Clinical trial NCT02981446
Conditions: Open Angle Glaucoma or Ocular Hypertension
Sponsor: Santen Pharmaceutical Co., Ltd.
Start date: 2017-01-01; Completion date: 2019-01-01
Enrollment: 370 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to investigate the intraocular pressure-lowering effect and the safety of DE-117 ophthalmic solution compared with Latanoprost ophthalmic solution in subjects with open angle glaucoma or ocular hypertension.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: DE-117 intervention 2: Latanoprost ophthalmic solution
Intervention descriptions: intervention 1: DE-117 ophthalmic solution will be taken one drop, once daily for 3 months in both eyes. intervention 2: Latanoprost ophthalmic solution will be taken one drop, once daily for 3 months in both eyes.

Protocol documents:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:  
A Phase III, Randomized, Observer-Masked, Active-Controlled, 
Parallel-Group, Multinational and Multicenter Study Assessing the 
Safety and Efficacy of DE-117 Ophthalmic Solution 0.002% 
Compared with Latanoprost Ophthalmic Solution 0.005% in 
Subjects with Open-Angle Glaucoma or Ocular Hypertension- 
PEONY Study 
 
 
NCT Number:  
NCT02981446
 
Date of the document:
 28 Jun 2016 
 
 
 























































































































































SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:  
A Phase III, Randomized, Observer-Masked, Active-Controlled, Parallel-
Group, Multinational and Multicenter Study Assessing the Safety and 
Efficacy of DE-117 Ophthalmic Solution 0.002% Compared with 
Latanoprost Ophthalmic Solution 0.005% in Subjects with Open-Angle 
Glaucoma or Ocular Hypertension- PEONY Study 
 
 
NCT Number:  
NCT02981446
 
Date of the document:
12 Feb 2019 
 
 
 


 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
PEONY Study 
 
 
 
Protocol 
Title: 
A Phase III, Randomized, Observer-Masked, Active-Controlled, Parallel-Group, 
Multinational and Multicenter Study Assessing the Safety and Efficacy of DE-
117 Ophthalmic Solution 0.002% Compared with Latanoprost Ophthalmic 
Solution 0.005% in Subjects with Open-Angle Glaucoma or Ocular 
Hypertension- PEONY Study 
 
 
Product: 
DE-117 
 
 
Protocol 
Number:  
01171505 
 
 
Sponsor: 
Santen Pharmaceutical Co., Ltd. 
 
Grand Front Osaka Tower A 
4-20, Ofukacyo, Kita-ku 
Osaka 530-8552, Japan. 
 
 
Date:  
Feb 12, 2019 
 
 
Status:  
Version 1 
 
CONFIDENTIAL 
 
The information in this document is considered privileged and confidential by Santen Ltd., 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 
regulatory agencies.  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. 
 
 
 


膉腂穲犕见膌


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TABLE OF CONTENTS 
ABBREVIATIONS .........................................................................................................................1 
1. 
INTRODUCTION ........................................................................................................3 
2. 
OBJECTIVES AND ENDPOINTS ..............................................................................4 
2.1. 
Objectives .....................................................................................................................4 
2.1.1. 
Primary Objective .........................................................................................................4 
2.1.2. 
Secondary objectives ....................................................................................................4 
2.1.3. 
Safety objective ............................................................................................................4 
2.2. 
Endpoints ......................................................................................................................4 
2.2.1. 
Primary Endpoint ..........................................................................................................4 
2.2.2. 
Key Secondary Endpoints .............................................................................................4 
2.2.3. 
Other Secondary Endpoints ..........................................................................................4 
2.2.4. 
Safety Endpoints ...........................................................................................................5 
3. 
STUDY DESIGN .........................................................................................................6 
3.1. 
General Study Design ...................................................................................................6 
3.2. 
Randomization and Masking ........................................................................................6 
3.3. 
Sample Size Planning ...................................................................................................7 
3.4. 
Visits and Assessments .................................................................................................7 
4. 
DEFINTIONS ...............................................................................................................9 
4.1. 
Time-Related Terms .....................................................................................................9 
4.1.1. 
Baseline Visit ................................................................................................................9 
4.1.2. 
Treatment Start Date .....................................................................................................9 
4.1.3. 
Treatment End Date ......................................................................................................9 
4.1.4. 
Study Day .....................................................................................................................9 
4.1.5. 
Out-of-Window Measurements, Analysis Visit, and Analysis Window ......................9 
4.1.6. 
Out-of-Time-Window Measurements, Analysis Timepoint and Analysis 
Timepoint Window .....................................................................................................10 
4.1.7. 
Extent of Exposure .....................................................................................................11 
4.2. 
Efficacy and Safety-Related Definitions ....................................................................11 
4.2.1. 
Study Eye and Non-Study Eye ...................................................................................11 
4.2.2. 
Baseline Score ............................................................................................................11 
4.2.3. 
Change (and Percent Change) from Baseline .............................................................11 
4.3. 
Efficacy-Related Definitions ......................................................................................11 


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4.3.1. 
Intraocular Pressure ....................................................................................................11 
4.3.2. 
Response Endpoint and Response Rate ......................................................................11 
4.4. 
Safety-Related Definitions ..........................................................................................12 
4.4.1. 
Adverse Event .............................................................................................................12 
4.4.1.1. 
Ocular Adverse Event .................................................................................................12 
4.4.1.2. 
Suspected Adverse Reaction .......................................................................................12 
4.4.1.3. 
Serious Adverse Event ................................................................................................12 
4.4.2. 
Safety Measures ..........................................................................................................12 
4.5. 
Other Definitions ........................................................................................................13 
4.5.1. 
Prior and Concomitant Medications ...........................................................................13 
5. 
STUDY POPULATION .............................................................................................15 
5.1. 
Intent-to-Treat Population ..........................................................................................15 
5.2. 
Full Analysis Set .........................................................................................................15 
5.3. 
Per-Protocol Population ..............................................................................................15 
5.4. 
Safety Population ........................................................................................................15 
6. 
GENERAL CONSIDERATIONS ..............................................................................16 
6.1. 
Adjustments for Covariates ........................................................................................16 
6.2. 
Handling of Missing Data ...........................................................................................16 
6.2.1. 
General ........................................................................................................................16 
6.2.2. 
Intraocular Pressure ....................................................................................................17 
6.3. 
Multi-Center Studies ...................................................................................................17 
6.4. 
Multiple Comparisons / Multiplicity ..........................................................................17 
6.5. 
Interim Analysis ..........................................................................................................18 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................19 
7.1. 
Subject Disposition .....................................................................................................19 
7.2. 
Demographics and Baseline Characteristics ...............................................................19 
7.3. 
Concurrent Disease .....................................................................................................19 
7.4. 
Protocol Deviations ....................................................................................................20 
7.5. 
Prior and Concomitant Medications ...........................................................................20 
7.6. 
Treatment Compliance ................................................................................................20 
7.7. 
Exposure to Study Medication ....................................................................................21 
8. 
EFFICACY ANALYSES ...........................................................................................22 
8.1. 
Analyses of Primary and Key Secondary Endpoint ...................................................22 


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8.1.1. 
Primary Analysis ........................................................................................................22 
8.1.1.1. 
Primary Analysis of Primary Endpoint .......................................................................22 
8.1.1.2. 
Primary Analysis of Key Secondary Endpoints .........................................................22 
8.1.2. 
Sensitivity Analyses ....................................................................................................23 
8.2. 
Analyses of Secondary Endpoints ..............................................................................23 
8.3. 
Subgroup Analyses .....................................................................................................24 
9. 
SAFETY ANALYSES ...............................................................................................25 
9.1. 
Adverse Event .............................................................................................................25 
9.2. 
Visual Acuity ..............................................................................................................25 
9.3. 
Slit-lamp Biomicroscopy ............................................................................................25 
9.4. 
Central corneal thickness ............................................................................................26 
9.5. 
Ophthalmoscopy .........................................................................................................26 
9.6. 
Iris Color, Eyelash and Eyelid ....................................................................................26 
9.7. 
Visual Field .................................................................................................................26 
10. 
ANALYSES OF OTHER MEASURES .....................................................................27 
11. 
REFERENCES ...........................................................................................................27 
12. 
APPENDICES ............................................................................................................28 
12.2. 
Changes from Protocol ...............................................................................................31 
 
 
 
 
 


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LIST OF TABLES 
Table 1. Assessment Schedule .........................................................................................................8 
Table 2. Analysis Visit and Analysis Window ..............................................................................10 
Table 3. Analysis Timepoint and Analysis Timepoint Window....................................................10 
Table 4. Response Endpoints .........................................................................................................11 
Table 5. Safety Assessments ..........................................................................................................13 
 
LIST OF FIGURES  
Figure 1: Study Design ....................................................................................................................6 
 
 
 


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ABBREVIATIONS 
  
AE 
Adverse Event 
Al-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AR(1) 
First-order autoregressive (covariance structure) 
AST 
Aspartate aminotransferase  
ATC 
Anatomical-Therapeutic-Chemical 
BUN 
Blood urea nitrogen 
CAI 
Carbonic Anhydrase Inhibitor 
Cl 
Chloride 
CS 
Compound Symmetry 
CSR 
Clinical Study Report 
eCRF 
electronic Case Report Form 
CSR 
Clinical Study Report 
FAS 
Full Analysis Set 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System 
K 
Potassium 
LDH 
Lactate dehydrogenase 
LOCF 
Last Observation Carried Forward 
MAR 
Missing At Random 
MCAR 
Missing Completely At Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effects Model for Repeated Measures 
MNAR 
Missing Not At Random 
Na 
Sodium 
OAG 
Open Angle Glaucoma 
OD 
Oculus Dexter (right eye) 
OHT 
Ocular Hypertension 


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OS 
Oculus Sinister (left eye) 
OU 
Oculus Uterque (both eyes) 
POAG 
Primary Open-Angle Glaucoma 
PP 
Per-Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SAS 
Statistical Analysis System 
SOC 
System Organ Classification 
UN 
Unstructured (covariance structure) 
VC 
Variance Components (covariance structure) 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
γ-GT 
Gamma Glutamyl Transferase 
 


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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 PEONY study within the scope of Santen’s Protocol 01171505, 
“A Phase III, Randomized, Observer-Masked, Active-Controlled, Parallel-Group, Multinational 
and Multicenter Study Assessing the Safety and Efficacy of DE-117 Ophthalmic Solution 
0.002% Compared with Latanoprost Ophthalmic Solution 0.005% in Subjects with Open-Angle 
Glaucoma or Ocular Hypertension”.  It applies to the study protocol dated 28 JUN 2016 and 20 
JAN 2017 (for India), 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 protocol.  Any deviations from the 
specified inferential analyses must be substantiated by sound statistical reasoning and 
documented in the CSR. 


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2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objective 
To determine if the mean diurnal intraocular pressure (IOP) reduction with DE-117 ophthalmic 
solution 0.002% is non-inferior to Latanoprost ophthalmic solution 0.005% at Month 3 in 
subjects with open-angle glaucoma (OAG) or ocular hypertension (OHT). 
2.1.2. 
Secondary objectives 
To determine if the mean IOP reduction with DE-117 ophthalmic solution 0.002% is non-inferior 
to Latanoprost ophthalmic solution 0.005% at each post baseline time point after 3 months of 
treatment in subjects with OAG or OHT.  This secondary objective will be used to meet the FDA 
non-inferiority requirement. 
To determine if the mean diurnal IOP reduction with DE-117 ophthalmic solution 0.002% is 
superior to that of Latanoprost ophthalmic solution 0.005% at Week 1 in subjects with OAG or 
OHT. 
 
2.1.3. 
Safety objective 
To determine the safety of DE-117 ophthalmic solution 0.002% as compared to Latanoprost 
ophthalmic solution 0.005% in subjects with OAG or OHT. 
2.2. 
Endpoints 
2.2.1. 
Primary Endpoint 
Mean diurnal IOP (average of IOP at three timepoints: 9:00, 13:00 and 17:00) in the study eye at 
Visit 5 (Month 3). 
2.2.2. 
Key Secondary Endpoints 
The key secondary endpoints are  
• Mean IOP in the study eye at the specified timepoints: 9:00, 13:00, and 17:00 at Week 1, 
Week 6 and Month 3. 
• Mean diurnal IOP in the study eye at Week 1.  This endpoint is set to confirm the early 
onset of DE-117 in the IOP lowering effect.  
2.2.3. 
Other Secondary Endpoints 
The following secondary endpoints will be assessed:  
• Mean diurnal IOP in the study eye at Visit 4 (Week 6).  


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•  Proportion of subjects with mean diurnal IOP reduction from baseline ≥ 20%, 25% and 
30% in the study eye at Visit 3 (Week 1), Visit 4 (Week 6) and Visit 5 (Month 3) 
• Proportion of subjects with mean diurnal IOP < 18 mmHg in the study eye at Visit 3 
(Week 1), Visit 4 (Week 6) and Visit 5 (Month 3).  
• Change and percent change from baseline (CFB) in mean diurnal IOP in the study eye at 
each post-baseline visit (Visit 3, 4, and 5 [Week 1, Week 6 and Month 3, respectively]). 
• Change and percent change from baseline (CFB) in IOP in the study eye at the specified 
timepoints: 9:00, 13:00, and 17:00 at each post-baseline visit. 
• Overall (grand) mean diurnal IOP (average of 4 visits) in the study eye. 
2.2.4. 
Safety Endpoints 
The following safety endpoints will be assessed:  
• Incidence of ocular and systemic adverse events (AEs) 
• Corrected visual acuity 
• Slit-lamp biomicroscopy 
• Ophthalmoscopy 
• Visual Field (India only) 
• Central corneal thickness 
• Iris color/eyelash/eyelid 


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3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is a randomized, observer-masked, active-controlled, parallel-group, multinational, 
multicenter study assessing the safety and efficacy of DE-117 ophthalmic solution 0.002% 
compared with Latanoprost ophthalmic solution 0.005% in subjects with OAG or OHT.  As 
shown in the study design diagram (Figure 1), this study consists of up to 4-Week washout 
period and a 3-Month treatment period.  Approximately 360 subjects are planned to be 
randomized. 
  
Figure 1: Study Design 
 
3.2. 
Randomization and Masking 
Subjects will be randomized on a 1:1 basis to two treatment groups. A blocked randomization 
will be stratified by 1) the mean diurnal IOP in the study eye at Baseline (< 25 mmHg and ≥ 25 
mmHg) and 2) diagnosis of disease in the study eye at Baseline (OAG or OHT). Randomization 
schedule with a fixed block size will be generated. Each eligible subject will receive a study 
medication kit numbered using IWRS system. 
DE-117 ophthalmic solution 0.002% or Latanoprost ophthalmic solution 0.005% will be 
supplied as a 2.5 mL solution in a 5 mL clear low-density polyethylene bottle. The shape of the 
bottle is different between DE-117 ophthalmic solution and Latanoprost ophthalmic solution. 
Therefore, the study will be observer-masked although eye drop bottles of study medication will 
be placed in a kit with indistinguishable appearance.  
To maintain masking of the Investigator, examiner, and Santen (or designee) during this study, 
an authorized study staff, other than the Investigator or examiner, will dispense and collect study 


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medications. The subjects will be instructed not to show the eye drop bottles to either the 
Investigator, examiner, or the other study subject(s). When collecting the study medications, the 
kit containing the used and unused four eye drop bottles will be sealed. 
In case of a medical emergency, the Principal Investigator may reveal the treatment information 
by unmasking through IWRS (Interactive Web Response System) 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. 
3.3. 
Sample Size Planning 
The primary endpoint is the mean diurnal IOP in the study eye at Month 3. Assuming a 
difference of 0 mmHg and a standard deviation of 4.0 mmHg for the comparison between the 
DE-117 group and the Latanoprost group, a total of 151 subjects per group will provide at least 
90% power to demonstrate the non-inferiority of the DE-117 group to the Latanoprost group 
(one-sided α = 0.025 and non-inferiority margin of 1.5 mmHg). The standard deviation of 4.0 
mmHg was assumed from a previous DE-117 study conducted in the United States, in which the 
standard deviation of mean diurnal IOP in the Latanoprost 0.005% group and DE-117 0.002% 
group ranged from 2.59 mmHg to 4.40 mmHg.  
Assuming that 16% subjects will prematurely discontinue the study, a total of 360 subjects (180 
subjects per group) are to be randomized to have 302 completers (151 per group) at Month 3. 
3.4. 
Visits and Assessments    
There are five 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 1).  
For subjects whose study participation is terminated prior to Visit 5 (Month 3), to the extent 
possible, all assessments scheduled for Visit 5 (Month 3) will be performed at the Exit Visit. 
 
 


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Table 1. Assessment Schedule 
 
a Informed Consent and authorization as appropriate for local privacy regulations must be signed and dated before study 
procedures are performed. 
b Urine pregnancy test will be conducted for all female subjects of childbearing potential. 
c Biomicroscopy examination will be completed right before the 9:00 IOP measurement at all visits except Visit 1/1a (Screening 
or mid washout visit).  
d IOP Measurements will be taken at 9:00±60min, 13:00±60min and 17:00±60min at all visits except Visit 1/1a (Screening or mid 
washout visit).  
e Central corneal thickness measurements will be performed right after the 9:00 IOP measurement at all visits except Visit 1/1a 
(Screening or mid washout visit). 
f Ophthalmoscopy (fundus) examination will be performed without pupil dilation.  
g Gonioscopy will be performed if not done within the prior 3 months of Visit 1.   
h Visual field measurement will be performed if not done within the prior 3 months of Visit 1.  
i One kit containing four eye drop bottles of study medication will be dispensed at Visit 2 and Visit 4, respectively. To maintain 
masking of the Investigator and examiner during this study, an authorized study staff, other than the Investigator or examiner, will 
dispense and collect study medications. 
j One kit containing four eye drop bottles of study medication will be collected at Visit 4 and Visit 5 Study Exit/Early 
Termination, respectively. When collecting the study medications, the kit containing the used and unused four eye drop bottles 
 The specified examinations and observations will be performed as much as possible.
m Visual field measurement at Visit 5 (Month 3)/Early Termination will be performed only in Indian sites. 
 
 
 
Screening Phase 
Treatment Phase 
Visit 1 
Screening 
Wash-out 
Period 
(optional 
Visit 1a) 
Visit 2 
Baseline 
(Day 1) 
Visit 3 
Week 1 
(Day 8±2) 
Visit 4 
Week 6 
(Day 
43±3) 
Visit 5 
Month 3 
(Day 
91±7, 
 Exit) 
Early 
Term l 
 
Informed Consent(s) a 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
 
Demographics 
and 
Medical 
History 
X 
 
 
 
 
 
 
Medications/Therapies 
X 
X 
X 
X 
X 
X 
X 
Dosing Compliance 
 
 
 
X 
X 
X 
X 
Adverse Events  
 
X 
X 
X 
X 
X 
X 
Pregnancy Test b 
X 
 
X 
 
 
X 
X 
Biomicroscopy c 
X 
X 
X (9:00) 
X (9:00) 
X (9:00) 
X (9:00) 
X (9:00) 
IOP d 
X 
X 
9:00 
13:00 
17:00 
9:00 
13:00 
17:00 
9:00 
13:00 
17:00 
9:00 
13:00 
17:00 
9:00 
13:00 
17:00 
Central corneal thickness e 
X 
 
X (9:00) 
X (9:00) 
X (9:00) 
X (9:00) 
X (9:00) 
Corrected visual acuity 
X 
X 
X 
X 
X 
X 
X 
Iris, Eyelash, Eyelid 
 
 
X (Photo) 
X 
X 
X 
X 
Ophthalmoscopy f 
X 
 
X 
 
 
X 
X 
Gonioscopy g 
X 
 
 
 
 
 
 
Visual Field h 
X 
 
 
 
 
X m 
X m 
Randomization via IWRS 
 
 
X 
 
 
 
 
Dispense Study Medication i 
 
 
X 
 
X 
 
 
Collect Study Medication j 
 
 
 
 
X 
X 
X 


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4. 
DEFINTIONS 
4.1. 
Time-Related Terms  
4.1.1. 
Baseline Visit 
In this study, Visit 2 is the baseline visit when the subject was randomized.   
4.1.2. 
Treatment Start Date 
Treatment start date is the date at which a randomized subject took the first dose of the study 
medication.  In this study, the treatment start date is usually the Visit 2 (Baseline) date. 
4.1.3. 
Treatment End Date 
Treatment end date is the date at which a randomized subject took the last dose of the study 
medication.  If the date of the last dose is missing, then 
 
The day before the Visit 5 (Month 3) date 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 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. 
4.1.4. 
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, Visit 2 (Baseline) date of the Treatment Period is the 
reference day and 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 
Note that there is no Study Day 0.   
For adverse events, prior and concomitant medications, the study day will be calculated from the 
date of First Exposure to treatment.  
4.1.5. 
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 a measurement should be mapped to 
(Table 2). 
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 with the study visit 
where the measurement was collected.  For example, an out-of-window measurement collected 
at the Week 1 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 2. Analysis Visit and Analysis Window 
Analysis Visit (Target 
Assessment Date) 
Visit Window 
Analysis Window 
Ophthalmoscopy and 
Visual Field 
Other Parameters 
Baseline (Day 1) 
[1, 1] 
- 1] 
- 1] 
Week 1 (Day 8) 
[6, 10] 
NA 
[2, 22] 
Week 6 (Day 43) 
[40, 46] 
NA 
[23, 61] 
Month 3 (Day 91) 
[64, 98] 
[2 - 
[62 - 
NA: Not Applicable. 
 
In case that there are two or more measurements at an analysis visit, the measurement closest to 
the target assessment day will be selected for that visit. In the case that two measurements are 
closest and 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 measurements that 
fall into the same analysis window of a post-baseline visit, then a visit in which IOP are 
measured at all the scheduled timepoints (9:00, 13:00 and 17:00) will be selected for that 
analysis visit.  The IOP data measured at 3 days or more after the last treatment will not be used 
for the efficacy analysis regardless of the analysis window. 
4.1.6. 
Out-of-Time-Window Measurements, Analysis Timepoint and Analysis 
Timepoint Window 
Analysis timepoint is a timing variable to be used for analyses involving timepoints. The IOP will 
be measured two or three times for each timepoint, and the last recorded time will be used for 
determining its timepoint. For each analysis timepoint, an analysis timepoint window is set up to 
determine the allowance range (Table 3). 
 
Table 3. Analysis Timepoint and Analysis Timepoint Window 
Analysis Timepoint 
Timepoint Window 
Analysis Timepoint Window 
9:00 
[8:00, 10:00] 
- 10:59] 
13:00 
[12:00, 14:00] 
[11:00, 14:59] 
17:00 
[16:00, 18:00] 
[15:00 - 
 
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. 


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4.1.7. 
Extent of Exposure 
The extent of exposure to study medication will be assessed by duration of treatment exposure, 
derived as: 
• 
Duration of treatment exposure = (Treatment end date – Treatment start date) + 1  
4.2. 
Efficacy and Safety-Related Definitions 
4.2.1. 
Study Eye and Non-Study Eye 
The study eye will be the eye that qualifies per inclusion/exclusion criteria at Visit 2 (Baseline). 
If both eyes meet the inclusion criteria, the eye with the higher mean diurnal IOP at Visit 2 
(Baseline) will be the study eye. If both eyes meet the inclusion 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. 
4.2.2. 
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 visit will be used to impute the baseline score. 
4.2.3. 
Change (and Percent Change) from Baseline 
The change and the percent change from Baseline in a measure at a post-baseline visit will be 
derived as: 
• Change = (Score at the Post-Baseline Visit) – (Baseline Score) 
• Percent Change from Baseline = 100 × Change / (Baseline Score) 
4.3. 
Efficacy-Related Definitions 
4.3.1. 
Intraocular Pressure 
For the IOP at each timepoint of measurement, a mean of two consecutive measurements using 
the Goldmann applanation tonometer will be used as the IOP score at that timepoint.  If a ≥3 
mmHg difference is shown between the two consecutive measurements, a third measurement 
will be obtained and the median value of the three measurements will be used. 
The mean diurnal IOP is derived as the mean of the IOP scores at the three scheduled timepoints 
(9:00, 13:00 and 17:00).   
4.3.2. 
Response Endpoint and Response Rate 
Four types of response endpoints (Table 4) will be evaluated at each post-Baseline visit (Week 1, 
Week 6, or Month 3) in this study: 
Table 4. Response Endpoints 
Response Endpoint 
Response criteria  in mean diurnal IOP 
IOP 20% response 
Percent Reduction from Baseline ≥ 20% 


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IOP 25% response 
Percent Reduction from Baseline ≥ 25% 
IOP 30% response 
Percent Reduction from Baseline ≥ 30% 
IOP < 18 mmHg response 
Mean diurnal IOP < 18 mmHg 
For a response endpoint, the response rate at a post-Baseline visit is calculated as the proportion 
of subjects who met the response criterion at the post-baseline visit.  
4.4. 
Safety-Related Definitions 
4.4.1. 
Adverse Event 
Under this study, an AE is any untoward medical occurrence in a subject participated in the 
study; it does not necessarily have a causal relationship with study treatment. Regardless of 
relationship to the investigational medicinal product, an AE can be an unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational medicinal product.  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 last study visit.  Treatment-emergent AEs 
are a subset of on-study AEs.  Both on-study and treatment-emergent AEs will be reported. 
Each AE will be classified into a system organ classification (SOC) and coded to a preferred 
term using Medical Dictionary for Regulatory Activities (MedDRA 19.0, 2016).   
4.4.1.1. 
Ocular Adverse Event 
An AE will be counted as an ocular AE if the Clinical Investigator selected ‘OD’, ‘OS’, or ‘OU’ 
under ‘Eye(s) affected’ on the Adverse Event eCRF form.  
4.4.1.2. 
Suspected Adverse Reaction  
An AE will be counted as a suspected adverse reaction (SAR) if the Clinical Investigator 
answered ‘Related’ to the question ‘Relationship to Study Drug?’ on the Adverse Event eCRF 
form. 
4.4.1.3. 
Serious Adverse Event 
An AE will be counted as a serious adverse event (SAE) if the Clinical Investigator selected 
‘Yes’ to the question “Is the Adverse Event Serious?” on the Adverse Event eCRF form.   
4.4.1.3.1. Important Adverse Event 
The following Significant Adverse Event will be identified throughout the study. 
• AE leading to drug withdrawn or drug interruption 
4.4.2. 
Safety Measures  
Table 5 lists the measures to be evaluated for this study. 
 


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Table 5. Safety Assessments 
Safety Measures 
Note 
Visual acuity 
Corrected visual acuity will be measured for each eye at each visit under 
normal room illumination using visual acuity chart (e.g., ETDRS chart, 
Snellen chart) and the logMAR scoring will be recorded in the subject’s 
source document.  Increase in logMAR scores means worsening in visual 
acuity. 
Slit-lamp biomicroscopy 
Slit-lamp biomicroscopy examinations (anterior chamber cells, anterior 
chamber flare, lid hyperemia, lid edema, conjunctival hyperemia, 
conjunctival chemosis, corneal edema, corneal staining, corneal 
endothelial change (i.e. keratic Precipitate), lens, anterior synechiae of 
iris, posterior synechiae of iris) will be performed and graded right 
before the 9:00 IOP measurement at all visits except Visit 1/1a 
(Screening or mid washout visit).   
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 right after the 
9:00 IOP measurement if it is a contact method at Visit 2, Visit 3, Visit 4 
and Visit 5 Study Exit/Early Termination. If it is a non-contact method, 
the CCT measurement can be performed prior to the IOP measurement at 
9:00.  For Visit 1 (Screening), central corneal thickness measurement 
should be performed after IOP measurement. 
Visual Field 
Visual field examinations will be performed using a static or dynamic 
perimeter without pupil dilation at Visit 1 (Screening) and Visit 5 (Month 
3)/Early Termination. The same perimeter will be used for each subject. 
Glaucomatous visual field loss will be evaluated by the investigator as 
presence or absence.  The visual field exam at Visit 5 will only be 
performed  in Indian sites. 
Ophthalmoscopy 
The ophthalmoscopy (fundus) examination will be performed for each 
eye without pupil dilation at Visit 1, Visit 2, and Visit 5 Study Exit/Early 
Termination, and graded as None (0), Mild (1), Moderate (2) or Severe 
(3). 
Iris color/eyelash/eyelid 
The investigator (or his/her designee) will take frontview and sideview 
photograph of each eye at Visit 2 (Baseline). The photographs must 
include iris, eye lids and eyelashes of each eye. The photographs taken at 
Visit 2 (Baseline) will be used to help the Investigator assess any 
changes (“No changes”, “Increased” or “Decreased”) from baseline in 
iris color pigmentation, eyelid pigmentation, eyelid hair growth, eyelash 
length, eyelash thickness, eyelash pigmentation and eyelash number  at 
Visit 3, Visit 4 and Visit 5 Study Exit/Early Termination. 
 
4.5. 
Other Definitions  
4.5.1. 
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 


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taken concurrently while on the study medication, i.e., the treatment period of a concomitant 
medication taken by a subject 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 be comprised of all randomized subjects.   
5.2. 
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized subjects who received at least one dose 
of study medication and provided at least one post-baseline IOP measurement.  
This will be the population used for efficacy analyses.  Unless specified otherwise, subjects in 
efficacy analyses are classified by planned treatment, irrespective of the actual treatment 
received. 
5.3. 
Per-Protocol Population 
The Per-Protocol (PP) population is a subset of the FAS.  It will include all FAS subjects without 
protocol deviations that could affect the primary efficacy endpoint.  
Santen’s study team will review all protocol deviations and identify subjects to be excluded from 
the PP population before the unmasking of treatment assignment.  
 
5.4. 
Safety Population 
The Safety population will include all randomized subjects who received at least one dose of the 
study medication.  It will be the analysis population for safety analyses to be performed with 
subjects as treated.  If a subject received both DE-117 and Latanoprost, the subject will be 
classified to the first treatment.   


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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 (%).   
The statistical testing will be conducted at a significance level of 0.05 (two-sided) and 95% the 
confidence interval will be shown, unless specified otherwise.  No statistical testing will be 
conducted for safety measures. 
All data manipulations, descriptive summaries, and statistical hypothesis testing will be 
performed using SAS® Version 9.4 or later.   
6.1. 
Adjustments for Covariates 
In general, baseline IOP score, diagnosis and country will be adjusted in the inferential analysis 
of each IOP endpoint.  Detailed information on covariate adjustment is provided in Section 8.1.   
6.2. 
Handling of Missing Data 
6.2.1. 
General  
For each post-baseline IOP endpoint, no imputation is needed for the analysis on observed cases 
using the mixed-effects model for repeated measures (MMRM).  The Last Observation Carried 
Forward (LOCF) imputation will be implemented in the sensitivity analysis (Section 8.1.2).  
Descriptive summaries of safety measures will be based on observed data only.  No imputation 
of missing scores will be implemented except for Baseline (Section 4.1.1).  
Completely or partially missing onset and resolution dates for AEs will be imputed in a 
conservative fashion as follows:   
Date 
Type of Missing Date 
Handling of Missing Date 
Event start date  
(e.g., YYYY-MM-
DD) 
Completely missing 
Use the treatment start date to impute the missing 
date  
Only YYYY is 
available 
If YYYY is the same as the year part of the 
treatment start date, then use the treatment start date 
to impute the partially missing date; otherwise 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 
If YYYY and MM are the same as the year and 
month parts of the treatment start date, then use the 
treatment start date to impute the partially missing 
date; otherwise use the first day of MM to impute 
the missing date part of the onset date. 
Event end date 
Completely missing 
No imputation will be applied.  The event will be 


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(e.g., YYYY-MM-
DD) 
 
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  
If the date above is a future date, no imputation will 
be applied.  The event will be considered ongoing 
(i.e., not resolved) at the last visit 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. 
If the date above is a future date, no imputation will 
be applied.  The event will be considered ongoing 
(i.e., not resolved) at the last visit date. 
Same rules will be followed to impute the completely or partially missing start and end dates of 
concomitant medications. If a medication was started prior to the washout period, the start dates 
of the concomitant medications will not be imputed. 
6.2.2. 
Intraocular Pressure 
In general, the assessment of IOP will be conducted for two or three times at a scheduled 
timepoint depending on the difference between the first two IOP measurements.  If the first two 
measurements differ by 2 mmHg or less, then the average of the two measurements becomes the 
recorded IOP.  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 mean diurnal IOP will be derived as the mean of the IOP measurements at three scheduled 
timepoints (9:00, 13:00 and 17:00).  If there is a missing IOP measurement at a scheduled 
timepoint, the mean diurnal IOP will not be calculated. 
6.3. 
Multi-Center Studies 
This is a multi-center study enrolling subjects from approximately 30 sites in Asian countries 
including Singapore, India, Taiwan and Korea.  Due to the large number of sites and the small 
numbers of subjects per center and treatment group, the sites may be pooled by country for 
analysis purposes. 
Unless specified otherwise, country will be included as a factor in the statistical models for the 
analyses of the primary and the secondary efficacy endpoints. 
6.4. 
Multiple Comparisons / Multiplicity 
To control the overall Type I error rate associated with the three comparisons on the primary 
endpoint (non-inferiority in the mean diurnal IOP at Month 3) and the two key secondary 
endpoints (non-inferiority in the IOP at each timepoint at Week 1, Week  6 and Month 3 and 
superiority in the mean diurnal IOP at Week 1) at the 0.05 level (two-sided), a fixed sequence 
procedure will be implemented. The three sets of hypothesis testing will be prioritized as 
follows: 


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1) Non-inferiority of 0.002% DE-117 to 0.005% Latanoprost in the mean diurnal IOP at 
Month 3 
2) Non-inferiority of 0.002% DE-117 to 0.005% Latanoprost in the IOP at all timepoints 
(9:00, 13:00 and 17:00) at Week 1, Week 6 and Month 3 
3) Superiority of 0.002% DE-117 to 0.005% Latanoprost in the mean diurnal IOP at 
Week 1 
The second hypothesis testing will be claimed only if the first one is confirmed.  The third 
hypothesis testing will be claimed only if the first and the second ones are confirmed. 
6.5. 
Interim Analysis 
No formal interim analysis is planned for this study.  


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7. 
SUMMARY OF STUDY POPULATION DATA 
7.1. 
Subject Disposition 
The number of subjects with informed consent will be shown. The disposition of the ITT 
population (i.e., all randomized subjects) will be summarized by treatment and overall.  The 
summary will include the number and percentage of ITT subjects in the Safety population, FAS, 
and the PP Population.  The disposition summary will also include the number and percentage of 
completers and non-completers at Visit 5 (Month 3), as well as the number and percentage of 
non-completers at Visit 5 (Month 3) by the primary discontinuation reason.   
7.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be descriptively summarized for FAS and 
Safety population by planned (or 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) 
• Race (categorical: American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, or Other/Multiracial)  
• Ethnicity (categorical: Hispanic or Latino or Not Hispanic or Latino)  
• Country (categorical: India, Korea, Singapore, or Taiwan)  
For baseline characteristics, the following variables will be summarized for study eye:   
• Iris Color (categorical: Blue/Gray, Blue/Gray with Slightly Brown, Blue/Gray – Brown, 
Green, Green with Slightly Brown, Green – Brown, Yellow – Brown, or Brown) 
• Diagnosis (categorical: OAG [subcategories: POAG, Pseudoexfoliative Glaucoma, 
Pigmentary Glaucoma], or OHT)  
• Prior use of IOP-lowering medication(s) (categorical: ß-adrenergic antagonist, prostamide 
or prostaglandin analogue, α-adrenergic agonist, carbonic anhydrase inhibitors, miotic 
agent, other, or none) 
• Baseline mean diurnal IOP score and baseline IOP score at each scheduled timepoint 
(09:00, 13:00, or 17:00) 
• Baseline central corneal thickness 
• Baseline degree of angle closure in Shaffer scale (ordinal: Grade 2, Grade 3, or Grade 4)  
• Baseline glaucoma visual field loss (categorical: No or Yes)  
• Baseline glaucomatous findings in fundus (categorical: None, Mild, Moderate, or Severe)  
7.3. 
Concurrent Disease 
For this study, concurrent disease will be coded using MedDRA 19.0, 2016.  Each concurrent 
disease will be classified into a system organ class (SOC) and mapped to a preferred term (PT).   


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The concurrent disease will be summarized for the FAS population.  Subjects reporting any 
concurrent disease at baseline will be tabulated by SOC and preferred term for each planned 
treatment and overall.  
7.4. 
Protocol Deviations 
In this study, important protocol deviations are categorized as follows: Protocol deviations 
related to: 
• Informed consent 
• Study conduct/procedure 
• Investigational product 
• Other 
ITT subjects with any protocol deviation(s) above will be summarized and listed.   
7.5. 
Prior and Concomitant Medications 
For this study, non-study medications, including prior and concomitant medications, will be 
coded using WHO-DDE (MAR 2016).  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 taking any 
concomitant medications will be tabulated similarly.  In addition, prior medications and 
concomitant medications will also be listed, separately.  
7.6. 
Treatment Compliance 
The compliance rate for a subject will be calculated as follows: 
• Compliance Rate (%) = (Duration – ∑Miss) / Duration × 100 
Where 
Duration: The number of days subject should have administered study medication, calculated 
as last visit date – Visit 2 date. The last visit date is the Visit 5 date for completers 
and the study Exit Visit date for subjects who prematurely discontinued the study. 
If the Exit Visit date of a non-completer is not available, then the last available visit 
date will be considered the Exit date. 
Miss: 
Total number of days that subject did not follow the proper dosing procedures and 
dosing schedule since the last visit day(s) 
For subject in FAS, the compliance rate will be summarized by post-baseline analysis visit for 
each planned treatment and overall. 


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7.7. 
Exposure to Study Medication 
The duration of exposure to a study medication is measured by days on treatment as derived in 
Section 4.1.7.  For subjects in the Safety Population, the duration of exposure will be 
summarized using descriptive statistics, and frequency and percentage of subjects will be 
tabulated by duration category (1-30 days, 31-60 days or ≥ 61 days) for each actual treatment 
received.   
 


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8. 
EFFICACY ANALYSES 
Unless specified otherwise, all 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 
non-study eye will be excluded.  
8.1. 
Analyses of Primary and Key Secondary Endpoint 
8.1.1. 
Primary Analysis 
8.1.1.1. 
Primary Analysis of Primary Endpoint 
The primary efficacy endpoint is the mean diurnal intraocular pressure at Month 3.   
For the primary endpoint, the comparison between the 0.002% DE-117 group (T) and the 
0.005% Latanoprost group (C) will be performed with the following pair of testing hypotheses: 
H0: µC + Δ ≤ µT 
Versus 
H1: µC + Δ > µT 
where µT and µC denote the mean values of the primary endpoint in the 0.002% DE-117 group 
and the 0.005% Latanoprost group, respectively, and Δ denotes the non-inferiority margin of 1.5 
mmHg.   
The primary analysis will be performed using MMRM on the FAS.  The model will include 
treatment, visit, diagnosis (OAG or OHT), country and treatment-by-visit interaction as fixed 
effects, baseline IOP as a covariate, and subject as a random effect.  Within-subject errors will be 
modeled using an unstructured covariance matrix.  Least squares means of the treatment 
response within each treatment group and treatment differences between the 0.002% DE-117 
group and the 0.005% Latanoprost group will be reported along with 95% confidence intervals.  
Non-inferiority is established if the upper limit of the 95% confidence interval for the difference 
between DE-117 and Latanoprost in the mean diurnal IOP at Month 3 is less than or equal to 
1.5 mmHg. 
8.1.1.2. 
Primary Analysis of Key Secondary Endpoints 
This study has two key secondary endpoints. 
One of the key secondary efficacy endpoint is the mean intraocular pressure at 9:00, 13:00 and 
17:00 at Week 1, Week 6 and Month 3.  The same MMRM for the primary efficacy endpoint 
will be applied.  A separate model will be fitted for each scheduled timepoint using baseline IOP 
at the corresponding timepoint as a covariate.  Non-inferiority is achieved if the upper limit of 
the 95% confidence interval for the difference between DE-117 and Latanoprost is less than or 
equal to 1.5 mmHg at all timepoints and less than or equal to 1.0 mmHg at the majority of the 
timepoints. 


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The other key secondary efficacy endpoint is the mean diurnal intraocular pressure at Week 1.  If 
non-inferiority in the primary and key secondary endpoints is achieved, then superiority will be 
tested for this key secondary endpoint as follows: 
H0: µT = µC 
Versus 
H1: µT ≠ µC 
The primary analysis of the key secondary endpoint will be performed using the same MMRM 
for the primary efficacy endpoint simultaneously (Section 8.1.1.1).  Superiority is claimed if the 
upper limit of the 95% confidence interval for the difference between DE-117 and Latanoprost in 
the mean diurnal IOP at Week 1 is less than 0 mmHg. 
 
8.1.2. 
Sensitivity Analyses 
For the primary endpoint and the key secondary endpoint, to assess the robustness of the results 
from the primary analysis, the following sensitivity analyses will be performed:   
Statistical Method 
Analysis 
Population 
Assumption of 
Missing 
Mechanism 
Handling of Missing Data 
MMRM 
PP population 
MAR 
Observed cases 
MMRM including treatment-by-
country interaction 
FAS 
MAR 
Observed cases 
ANCOVA 
(factor: 
treatment, 
diagnosis and country; covariate: 
baseline IOP) 
FAS 
- 
Last observation carried forward 
(LOCF) 
PP population 
- 
LOCF 
Completers at 
Month 3 
MCAR 
not applicable 
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 and ANCOVA are provided in 
Appendix 12.1.1 and 12.1.2, respectively.  
8.2. 
Analyses of Secondary Endpoints 
The following secondary endpoints will be analyzed using the same MMRM for the primary and 
the first key secondary efficacy endpoints simultaneously (Section 8.1.1).  
• The mean diurnal IOP in the study eye at Week 6 
• The overall (grand) mean diurnal IOP in the study eye, defined as the average of the 
mean diurnal IOP in the study eye at 3 post-baseline visits (Week 1, Week 6, and Month 
3)  
The following secondary endpoints will be analyzed using the same MMRM for the primary 
efficacy endpoint.  A separate model will be fitted for each scheduled timepoint using baseline 
IOP at the corresponding timepoint as a covariate.  


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• The percent change from baseline (CFB) in mean diurnal IOP in the study eye at a post-
baseline visit (Week 1, Week 6, Month 3, or Overall)  
• The percent change in IOP in the study eye at a specified timepoint (9:00, 13:00, or 
17:00) at a post-baseline visits (Week 1, Week 6, Month 3, or Overall)  
The following secondary endpoints will be presented descriptively by treatment group.  
• The CFB in mean diurnal IOP in the study eye at a post-baseline visit (Week 1, Week 6, 
or Month 3)  
• The CFB in IOP in the study eye at a specified timepoint (9:00, 13:00, or 17:00) at a post-
baseline visit (Week 1, Week 6, or Month 3)  
The following response rates will be summarized by treatment group and visit.  
• IOP 20% response  (having a percent  reduction in mean diurnal IOP in the study eye of ≥ 
20% from Baseline) at a post-Baseline visit (Week 1, Week 6, or Month 3)  
• IOP 25% response (having a percent  reduction in mean diurnal IOP in the study eye of ≥ 
25% from Baseline) at a post-Baseline visit (Week 1, Week 6, or Month 3) 
• IOP 30% response (having a percent  reduction in mean diurnal IOP in the study eye of ≥ 
30% from Baseline) at a post-Baseline visit (Week 1, Week 6, or Month 3) 
• IOP < 18 mmHg response (having a mean diurnal IOP < 18 mmHg in the study eye) at a 
post-Baseline visit (Week 1, Week 6, or Month 3)  
A logistic model for repeated measures will be fitted to response (response/non response).  The 
model will include treatment, visit, diagnosis, country and treatment-by-visit interaction as fixed 
effects, baseline IOP as a covariate, and subject as a random effect.  Within-subject errors will be 
modeled using an unstructured (UN) covariance matrix.  If the model is not converged, 
covariance matrices will be applied with the following order: first-order autoregressive [AR(1)], 
compound symmetry (CS) or variance components (VC). Odds ratios will be calculated along 
with 95% confidence intervals.   The main part of the SAS code is provided in Appendix 12.1.3.  
8.3. 
Subgroup Analyses 
To assess the homogeneity of treatment effects among subgroups, descriptive summaries by age 
group (< 65 or ≥ 65 years), sex (Male or Female) , country (India, Korea , Singapore or Taiwan), 
diagnosis (Open Angle Glaucoma or Ocular Hypertension), prior use of IOP lowering 
medication (ß-adrenergic antagonist, prostamide or prostaglandin analogue, α-adrenergic agonist, 
carbonic anhydrase inhibitors, miotic agent, other, or none), mean diurnal IOP at baseline (< 25 
or ≥ 25 mmHg) and IOP (9:00) at baseline (< 25 or ≥ 25 mmHg) will be reported for mean 
diurnal IOP and its change from baseline.   
Other subgroup analyses may be performed as needed.   


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9. 
SAFETY ANALYSES 
The safety-related measures collected in this study include AEs, visual acuity, slit-lamp 
biomicroscopy, central corneal thickness, ophthalmoscopy and iris color/eyelash/eyelid.  The 
Safety population will be used for all safety summaries, where subjects will be classified by 
actual treatment received.  In the event that a subject accidently took both DE-117 and 
Latanoprost during the study, that subject will be included in the 0.002% DE-117 group.   
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.  
9.1. 
Adverse Event 
Subjects with any AE(s), SAE(s), SAR(s) serious SAR(s) and significant AE (AE leading to 
study 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.   
Subjects with any AE(s) and any SAR(s) will be tabulated by SOC, preferred term and maximum 
severity.  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.   
The same analysis above will be performed for ocular AEs and non-ocular AEs. 
AEs, AEs leading to death, SAEs and AEs leading to discontinuation, if any, will be listed 
separately.  
The following AE summary tables will also be prepared by countries:  
• Overall AE summary 
• AE(s) by SOC and preferred term 
• SAR(s) by SOC and preferred term 
9.2. 
Visual Acuity 
The logMAR scores and changes from baseline will be summarized by treatment and analysis 
visit for study eyes and non-study eyes, separately.  In addition, any change (worsening or 
improvement) of ≥ 0.2 LogMAR (2 lines) from baseline will be summarized and listed.  
9.3. 
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 
worsening (increase) of ≥ 2 units from baseline will be summarized and listed.  


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9.4. 
Central corneal thickness 
Central corneal thickness scores and changes from baseline will be summarized by treatment and 
analysis visit for study eyes and non-study eyes, separately.  In addition, any increase of > 50 µm 
from baseline will be summarized and listed.  
9.5. 
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.  
9.6. 
Iris Color, Eyelash and Eyelid 
For changes from baseline in Iris Color Pigmentation, Eyelid Pigmentation, Eyelid Hair Growth, 
Eyelash Length, Eyelash Thickness, Eyelash Pigmentation and Eyelash Number, frequency and 
percentage of changes (No change, Increased or Decreased) will be summarized by treatment 
and analysis visit for study eyes and non-study eyes, separately.   In addition, any changes from 
baseline will be listed. 
9.7. 
Visual Field 
Visual field loss (Yes or No) will be summarized by treatment and analysis visit for study eyes 
and non-study eyes, separately.  In addition, any worsening in status from No at baseline to Yes 
after screening will also be summarized and listed.  
 


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10. 
ANALYSES OF OTHER MEASURES 
11. 
REFERENCES 
None. 
 


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12. 
APPENDICES 


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12.2. 
Changes from Protocol 
Change 1: 
The secondary objective and the key secondary endpoint were modified as follows in order to 
evaluate the non-inferiority of DE-117 to Latanoprost in IOP lowering effect at each timepoint.  
The following secondary objective was added. 
 “To determine if the mean intraocular pressure (IOP) reduction with DE-117 ophthalmic 
solution 0.002% is non-inferior to Latanoprost ophthalmic solution 0.005% at each post baseline 
timepoint after 3 months of treatment in subjects with open-angle glaucoma (OAG) or ocular 
hypertension (OHT).” 
The following key secondary endpoint was added. 
• Mean IOP in the study eye at the specified timepoints: 9:00, 13:00, and 17:00 at week1, 
week6 and Month 3. 
 
Change 2: 
Due to incorrect expression in signs of hypothesis, the following change was applied from the 
protocol: 
 
Original text (Protocol 14.6.1): 
H0: µC – Δ ≥ µT  versus H1: µC – Δ< µT 
Revised text (SAP 8.1.1.1): 
H0: µC + Δ ≤ µT  versus H1: µC + Δ > µT 
 
Change 3: 
Due to incorrect expression in signs, the following change was applied from the protocol: 
 
Original text (Protocol 14.6.2.2): 
• Proportion of subjects with mean diurnal IOP ≤ 18 mmHg in the study eye at Visit 3 
(Week 1), Visit 4 (Week 6) and Visit 5 (Month 3).  
Revised text (SAP 2.2.3): 
• Proportion of subjects with mean diurnal IOP < 18 mmHg in the study eye at Visit 3 
(Week 1), Visit 4 (Week 6) and Visit 5 (Month 3).