration – ∑Miss) / (2*Duration) × 100 
Where: 
Duration: 
The number of days subject should have administered study medication, 
calculated as treatment end date – Baseline date.  
Miss: The number of missed doses since the last visit day(s) 
For subjects in the FAS, the compliance rate will be summarized by post-baseline analysis visit 
for each planned treatment. 
7.7. 
Exposure to Study Medication 
The duration of exposure to a study medication is measured by days on treatment as derived in 
Section 4.1.3.  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 (1-14 days, 15-28 days, or > 28 days) for each actual treatment 
received. 


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8. 
EFFICACY ANALYSES 
Unless specified otherwise, the efficacy analyses will be performed on the FAS, where subjects 
are classified by planned treatment, irrespective of the actual treatment received. 
Unless specified otherwise, all efficacy analyses will be performed on the study eye, and the data 
on fellow eye will not be used.  
8.1. 
Analyses of Primary Endpoint  
8.1.1. 
Primary Analyses 
The primary efficacy endpoint is IOP in the study eye at each scheduled timepoint (08:00, 12:00 
and 16:00) at Weeks 2 and 6 (Visits 3 and 4).  The comparison between DE-117 BID arm and 
QD arm will be performed with the following hypotheses: 
H0i: µBi = µQi 
versus 
H1i: µBi ≠ µQi 
where µB and µQ denote the mean values of the primary endpoint in DE-117 BID arm and QD 
arm at i =1,2, …6 timepoints, with i = 1, 2, 3 represent 08:00, 12:00 and 16:00 at Week 2 and  
i = 4, 5, 6 represent 08:00, 12:00 and 16:00 at Week 6, respectively. 
The primary analyses will be performed on the FAS.  A mixed-effect model for repeated 
measures (MMRM) will be carried out for each timepoint.  Each model will include treatment, 
visit, and treatment-by-visit interaction as fixed effects, baseline IOP as a covariate.  Within-
subject errors will be modeled using an unstructured covariance matrix.  Least squares mean of 
the endpoint within each treatment arm will be reported.  The 95% confidence intervals (CIs) for 
the difference in means between DE-117 BID arm and QD arm at each timepoint and the 
corresponding p-values will be provided.   
If the model with unstructured covariance matrix fails to converge, the following structures  
other than unstructured are to be used in order of 1) heterogeneous toeplitz (TOEPH),  
2) heterogeneous autoregressive of order 1 (ARH(1)), 3) heterogeneous compound symmetry 
(CSH), 4) compound symmetry (CS) and the first (co)variance structure that converges would  
be used as the primary analysis.  
8.1.2. 
Sensitivity Analyses 
To assess the robustness of the results from the primary analysis for primary endpoint, the 
sensitivity analysis will be performed using the same MMRM model on PPS. All the primary 
and sensitivity analyses will be implemented using SAS PROC MIXED.  The main part of the 
SAS code for the specified MMRM analysis is provided in Appendix 12.1. 
8.2. 
Analyses of Secondary Endpoints 
For continuous secondary endpoints (mean diurnal IOP, change and percent change from 
baseline) at Week 2 (Visit 3) and Week 6 (Visit 4), MMRM and descriptive summaries will be 
performed.  The MMRM will be the same as the one for primary endpoint.   


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For binary secondary endpoints, the responder rates will be summarized at each post-baseline 
visit.  Pearson’s Chi-square test will be used for comparison between DE-117 BID arm and QD 
arm.   
8.3. 
Subgroup Analyses 
To assess the homogeneity of treatment effects among subgroups, descriptive summaries by age 
groups (< 65 vs ≥ 65 years), sex (males or females), race (White vs Non-white), primary ocular 
diagnosis (POAG or OHT), and mean diurnal IOP at baseline (< 25 or ≥ 25 mmHg) will be 
reported for primary efficacy endpoint. 
Other subgroup analyses may be performed as suggested by the data.   
9. 
SAFETY ANALYSES 
Safety of DE-117 will be primarily assessed by AEs, BCVA and evaluation with slit-lamp 
biomicroscopy and ophthalmoscopy.  The Safety population will be used for all safety 
summaries, where subjects will be classified by actual treatment received.   
All the safety-related measures will be summarized descriptively by actual treatment received.  
Except AEs, the descriptive summary of each safety-related measure and the change from 
baseline in that measure will be performed if applicable.  
9.1. 
Adverse Event 
Subjects with any AE(s), SAE(s), SAR(s) serious SAR(s) and significant AE (AE leading to 
study drug discontinuation) will be tabulated by type of AE(s) for each actual treatment received.   
Besides the overall AE summary, subjects with any AE(s) and any SAR(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.   
The same analysis above will be performed for ocular AEs and non-ocular AEs. 
AEs, AEs leading to death, AEs leading to study drug discontinuation, SAEs, SARs and ESIs, if 
any, will be listed separately.  
9.2. 
Slit-lamp Biomicroscopy 
For each biomicroscopy parameter, frequency and percentage of rating scores will be 
summarized by analysis visit for study eyes and non-study eyes, separately.  In addition, any 
clinically significant worsening (increase) from baseline will be summarized and listed.  
9.3. 
Ophthalmoscopy  
Frequency and percentage of rating scores will be summarized by treatment and analysis visit for 
study eyes and non-study eyes, separately.  In addition, any worsening (increase) of ≥ 2 units 
from baseline will be summarized and listed.  


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9.4. 
Best Corrected Visual Acuity 
Corrected visual acuity scores measured in logMAR scale and changes from baseline will be 
summarized by actual treatment received and analysis visit for study eyes and fellow eyes, 
separately.  In addition, any change such as worsening or improvement of at least 0.2 logMAR  
(2 lines) or maintained within 0.2 from baseline will be summarized.  Subjects with worsening of 
at least 0.2 from baseline will be listed. 
10. 
ANALYSES OF OTHER MEASURES 
None. 
11. 
REFERENCES 
None. 


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12. 
APPENDICES 
12.1. 
PROC MIXED for MMRM 
 
PROC MIXED data = dataset_name METHOD=REML; 
WHERE fasfl='Y' AND paramcd=" IOP " AND avisitn IN (2, 6) AND steyefl=’Y’ AND  atpt IN 
('8:00', '12:00', '16:00'); 
By atpt; 
CLASS usubjid trtpn avisitn; 
MODEL aval = base trtpn avisitn trtpn*avisitn/DDFM =KR; 
REPEATED avisitn/SUBJECT = usubjid TYPE= UN; 
LSMEANS trtpn*avisitn/DIFF CL; 
ESTIMATE “0.002% DE-117 QD – 0.002% DE-117 BID at Week 2” trtpn 1 -1 
 trtpn*avisitn 1 0 -1 0 /CL; 
ESTIMATE “ 0.002% DE-117 QD – 0.002% DE-117 BID at Week 6” trtpn 1 -1 
 trtpn*avisitn 0 1 0 -1 /CL; 
RUN; 
 
where 
 
fasfl: Full Analysis Set Population Flag 
 
paramcd: Parameter Code 
 
avisitn: Analysis Visit (N) 
 
steyefl: Study Eye Flag 
 
usubjid: Unique Subject ID 
 
trtpn: Planned Treatment (N) for  0.002% DE-117 QD and 0.002% DE-117 BID  
 
aval: Post baseline IOP score 
 
base: Baseline Value 
 
 


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