Clinical trial NCT03691649
Conditions: Glaucoma and Ocular Hypertension
Sponsor: Santen Inc.
Start date: 2018-09-14; Completion date: 2020-09-03
Enrollment: 426 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, randomized, double-masked, active-controlled, parallel-group, multi-center study. Subjects diagnosed with glaucoma or OHT who meet eligibility criteria at Visit 1 (Screening) will washout of 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 baseline will be randomized to receive double-masked treatment for 3 months. Adult subjects will receive open-label DE-117 Ophthalmic Solution for an additional 9 months.

Approximately 400 adult subjects and up to 30 pediatric subjects with glaucoma or OHT who meet all eligibility criteria will be randomized in a 1:1 ratio to receive either:

* DE-117 Ophthalmic Solution once daily and Vehicle once daily, or
* Timolol Maleate Ophthalmic Solution 0.5% twice daily. The study will evaluate the efficacy and safety of DE-117 Ophthalmic Solution compared with Timolol Maleate Ophthalmic Solution 0.5% in subjects with glaucoma or OHT through Month 3 and will provide additional safety data through Month 12 for subjects receiving DE-117.

Detailed description:

Arms: arm 1: Topical DE-117 Ophthalmic Solution once daily and Vehicle once daily for 3 months for all subjects, followed by DE-117 Ophthalmic Solution once daily for additional 9 month for adult subjects only arm 2: Topical Timolol Maleate Ophthalmic Solution 0.5% twice daily for 3 months for all subjects, followed by DE-117 Ophthalmic Solution once daily for additional 9 month for adult subjects only
Interventions: intervention 1: DE-117 Ophthalmic Solution intervention 2: Timolol Maleate Ophthalmic Solution 0.5%
Intervention descriptions: intervention 1: Topical DE-117 Ophthalmic Solution once daily and Vehicle once daily for 3 months for all subjects, followed by DE-117 Ophthalmic Solution once daily for additional 9 month for adult subjects only intervention 2: Topical Timolol Maleate Ophthalmic Solution 0.5% twice daily for 3 months for all subjects, followed by DE-117 Ophthalmic Solution once daily for additional 9 month for adult subjects only

Protocol documents:
Prot_000.pdf: 



























































































































































































































SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:   
A Phase III, Randomized, Double-Masked, Active-Controlled, 
Parallel-Group, Multi-center Study Assessing the Efficacy and 
Safety of DE-117 Ophthalmic Solution 0.002% Compared with 
Timolol Maleate Ophthalmic Solution 0.5% in Subjects with 
Glaucoma or Ocular Hypertension - Spectrum 3 Study 
 
 
NCT Number:  
NCT03691649 
 
Date of the document: 
15 Jan 2020 
 
 
 


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STATISTICAL ANALYSIS PLAN 
DE-117 SPECTRUM 3 
 
 
 
Protocol Title: 
A Phase III, Randomized, Double-Masked, Active-Controlled, Parallel-Group,  
Multi-center Study Assessing the Efficacy and Safety of DE-117 Ophthalmic 
Solution 0.002% Compared with Timolol Maleate Ophthalmic Solution 0.5% in 
Subjects with Glaucoma or Ocular Hypertension ─ Spectrum 3 Study 
 
 
Product: 
DE-117  
 
 
Protocol Number:  
011709IN 
 
 
Sponsor: 
Santen Inc. 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608 
USA. 
 
 
Date:  
January 15, 2020 
 
 
Status:  
Version 1.0 
 
 
 
 
CONFIDENTIAL 
 
The information in this document is considered privileged and confidential by Santen Inc. and 
may not be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by Federal and State Laws.  Persons to 
whom this information is disclosed must be informed that this information is privileged and 
confidential and that it should not be further disclosed. 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
1. 
INTRODUCTION ........................................................................................................9 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................10 
2.1. 
Objectives ...................................................................................................................10 
2.1.1. 
Primary Objectives .....................................................................................................10 
2.1.2. 
Secondary Objectives .................................................................................................10 
2.1.3. 
Safety Objective ..........................................................................................................10 
2.2. 
Endpoints ....................................................................................................................10 
2.2.1. 
Primary Efficacy Endpoint .........................................................................................10 
2.2.2. 
Key Secondary Efficacy Endpoints ............................................................................10 
2.2.3. 
Other Secondary Efficacy Endpoints ..........................................................................10 
2.2.4. 
Safety Endpoints .........................................................................................................11 
3. 
STUDY DESIGN .......................................................................................................12 
3.1. 
General Study Design .................................................................................................12 
3.2. 
Randomization and Masking ......................................................................................12 
3.3. 
Sample Size Planning .................................................................................................13 
3.4. 
Visits and Assessments ...............................................................................................13 
4. 
DEFINTIONS .............................................................................................................18 
4.1. 
Time-Related Terms ...................................................................................................18 
4.1.1. 
Baseline Visit ..............................................................................................................18 
4.1.2. 
Treatment Start Date and Treatment End Date ...........................................................18 
4.1.3. 
Study Day ...................................................................................................................19 
4.1.4. 
Out-of-Window Measurements, Analysis Visit, and Analysis Window ....................19 
4.1.5. 
Extent of Exposure .....................................................................................................20 
4.2. 
Endpoint-Related Definitions .....................................................................................20 
4.2.1. 
Study Eye and Fellow Eye ..........................................................................................20 
4.2.2. 
Baseline Score ............................................................................................................20 
4.2.3. 
Change and Percent Change from Baseline ................................................................21 
4.3. 
Efficacy-Related Definitions ......................................................................................21 


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4.3.1. 
Response Endpoint and Response Rate ......................................................................21 
4.4. 
Safety-Related Definitions ..........................................................................................21 
4.4.1. 
Adverse Event .............................................................................................................21 
4.4.1.1. 
Serious Adverse Event ................................................................................................22 
4.4.1.2. 
Ocular Adverse Event .................................................................................................22 
4.4.1.3. 
Suspected Adverse Reaction .......................................................................................22 
4.4.1.4. 
Events of Special Interest ...........................................................................................22 
4.4.2. 
Other Safety Measures ................................................................................................22 
4.5. 
Other Definitions ........................................................................................................23 
4.5.1. 
Prior and Concomitant Medications ...........................................................................23 
4.5.2. 
Concurrent Medical Conditions ..................................................................................24 
5. 
STUDY POPULATION .............................................................................................25 
5.1. 
Intent-to-Treat Population ..........................................................................................25 
5.2. 
Safety Population ........................................................................................................25 
5.3. 
Full Analysis Set .........................................................................................................25 
5.4. 
Per-Protocol Set ..........................................................................................................25 
6. 
GENERAL CONSIDERATIONS ..............................................................................26 
6.1. 
Adjustments for Covariates ........................................................................................26 
6.2. 
Handling of Missing Data ...........................................................................................26 
6.2.1. 
Efficacy Measures ......................................................................................................26 
6.2.2. 
Safety Measures ..........................................................................................................26 
6.2.3. 
Dates for Medical Events and Medications ................................................................26 
6.3. 
Multi-Center Studies ...................................................................................................27 
6.4. 
Multiple Comparisons / Multiplicity ..........................................................................27 
6.5. 
Interim Analysis ..........................................................................................................28 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................29 
7.1. 
Subject Disposition .....................................................................................................29 
7.2. 
Demographics and Baseline Characteristics ...............................................................29 
7.3. 
Medical and Surgical History .....................................................................................30 
7.4. 
Protocol Deviations ....................................................................................................30 
7.5. 
Prior and Concomitant Medications ...........................................................................31 
7.6. 
Treatment Compliance ................................................................................................31 
7.7. 
Exposure to Study Medication ....................................................................................32 


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8. 
EFFICACY ANALYSES ...........................................................................................33 
8.1. 
Efficacy Analyses for Double-Masked Period ...........................................................33 
8.1.1. 
Analyses of Primary Endpoint and Key Secondary Endpoints ..................................33 
8.1.1.1. 
Primary Analyses ........................................................................................................33 
8.1.1.2. 
Sensitivity Analyses ....................................................................................................35 
8.1.2. 
Analyses of Other Secondary Efficacy Endpoints ......................................................36 
8.1.3. 
Subgroup Analyses .....................................................................................................37 
8.2. 
Efficacy Analyses for Open-Label Period ..................................................................37 
9. 
SAFETY ANALYSES ...............................................................................................38 
9.1. 
Adverse Events ...........................................................................................................38 
9.1.1. 
Ocular Inflammation ...................................................................................................38 
9.1.2. 
Macular Edema ...........................................................................................................39 
9.1.3. 
Cosmetic Change(s) ....................................................................................................39 
9.2. 
Best-Corrected Visual Acuity .....................................................................................40 
9.3. 
Slit-lamp Biomicroscopy ............................................................................................40 
9.4. 
Ophthalmoscopy .........................................................................................................40 
9.5. 
Eyelid Sulcus, Eyelid, Eyelash, and Iris Color ...........................................................41 
9.6. 
Vital Signs ..................................................................................................................41 
10. 
ADDITIONS AND CHANGES TO THE PROTOCOL-SPECIFIED 
ANALYSES ...............................................................................................................42 
10.1. 
Full Analysis Set Definition .......................................................................................42 
10.2. 
Key Secondary Endpoint ............................................................................................42 
10.3. 
Sensitivity Analysis of the Primary and Secondary Efficacy Endpoints ....................42 
11. 
REFERENCES ...........................................................................................................43 
12. 
APPENDICES ............................................................................................................44 
 
 
 
 


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LIST OF TABLES 
Table 1: 
Schedule of Events and Procedures for ADULT Subjects .........................................14 
Table 2: 
Schedule of Events and Procedures Specially for PEDIATRIC Subjects ..................16 
Table 3: 
Definitions for Treatment Start and End Dates by Treatment Period ........................18 
Table 4: 
Analysis Visit and Analysis Window .........................................................................19 
Table 5: 
Response Endpoints ....................................................................................................21 
Table 6: 
Safety Assessments .....................................................................................................22 
Table 7: 
Handling of Missing Date for Medical Events and Medications ...............................27 
Table 8: 
Overview of Primary and Sensitivity Analysis Methods ...........................................36 
 
LIST OF FIGURES 
Figure 1: 
Study Design Diagram ................................................................................................12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Abbreviations 
Abbreviation 
Explanation 
AE 
adverse event 
ATC 
anatomical-therapeutic-chemical 
BCVA 
best-corrected visual acuity 
CI 
confidence interval 
CRO 
contract research organization 
CSR 
clinical study report 
eCRF 
electronic case report form 
ESI 
event of special interest 
ET 
early termination 
FAS 
full analysis set 
IOP 
intraocular pressure 
JOAG 
juvenile open-angle glaucoma 
LOCF 
last-observation-carried-forward 
LogMAR 
logarithm of the minimum angle of resolution 
MAR 
missing at random  
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM  
mixed-effects model for repeated measures 
mmHg 
millimeter of mercury 
MI 
multiple imputation  
OAG 
open-angle glaucoma 
OHT 
ocular hypertension 
OD 
oculus dexter (right eye) 
OS 
oculus sinister (left eye) 
OU 
oculus uterque (both eyes) 
MCMC 
markov chain monte carlo 
PMM 
pattern mixture models 
POAG 
primary open-angle glaucoma 
PPS 
per-protocol set 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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Abbreviations (Continued) 
Abbreviation 
Explanation 
SAR 
suspected adverse reaction 
SAS 
statistical analysis system 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
US 
united states 
WHO 
world health organization 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the statistical methods to be implemented for the 
analysis of data collected from the SPECTRUM 3 study within the scope of Santen’s Protocol 
011709IN, “A Phase III, Randomized, Double-Masked, Active-Controlled, Parallel-Group, 
Multicenter Study Assessing the Efficacy and Safety of DE-117 Ophthalmic Solution 0.002% 
Compared with Timolol Maleate Ophthalmic Solution 0.5% in Subjects with Glaucoma or 
Ocular Hypertension – Spectrum 3 Study”  It applies to the study protocol Amendment 1 
(Version 1.1), dated 13JUL2018, and provides detailed instructions as to how each analysis will 
be performed. 
Results 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. 


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2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives 
To determine whether DE-117 Ophthalmic Solution 0.002% given once daily is noninferior to 
Timolol Maleate Ophthalmic Solution 0.5% given twice daily in reducing the IOP in subjects 
with glaucoma or OHT after 3 months of treatment. 
2.1.2. 
Secondary Objectives 
To determine whether DE-117 Ophthalmic Solution 0.002% is noninferior to Timolol Maleate 
Ophthalmic Solution 0.5% in reducing mean diurnal IOP in subjects with glaucoma or OHT after 
3 months of treatment. 
To determine whether DE-117 Ophthalmic Solution 0.002% is superior to that of Timolol 
Maleate Ophthalmic Solution 0.5% in reducing mean diurnal IOP in subjects with glaucoma or 
OHT after 1 week of treatment. 
2.1.3. 
Safety Objective 
To determine the safety of DE-117 Ophthalmic Solution 0.002% as compared to Timolol 
Maleate Ophthalmic Solution 0.5% in subjects with glaucoma or OHT. 
2.2. 
Endpoints 
2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the IOP in the study eye measured at the specified time points: 
08:00, 10:00 and 16:00 at Week 1, Week 6 and Month 3 (Visits 3, 4 and 5). 
2.2.2. 
Key Secondary Efficacy Endpoints 
If noninferiority in the primary endpoint is achieved, then the 3 key secondary endpoints will be 
tested sequentially (see details in Section 6.4).  
1. Mean diurnal IOP in the study eye at Month 3 (Visit 5). 
2. IOP at each scheduled timepoint (08:00, 10:00, and 16:00) at Week 1 (Visit 3), Week 6 
(Visit 4), and Month 3 (Visit 5) in the study eyes with mean diurnal IOP < 25 mmHg at 
the Baseline Visit.  Note: This key secondary efficacy endpoint was not included in the 
protocol; this secondary efficacy endpoint addition is addressed in Section 10.2. 
3. Mean diurnal IOP in the study eye at Week 1 (Visit 3). 
2.2.3. 
Other Secondary Efficacy Endpoints 
The following secondary endpoints will be assessed: 
 Change and percent change from baseline in IOP at each scheduled timepoint of each 
post-baseline visit 


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 Change and percent change from baseline in mean diurnal IOP at each post-baseline 
visit 
 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 
2.2.4. 
Safety Endpoints 
The safety of DE-117 will be evaluated by: 
 Incidence of ocular and non-ocular adverse events (AEs) 
 Events of special interest (ESIs, which were defined to be macular edema, medication 
administration errors, and pregnancy) 
 Vital signs: blood pressure and pulse rate 
 Best-corrected visual acuity (BCVA) 
 Slit-lamp biomicroscopy; severity scores for the following 12 parameters: lid 
hyperemia, lid edema, conjunctival hyperemia, conjunctival chemosis, corneal 
staining, corneal edema, keratic precipitate, anterior chamber cells, anterior chamber 
flare, anterior synechiae of iris, posterior synechiae of iris, and cataract 
 Ophthalmoscopy (cup-to-disc ratio, glaucomatous optic nerve severity score, and 
assessments of retina, macula, choroid, and vitreous) 
 Assessments for deepening of the upper eyelid sulcus (DUES) and other changes in 
eyelid, eyelash, and iris 


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3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is a phase 3, randomized, double-masked, active-controlled, parallel-group, multi-center 
study.  Subjects diagnosed with glaucoma or OHT who meet eligibility criteria at Visit 1 
(Screening) will discontinue 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 baseline will be randomized to receive double-
masked treatment for 3 months.  
Approximately 400 eligible adults and up to 30 eligible pediatric subjects with glaucoma or OHT 
were planned to be randomized in a 1:1 ratio to receive either: 
 Test regimen  DE-117 0.002% QD: DE-117 0.002% QD (one drop/eye each day at 
20:00) and vehicle QD (one drop/eye each day at 08:00) for the three-month duration 
of the double-masked treatment period.  
 Control regimen  Timolol 0.5% BID: Timolol 0.5% BID (one drop/eye each day 
at 20:00 and one drop/eye each day at 08:00) for the three-month duration of the 
double-masked treatment period. 
At the end of the double-masked period, all adult subjects will enter the open-label period and 
receive DE-117 Ophthalmic Solution 0.002% for an additional 9 months (Figure 1). 
Figure 1: 
Study Design Diagram 
 
3.2. 
Randomization and Masking 
A blocked randomization stratified by age (< 18 and :18 years old) will be employed to 
randomize eligible subjects in a 1:1 ratio to receive either DE-117 or Timolol.  The 
randomization schedule will be generated and implemented by an independent CRO, Medidata 
Solutions, Inc. (New York City, NY). 


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During the 3-month double-masked treatment period, the subjects, Investigators, Examiners, and 
Santen personnel involved in the conduct of the study will be masked to the study treatment.  An 
authorized unmasked study staff member who is not the Investigator or Examiner at the 
investigative site will dispense and collect study medication(s) and will query about dosing 
compliance.  In case of a medical emergency, when the unmasking of a subject’s treatment 
assignment code becomes necessary for the welfare of that subject, the Clinical Investigator may 
reveal the treatment information by unmasking which treatment the subject has received through 
the study’s interactive web response system (Medidata RTSM). 
3.3. 
Sample Size Planning 
The sample size calculation was based on a two-sided Type I error rate of 5% and a non-
inferiority margin of 1.5 mmHg.  Assuming a treatment difference of 0 mmHg between the 
DE-117 arm and the Timolol arm, a standard deviation (SD) of 4.0 mmHg, and a correlation 
coefficient of 0.6 among repeated measures, approximately 400 adult subjects in total (200 
subjects per treatment arm) will provide 90% power to demonstrate noninferiority of DE-117 
Ophthalmic Solution 0.002% to Timolol Maleate Ophthalmic Solution 0.5% in IOP-lowering 
effect.  Up to 30 pediatric subjects will be enrolled with the agreement from FDA. 
The standard deviation of 4.0 mmHg was determined from previous DE-117 studies conducted 
in the United States: 33-002 and 33-003. 
3.4. 
Visits and Assessments 
There are 5 scheduled visits for pediatric subjects and 9 scheduled visits for adult subjects.  
Assessments at each visit and the time/visit window for each post-baseline assessment are 
specified in the Assessment Schedule for adult (Table 1) and pediatric subjects (Table 2), 
respectively. 
If the study drug administration is discontinued prior to Visit 5 (end of the double-masked 
treatment period), the subject should be encouraged to still participate in follow-up study visits 
until Visit 5 on an observational basis.  For subjects whose study participation is terminated prior 
to Visit 8 (Month 12), to the extent possible, all assessments scheduled for Visit 8 (Month 12) 
will be performed at the Exit Visit. 


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Table 1: 
Schedule of Events and Procedures for ADULT Subjects 
 
 
 
 
Washout Period 
Double-Masked Treatment Period 
Open-Label Treatment Period 
Visit 1 
Screening 
Washout 
Period 
(up to 4 
weeks) 
Optional 
Visit 1a 
Visit 2 
Eligibility / 
Baseline 
(Day 1) 
Visit 3 
Week 1 
(Day 8±2) 
Visit 4 
Week 6 
(Day 43 ±3) 
Visit 5 
Month 3 
(Day 91±7) 
Visit 6 
Month 6 
(Day 181 ±10) 
Visit 7 
Month 9 
(Day 271±10) 
Visit 8 
Month 12 
(Day 361±10) 
Exit or Early 
Termination n 
Informed Consent(s) including 
the optional consent for 
pharmacogenomics/ genomics 
laboratory research study a 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
 
 
 
Demographics and 
Medical History, including prior 
PGA b 
X 
 
 
 
 
 
 
 
 
Concomitant Medications/ 
Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dosing Compliance 
 
 
 
X 
X 
X 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test c 
X 
 
X 
 
 
X 
X 
X 
X 
Vital Signs (blood pressure/pulse 
rate) d 
X 
 
X (08:00) 
 
 
X (08:00) 
 
 
X (08:00) 
Refraction e 
X 
 
 
 
 
 
 
 
 
BCVAe 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
Biomicroscopy f 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
IOP g 
X 
X 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
Pachymetry h 
X 
 
 
 
 
 
 
 
 
Instill study medication after IOP 
measurement 
 
 
 
X (08:00) 
X (08:00) 
X (08:00) 
 
 
 
Iris color, eyelash, eyelid i 
 
 
X (photo) 
 
 
X (photo) 
X 
X 
X (photo) 
Gonioscopy j 
X 
 
 
 
 
 
 
 
 
Visual Field k 
X 
 
 
 
 
 
 
 
 
Ophthalmoscopy l 
X (pupil 
dilation) 
 
X (16:00) 
 
 
X (16:00) 
 
 
X (16:00, pupil 
dilation) 
 


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Table 1: 
Schedule of Events and Procedures for ADULT Subjects (Continued) 
 
 
 
 
Washout Period 
Double-Masked Treatment Period 
Open-Label Treatment Period 
Visit 1 
Screening 
Washout 
Period 
(up to 4 
weeks) 
Optional 
Visit 1a 
Visit 2 
Eligibility / 
Baseline 
(Day 1) 
Visit 3 
Week 1 
(Day 8±2) 
Visit 4 
Week 6 
(Day 43 ±3) 
Visit 5 
Month 3 
(Day 91±7) 
Visit 6 
Month 6 
(Day 181 ±10) 
Visit 7 
Month 9 
(Day 271±10) 
Visit 8 
Month 12 
(Day 361±10) 
Exit or Early 
Termination n 
Blood Sampling for 
Pharmacogenomics/genomics m 
 
 
 
X 
Dispense Study Medication 
 
 
X 
 
X 
X 
X 
X 
 
Collect Study Medication 
 
 
 
 
X 
X 
X 
X 
X 
Phone call to remind subject to 
take evening dose on the day 
before each visit 
 
 
 
X 
X 
X 
X 
X 
X 
a. Informed Consent Form 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. Prostaglandin naive subjects are defined as subjects who are not known to have used prostaglandin as their glaucoma treatment. The previous use of prostaglandin should be 
confirmed by either subject’s medical records or subject history. 
c. A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
d. Vital signs (resting blood pressure and pulse rate) will be collected in sitting position anytime at Visit 1 (Screening), and approximately 08:00 for Visit 2 (Baseline), and Visit 5 
before the morning dose. Vital signs will also be collected at Visit 8 at approximately 08:00.  
e. Refraction will be performed at the screening visit. If more than 10 letters in BCVA are lost compared to the screening visit, then refraction should be performed again. BCVA 
examination will be completed before IOP measurement at 08:00.  
f. Biomicroscopy examination must be completed before IOP is measured at 08:00. Aqueous flare and cell evaluation will be performed before fluorescein instillation.  
g. IOP measurements will be performed at 08:00, 10:00 and 16:00 (±60 min) at all visits except for Visit 1 and the optional Visit 1a (screening and mid-washout).  
h. Pachymetry will be performed after IOP measurement at Visit 1 (Screening). 
i. Eye photograph will be taken at Visits 2 (Baseline), 5 (Month 3) and 8 (Month 12).  
j. 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. Gonioscopy will be performed after IOP measurement at Visit 1 (Screening). 
k. 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.  
l. Ophthalmoscopy will be performed at Visits 1, 2, 5 and 8 (i.e., Screening, Baseline, Month 3 and Month 12) after the 16:00 IOP measurements. Ophthalmoscopy will be 
performed with pupil dilation at screening and visit 8/exit or early termination. Dilation of the pupil will be performed after the 16:00 IOP measurement. 
m. Blood sampling for the pharmacogenomics/genomics laboratory research study may be performed at any visit after pharmacogenomics/genomics informed consent obtained, 
subject randomized and study drug dosing has begun. 
n. Optional at unscheduled visit, required for early terminated subjects. 


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Table 2: 
Schedule of Events and Procedures Specially for PEDIATRIC Subjects 
 
Washout Period 
Double-Masked Treatment Period 
Visit 1 
Screening 
Washout 
Period 
(up to 4 
weeks) 
Optional Visit 
1a 
Visit 2 
Eligibility/ 
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 or Early 
Termination n 
Informed Consent(s) including the 
optional consent for 
pharmacogenomics/ genomics 
laboratory research study a 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
Demographics and 
Medical History, including prior 
PGA b 
X 
 
 
 
 
 
Concomitant Medications/ 
Therapies 
X 
X 
X 
X 
X 
X 
Dosing Compliance 
 
 
 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
Pregnancy Test c 
X 
 
X 
 
 
X 
Vital Signs (blood pressure/pulse 
rate) d 
X 
 
X (08:00) 
 
 
X (08:00) 
Refraction e 
X 
 
 
 
 
 
BCVAe 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
Biomicroscopy f 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
IOP g 
X 
X 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
Pachymetry h 
X 
 
 
 
 
 
Instill study medication after IOP 
measurement 
 
 
 
X (08:00) 
X (08:00) 
X (08:00) 
Iris color, eyelash, eyelid i 
 
 
X (photo) 
 
 
X (photo) 
Gonioscopy j 
X 
 
 
 
 
 
Visual Field k 
X 
 
 
 
 
 
Ophthalmoscopy l 
X (pupil 
dilation) 
 
X (16:00) 
 
 
X (16:00 pupil 
dilation) 
Blood Sampling for 
Pharmacogenomics/genomics m 
 
 
 
X 
Dispense Study Medication 
 
 
X 
 
X 
 
Collect Study Medication 
 
 
 
 
X 
X 


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Table 2: 
Schedule of Events and Procedures Specially for PEDIATRIC Subjects 
(Continued) 
 
Washout Period 
Double-Masked Treatment Period 
Visit 1 
Screening 
Washout 
Period 
(up to 4 
weeks) 
Optional Visit 
1a 
Visit 2 
Eligibility/ 
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 or Early 
Termination n 
Phone call to remind subject to 
take evening dose on the day 
before each visit 
 
 
 
X 
X 
X 
a. 
Informed Consent Form and the Assent Form 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. 
Prostaglandin-naive subjects are defined as subjects who are not known to have used prostaglandin as their glaucoma 
treatment. The previous use of prostaglandin should be confirmed by either subject’s medical records or subject history. 
c. 
A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
d. 
Vital signs (resting blood pressure and pulse rate) will be collected in anytime at Visit 1 (Screening), and approximately 
08:00 for Visit 2 (Baseline), and Visit 5 before the morning dose.  
e. 
Refraction will be performed at the screening visit if the pediatric subject is able to cooperate. Autorefraction is also 
acceptable. If more than 10 letters in BCVA are lost compared to the screening visit level, then refraction should be 
performed again if the pediatric subject is able to cooperate. BCVA examination will be completed before IOP measurement 
at 08:00. BCVA will be performed for the pediatric subjects who are able to cooperate using an age-appropriate eye chart 
and method (e.g., ETDRS chart, LEA symbols chart with logMAR notation, Tumbling E’s with logMAR notation, Landolt's 
broken rings with LogMAR notation, fix and follow) under normal room illumination. Same eye chart should be used for a 
given subject throughout the study.  
f. 
Biomicroscopy examination must be completed before IOP is measured at 08:00. Aqueous flare and cell evaluation will be 
performed before instillation of fluorescein.  
g. 
IOP measurements will be performed at 08:00, 10:00 and 16:00 (±60 min) at all visits except for Visit 1 and the optional 
Visit 1a (screening and mid-washout). IOP will be measured with age-appropriate tonometers (e.g., Goldmann applanation 
tonometer, a Perkins tonometer, or a tonopen, or iCare tonometer etc.) to the extent the subject is able to cooperate.  
h. 
Pachymetry will be performed after IOP measurement at Visit 1 (Screening) if the subject is able to cooperate. Subject must 
have a sufficiently clear cornea that allows for a complete ophthalmic exam to be enrolled if pachymetry is not able to be 
obtained. 
i. 
Eye photograph will be taken at Visits 2 (baseline), and 5 (month 3) if the subject is able to cooperate.  
j. 
Gonioscopy will be performed at Visit 1 (Screening) if the subject is able to cooperate. If unable to cooperate, historical 
gonioscopy performed within 12 months prior to screening and documented in the subject’s records is acceptable. 
Gonioscopy performed at Visit 1 (Screening) should occur after IOP measurement. 
k. 
Visual field test will be performed if the subject is able to cooperate. 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.  
l. 
Ophthalmoscopy will be performed if the subject is able to cooperate. Ophthalmoscopy will be performed at Visits 1, 2, and 
5 (i.e., Screening, Baseline and Month 3) after the 16:00 IOP measurements. Ophthalmoscopy will be performed with pupil 
dilation at Visit 1 and visit 5/exit or early termination. Dilation of the pupil will be performed after the 16:00 IOP 
measurement. 
m. Blood sampling for the pharmacogenomics/genomics laboratory research study may be performed at any visit after the 
pharmacogenomics/genomics informed consent is obtained, subject is randomized and study drug dosing has begun. 
n. 
Optional at unscheduled visit, 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 Date and Treatment End Date 
Treatment start date and treatment end date for each treatment period are defined as follows in 
Table 3. 
Table 3: 
Definitions for Treatment Start and End Dates by Treatment Period 
Treatment 
Period 
Treatment Start 
Date 
Treatment End Date 
Double-
Masked (DM) 
Treatment 
Period 
The date at which a 
randomized subject 
takes the first dose of 
the DM study drug 
The date at which a randomized subject takes the last 
dose of the DM study drug.  If the date of the last dose 
is missing and the subject does not receive any OL 
study drug:  
 The day before the Visit 5 (Month 3) date will 
be considered the treatment end date for subjects 
who completed the Month 3 Visit 
 
The day before the Exit Visit date will be used 
for subjects who prematurely discontinued from 
the study before Visit 5 (Month 3).  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 
Open-Label 
(OL) 
Treatment 
Period 
The date at which a 
randomized adult 
subject takes the first 
dose of the OL study 
drug 
The date at which a randomized adult subject takes the 
last dose of the OL study drug.  If the date of the last 
dose is missing: 
 The day before the Visit 8 (Month 12) date will 
be considered the treatment end date for subjects 
who completed the Month 12 Visit 
 
The day before the Exit Visit date will be used 
for subjects who prematurely discontinued from 
the study during OL period.  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 


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Table 3: 
Definitions for Treatment Start and End Dates by Treatment Period 
(Continued) 
Treatment 
Period 
Treatment Start Date 
Treatment End Date 
Entire Study 
The date at which a randomized subject 
takes the first dose of the DM study drug 
The date at which a randomized subject 
takes the last dose of the study drug. 
Missing last dose date will be handled the 
same way as mentioned above. 
Notes: 
1. Pediatric subjects only participate in the double-masked period. 
2. For each treatment period, the treatment end date will be set to missing if the treatment start date is missing. 
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 treatment start date is the reference date.  Thus, the 
study day will be calculated as: 
 For days prior to the treatment start date, Study Day = Date – Treatment Start Date  
 For days on/after the treatment start date, Study Day = Date – Treatment Start 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 4). 
The analysis visit of a measurement will be determined based on the study day of the 
measurement and specified analysis windows and is not necessarily the same as the study visit at 
which 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. 
Table 4: 
Analysis Visit and Analysis Window 
Analysis Visit Name 
(Target Day) 
Protocol 
Visit 
Window 
Analysis Window 
Iris Color, 
Eyelash, and 
Eyelid 
Ophthalmoscopy 
and Vital Signs 
Other 
Parameters 
Baseline (Day 1) 
[1, 1] 
- 1] 
- 1] 
- 1] 
Week 1 (Day 8) 
[6, 10] 
NA* 
NA* 
[2, 22] 
Week 6 (Day 43) 
[40, 46] 
NA* 
NA* 
[23, 61] 


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Table 4: 
Analysis Visit and Analysis Window (Continued) 
Analysis Visit Name 
(Target Day) 
Protocol 
Visit 
Window 
Analysis Window 
Iris Color, 
Eyelash, and 
Eyelid 
Ophthalmoscopy 
and Vital Signs 
Other 
Parameters 
Month 3 (Day 91) 
[84, 98] 
[2, day of Month 3 
Visit] 
[2 -, day of Month 3 
Visit] 
[62, day of Month 
3 Visit] 
Month 6 (Day 181) 
[171, 191] 
[First Day of OL 
period + 1, 225] 
NA* 
[First Day of OL 
period + 1, 225] 
Month 9 (Day 271) 
[261, 281] 
[226, 315] 
NA* 
[226, 315] 
Month 12 (Day 361) 
[351, 371] 
[316 - 
[Day of Month 3 
Visit + 1, - 
[316 - 
*Not collected at this visit. 
If there are two or more visits that fall into the same analysis window, then the visit closest to the 
target assessment day will be selected for that visit window.  In the case that two visits are 
equidistant to the target assessment day, i.e., one is before and one is after the target assessment 
day, the 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, 10:00, and 16:00) will be selected for that analysis visit first, before 
applying the above rule. 
4.1.5. 
Extent of Exposure 
The extent of exposure to study medication will be assessed by duration of treatment exposure, 
derived as: 
Duration of treatment exposure = Treatment end date – Treatment start date + 1 
4.2. 
Endpoint-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. 
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. 


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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. 
Response Endpoint and Response Rate 
Four IOP response endpoints (Table 5) will be evaluated at each post-Baseline visit  
during the double masked-period (Week 1, Week 6, or Month 3) and open-label period  
(Month 6, Month 9, and Month 12) in this study: 
Table 5: 
Response Endpoints 
Response Endpoint 
Response criteria in mean diurnal IOP 
IOP 20% response 
Percent reduction from Baseline ≥ 20% 
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. 
The open-label analysis of these endpoints will be performed only at the end of this study when 
all adult subjects complete their Month 12 Visit. 
4.4. 
Safety-Related Definitions 
4.4.1. 
Adverse Event 
Under Protocol 011709IN, an AE is defined as any untoward medical occurrence that occurs in a 
study subject, regardless of the causal relationship with the study treatment.  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 onset date of the AE occurred on or after the treatment 
start date till up to 2 days (twice the scheduled dosing interval) after treatment end date.  
Treatment-emergent AEs (TEAEs) are a subset of on-study AEs.  Both on-study and TEAEs will 
be collected, but only TEAEs will be tabulated. 
The severity of each AE will be graded by the Clinical Investigator as Mild, Moderate, or 
Severe.  AEs will also be rated by the Investigator as to their causality/relationship to the study 
drug. 
Each AE will be classified into a system organ class (SOC) and coded to a preferred term (PT) 
using Medical Dictionary for Regulatory Activities (MedDRA), Version 21.1 published in 2018. 


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4.4.1.1. 
Serious Adverse Event 
An AE will be counted as a serious adverse event (SAE) if the Clinical Investigator selected 
“Yes” to the question ‘Is the adverse event serious?’ on the AE eCRF.  Any AE is considered a 
SAE if it fulfills one or more of the following criteria: 
 Death (i.e., the AE caused or led to death) 
 Life threatening (i.e., immediately life-threatening) 
 It required or prolonged inpatient hospitalization. 
 It resulted in a persistent or significant disability/incapacity (i.e., the AE resulted in a 
substantial disruption of the subject’s ability to carry out normal life functions). 
 It resulted in a congenital anomaly/birth defect in the offspring of a study subject who 
was exposed to study therapy prior to conception or during pregnancy. 
 It is a medically significant event(s), which may include “sight-threatening events,” 
that may not meet any of the above serious criteria but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the outcomes listed above. 
4.4.1.2. 
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 AE eCRF. 
4.4.1.3. 
Suspected Adverse Reaction 
An AE will be counted as a suspected adverse reaction (SAR) if the Clinical Investigator 
answered ‘Related’ to the AE eCRF question “Relationship to Study Drug”. 
4.4.1.4. 
Events of Special Interest 
Events of special interest (ESI) are pregnancy, clinically significant study medication 
administration error, and macular edema/cystoid macular edema. 
4.4.2. 
Other Safety Measures 
Table 6 lists the safety measures to be evaluated for this study. 
 
Table 6: 
Safety Assessments 
Safety Measures 
Note 
BCVA 
Best-corrected visual acuity will be measured for each eye at 
each visit under normal room illumination using visual acuity 
chart (e.g., ETDRS chart) and the logMAR scoring will be 
recorded in the subject’s source document.  Increase in 
logMAR scores means worsening in visual acuity. 


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Table 6: 
Safety Assessments (Continued) 
Safety Measures 
Note 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy examinations (severity scores for  
12 parameters: lid hyperemia, lid edema, conjunctival 
hyperemia, conjunctival chemosis, corneal staining, corneal 
edema, keratic precipitate, anterior chamber cells, anterior 
chamber flare, anterior synechiae of iris, posterior synechiae of 
iris, and cataract) will be performed and graded immediately 
before the 8:00 IOP measurement at all visits except Visit 1/1a 
(Screening or mid-washout visit).  Cataract severity will be 
assessed for phakic eyes.  
Ophthalmoscopy 
The ophthalmoscopy (fundus) examination will be performed 
for each eye at Visit 1, Visit 2, Visit 5, and Visit 8/ Study 
Exit/Early Termination.  Variables from ophthalmoscopy are 
cup-to-disc ratio, glaucomatous optic nerve severity, and 
assessments of vitreous, retina, macula, and choroid.  
Eyelid Sulcus, eyelid, and iris color 
The investigator (or his/her designee) will take front- and side-
view photographs of each eye at Visit 2 (Baseline).  The 
photographs must include the 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 eyelid, 
eyelashes, and iris color at each follow-up visit, and assess for 
DUES (“Yes”, “No”) at Visit 5, Visit 6, Visit 7, and Visit 8/ 
Study Exit/Early Termination. 
Vital Signs  
Resting blood pressure and pulse rate will be collected at  
Visit 1, Visit 2, Visit 5, and Visit 8/ 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, prior medication is defined as any non-study medication taken and ended prior to 
the study medication start date.  Concomitant medication is defined as any non-study medication 
taken concurrently while receiving study medication, i.e., the treatment period (period of time 
from first dose to last dose) of a concomitant medication taken by a subject must overlap with 
the treatment period (period of time from first dose to last dose) of the study medication. 
All prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Global, Version September 2018, format B3.  Each prior or concomitant 
medication will be classified using the Anatomical-Therapeutic-Chemical (ATC) classification 
system and mapped to a WHO Drug preferred drug name. 


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4.5.2. 
Concurrent Medical Conditions 
Concurrent medical conditions are those ongoing conditions or diseases that are present at the 
signing of informed consent. 


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5. 
STUDY POPULATION 
During masked data review before database lock, subject 011709IN-8400217-3609 was excluded 
from all the analysis populations.  The background and rationale for excluding this subject can be 
found in 011709IN-rationale-for-exclusion-of-a-subject. 
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 
summarizing by actual treatment received. 
5.3. 
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized subjects who received at least one dose 
of study medication and provided Baseline IOP data (at any timepoint) and at least one  
post-baseline IOP measurement (at any timepoint).  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 that will be conducted for the primary and key secondary efficacy endpoint 
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 affect the efficacy outcome, 
and determine whether or not to exclude the subject from the PPS. 


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6. 
GENERAL CONSIDERATIONS 
All measures will be summarized by treatment (planned or actual 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 the  
95% confidence interval will be shown, unless specified otherwise.  No statistical testing will be 
conducted for safety measures. 
All data manipulations, descriptive summaries, and statistical hypothesis testing will be 
performed using Statistical Analysis System (SAS) Version 9.4 or later. 
6.1. 
Adjustments for Covariates 
In general, the inferential analysis of each IOP endpoint will adjust for the baseline IOP.  
Detailed information on covariate adjustment is provided in Section 8.1. 
6.2. 
Handling of Missing Data 
6.2.1. 
Efficacy Measures 
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 in both double-masked and open-label periods. 
For efficacy measures during double-masked period, 
 For each IOP endpoint, no imputation is needed for the analysis on observed cases 
using the mixed-effects model for repeated measures (MMRM).  Sensitivity analysis 
will be performed using a Pattern-Mixture Model (PMM) approach. 
 In the PMM approach, Multiple Imputation (MI) with mixed missing data 
mechanisms will be used to investigate the appropriateness of the missing at random 
(MAR) assumption for missing values resulting from censoring due to the use of IOP-
lowering rescue therapy, or resulting from study discontinuation due to lack of 
efficacy or AE. 
For efficacy measures during open-label treatment period, no inferential analysis will be 
performed.  Summary statistics will be provided for IOP and mean diurnal IOP for each 
scheduled visit, using observed data. 
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), AE, and 
concomitant medications (CM) will be imputed as follows (Table 7): 


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Table 7: 
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 date of YYYY to impute the 
missing month and day of the onset date. 
YYYY and MM are 
available, but DD is 
missing 
Use the first date of MM to impute the 
missing day 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 date of YYYY to impute the 
missing month and day of the resolution date.  
YYYY and MM are 
available, but DD is 
missing 
Use the last date of MM to impute the missing 
day of the resolution date. 
6.3. 
Multi-Center Studies 
This is a multi-center study enrolling subjects from 49 US sites.  The number of subjects per site 
might be small.  Therefore, there are no analyses adjusting for sites. 
6.4. 
Multiple Comparisons / Multiplicity 
To control the overall Type I error rate across the seven hypothesis tests involving the primary 
endpoint and the key secondary endpoints (listed below) at the 0.05 level (two-sided), a fixed 
sequence procedure will be implemented.  The hypothesis tests will be assessed sequentially as 
follows: 
1. Noninferiority of 0.002% DE-117 to 0.5% timolol maleate for the primary endpoint, IOP 
at each scheduled timepoint (08:00, 10:00, and 16:00) at Week 1, Week 6, and Month 3. 
2. Noninferiority of 0.002% DE-117 to 0.5% timolol maleate for the first key secondary 
endpoint, mean diurnal IOP at Month 3. 
3. Noninferiority of 0.002% DE-117 to 0.5% timolol maleate for the second key secondary 
endpoint, IOP at each scheduled timepoint (08:00, 10:00, and 16:00) at  
Week 1, Week 6, and Month 3 in the study eyes with mean diurnal IOP < 25 mmHg at 
the Baseline Visit. 


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4. Superiority of 0.002% DE-117 to 0.5% timolol maleate for the third key secondary 
endpoint, mean diurnal IOP at Week 1. 
5. Superiority of 0.002% DE-117 to 0.5% timolol maleate for the first key secondary 
endpoint, mean diurnal IOP at Month 3. 
6. Superiority of 0.002% DE-117 to 0.5% timolol maleate for the second key secondary 
endpoint, IOP at each scheduled timepoint (08:00, 10:00, and 16:00) at Week 1,  
Week 6, and Month 3 in the study eyes with mean diurnal IOP < 25 mmHg at the 
Baseline Visit. 
7. Superiority of 0.002% DE-117 to 0.5% timolol maleate for the primary endpoint, IOP at 
each scheduled timepoint (08:00, 10:00, and 16:00) at Week 1, Week 6, and Month 3. 
The second hypothesis testing 2) will be tested only if the first hypothesis 1) is rejected.  The 
third hypothesis testing 3) will be tested only if the second hypothesis 2) is rejected, and so on. 
6.5. 
Interim Analysis 
No interim analysis is planned for this study. 
Analysis of the double-masked period data will be conducted when all the randomized subjects 
complete their Month 3 Visit, data cleaned and frozen. All efficacy and safety data from open-
label period at the time of this data cut will also be analyzed and reported. The 011709IN Data 
Cut Plan details how data collected during open-label period will be cut for this “snapshot”. 


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7. 
SUMMARY OF STUDY POPULATION DATA 
7.1. 
Subject Disposition 
The disposition of ITT population (i.e., all randomized subjects) will be summarized by 
treatment period (double-masked and open-label) and by planned treatment (for double-masked 
period) and overall. 
For the double-masked period, the summary will include the number and percentage of ITT 
subjects in the Safety population, FAS, and PPS.  The disposition summary will also include the 
number and percentage of subjects who completed the study drug, subjects who discontinued the 
study drug prematurely but continued with study participation until the Month 3 Visit and among 
which who completed or not completed the Month 3 Visit, as well as the number and percentage 
of subjects who discontinued from the study or discontinued from the study drug prior to Month 
3 Visit by the primary discontinuation reason. 
For the open-label period, the summary will include the number and percentage of subjects who 
received any study treatment during open-label period, and subjects who are still on the study at 
the time of data cut (for reports other than the final clinical study report).  The disposition 
summary will also include the number and percentage of subjects who completed the study drug, 
and subjects who discontinued from the study prior to Month 12 Visit by the primary 
discontinuation reason. 
7.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be descriptively summarized for the FAS, 
adult subjects, pediatric subjects, Safety population, and subjects who received open-label 
treatment period therapy with DE-117, separately, by planned treatment (for double-masked 
period).  Specifically, for subject demographics, the following variables will be summarized: 
 Age at randomization (continuous and categorical: (< 18 years, ≥ 18 and < 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 and fellow 
eye, separately by treatment period (double-masked and open-label): 
 Primary ocular diagnosis [categorical: POAG, Pseudoexfoliative Glaucoma, 
Pigmentary Glaucoma, or OHT for adult subjects, and juvenile open angle glaucoma 
(JOAG) for pediatric subjects] 
 Prior use of IOP-lowering medications (categorical: oral/topical carbonic anhydrase 
inhibitors, alpha agonists, beta-blockers, prostaglandin/prostaglandin analogues, or 
none) 
 Prostaglandin naive (Yes or No) 


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 Baseline lens status (categorical: phakic or pseudophakic/aphakic) 
 Baseline mean diurnal IOP score and baseline IOP score at each scheduled timepoint 
(08:00, 10:00, and 16:00) 
 BCVA (logMAR) 
 Central corneal thickness (µm) 
 Glaucomatous optic nerve findings (categorical: none, mild, moderate, or severe) 
 Anterior chamber angle classification (Shaffer scale; categorical: approximately  
5 degrees or less, approximately 10 degrees, approximately 20 degrees, 
approximately 30 degrees, or approximately 40 degrees or more) 
 Iris Color (categorical: Blue/Gray, Blue/Gray with Slightly Brown,  
Blue/Gray – Brown, Green, Green with Slightly Brown, Green – Brown,  
Yellow – Brown, or Brown) 
 Visual field (parameters: glaucoma Hemifield test, visual field mean deviation by 
device, and visual field pattern standard deviation by device) 
7.3. 
Medical and Surgical History 
For this study, medical and surgical history and adverse events will be coded using  
MedDRA 21.1, 2018.  Each medical event will be classified into a SOC and mapped to a 
Preferred Term (PT). 
The medical and surgical history will be summarized for the FAS.  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 
 Randomization 
 Safety reporting  
 Time Window 
 Other 


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A protocol deviation is considered significant if it may affect the subject’s rights, safety, or  
well-being, and/or the completeness, accuracy, or reliability of the study data.  Santen’s study 
team will review all protocol deviations and determine the list of significant protocol deviations 
prior to database lock.  All randomized subjects with any significant protocol deviation(s) will be 
tabulated by treatment period (double-masked and open-label) and by deviation category for 
each planned treatment (for double-masked period) and overall.  In addition, two listings will be 
provided for double-masked period: (1) all significant protocol deviations and (2) subjects 
excluded from the per protocol population.  All significant protocol deviations will also be listed 
for open-label period. 
7.5. 
Prior and Concomitant Medications 
For this study, non-study medications, including prior and concomitant medications for double-
masked period and concomitant medications for open-label period, will be coded using World 
Health Organization (WHO) Drug Global, Version September 2018, format B3.  Each non-study 
medication will be classified using the Anatomical-Therapeutic-Chemical (ATC) classification 
system and mapped to a WHODrug 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. 
For the same concomitant medications that are used in both double-masked and open-label 
treatment periods, they will be summarized in both double-masked and open-label periods. 
7.6. 
Treatment Compliance 
For the purpose of compliance calculation, there will be six study intervals: 
 Baseline Visit to Week 1 
 Week 1 to Week 6 
 Week 6 to Month 3 
 Month 3 to Month 6 
 Month 6 to Month 9 
 Month 9 to Month 12 
The compliance rate for a subject will be calculated as follows for each study interval during 
double-masked period: 
Compliance Rate (%) = (2*Duration – ∑Miss) / (2*Duration) × 100 
And, for open-label period: 
Compliance Rate (%) = (Duration – ∑Miss) / (Duration) × 100 


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Where 
Duration:The number of days subject should have administered study medication, 
calculated as: 
Study Interval 
Equation for Duration Calculation 
Baseline Visit to Week 1 
Week 1 Visit date – Date of first drug dispensation 
Week 1 to Week 6 
Week 6 Visit date – Week 1 Visit date 
Week 6 to Month 3 
Month 3 Visit date – Week 6 Visit date 
Month 3 to Month 6 
Month 6 Visit date – Month 3 Visit date 
Month 6 to Month 9 
Month 9 Visit date – Month 6 Visit date 
Month 9 to Month 12 
Month 12 Visit date – Month 9 Visit date 
Miss:The number of missed doses since the last visit. 
For subjects in the FAS, the compliance rate will be summarized by treatment period (double-
masked and open-label), post-baseline study interval, and by planned treatment (for double-
masked treatment period). 
7.7. 
Exposure to Study Medication 
The duration of exposure to a study medication is measured by days on treatment as derived in 
Section 4.1.5.  For subjects in the Safety Population, the duration of exposure will be 
summarized using descriptive statistics, and frequency and percentage of subjects will be 
tabulated by actual treatment received for double masked period and for the entire study 
separately.  For the entire study period, the duration of exposure to overall DE-117 treatment will 
also be provided, which will combine exposure to DE-117 from both double-masked arms.  For 
subjects who were in the Timolol arm during double-masked treatment period, their duration of 
exposure to DE-117 will be the total duration on the study minus the number of days they were 
exposed to Timolol treatment. 
The duration of exposure categories are: 
 
Double-masked period: 1-30, 31-60, or ≥ 61 days 
 Entire study period: 1-30, 31-60, 61-90, 91-120, 121-150, 151-180, 181-210, 211-240, 
241-270, 271-300, 301-330, or ≥ 331 days 


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8. 
EFFICACY ANALYSES 
Unless specified otherwise, efficacy analyses will be performed on the study eye, based on the 
FAS, and summarized by planned treatment, irrespective of the actual treatment received. 
Unless otherwise specified, for subjects who receive IOP-lowering rescue therapy, any IOP 
values collected after the receipt of rescue therapy will be censored (i.e., treated as missing) in 
the analyses. 
8.1. 
Efficacy Analyses for Double-Masked Period 
8.1.1. 
Analyses of Primary Endpoint and Key Secondary Endpoints 
8.1.1.1. 
Primary Analyses 
8.1.1.1.1. Primary Endpoint 
The primary efficacy endpoint is IOP in the study eye at each scheduled timepoint (08:00, 10:00, 
and 16:00) at each of three follow-up visits, Week 1, Week 6, and Month 3.  The nine 
combinations of three scheduled timepoints at each of three follow-up visits are referred to 
subsequently as nine timepoints.  For the primary endpoint, the following null (versus 
alternative) hypothesis will be tested: 
H0: µT – µC > Δ, for at least one timepoint 
versus 
HA: µT –  µC ≤  Δ at all nine timepoints 
where µT and µC denote the mean values of the primary endpoint in the DE-117 arm and the 
Timolol arm, respectively, and Δ denotes the noninferiority margin of 1.5 mmHg or 1.0 mmHg 
as specified below. 
The primary analysis of the primary efficacy endpoint will be performed using a MMRM of IOP 
based on the FAS.  A separate MMRM will be used for IOP at each scheduled timepoint  
(8:00, 10:00, or 16:00).  For each scheduled timepoint, the model will include treatment (Ti), 
analysis visit (Vj), and treatment-by-visit interaction (TVij) as fixed effects, and baseline IOP at 
the scheduled timepoint as a covariate.  Correlations of IOP measurements within-subject will be 
modeled using an unstructured covariance matrix.  The mathematical model is given by: 
IOPijn  = µ + Ti + Vj +  TVij + ɛijn 
where µ denotes the overall mean, and ɛ denotes the random error associated with the individual 
subject.  The above model allows treatment effect and its variability to vary over study visits. 
If there are convergence issues, covariance matrix structures other than unstructured will be tried 
in the following order: (1) heterogeneous Toeplitz (TOEPH), (2) heterogeneous autoregressive of 
order 1 (ARH(1)), (3) heterogeneous compound symmetry (CSH), and (4) compound  
symmetry (CS).  The first covariance structure that converges will be used as the primary 
analysis.  Least squares mean IOP values for each treatment arm and differences between least 
squares treatment arm means and associated 95% confidence intervals will be reported for each 
of the nine timepoints. 


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The primary analysis will be repeated on pediatric subjects. 
Noninferiority criteria for primary endpoint: With respect to the primary study objective, 
noninferiority of DE-117 to Timolol is achieved if the upper limit of the two-sided  
95% confidence interval for the difference in the mean IOP (DE-117 minus Timolol) is  
≤ 1.5 mmHg at all nine timepoints and ≤ 1.0 mmHg at a majority (five or more) of the nine 
timepoints. 
Superiority of DE-117 to Timolol for the primary efficacy endpoint is achieved if the upper limit 
of the two-sided 95% confidence interval for the difference in the mean IOP (DE-117 minus 
Timolol) is < 0 mmHg at all nine timepoints. 
8.1.1.1.2. Key Secondary Endpoints 
8.1.1.1.2.1. 
Mean Diurnal IOP at Month 3 
The first key secondary endpoint is the mean diurnal IOP in the study eye at Month 3.  The 
following null (versus alternative) hypothesis will be tested: 
H0S1: µT1 – µC1 > Δ versus HAS1: µT1– µC1 ≤ Δ 
where µT1 and µC1 denote the mean diurnal IOP at Month 3 in the DE-117 and Timolol arm, 
respectively, and Δ denotes the noninferiority margin of 1.5 mmHg.  The primary analysis of this 
key secondary efficacy endpoint will be performed using a MMRM based on the FAS.  The 
model will include treatment, analysis visit (Week 1, Week 6, or Month 3), and treatment-by-
visit interaction as fixed effects, and baseline mean diurnal IOP at as a covariate.  Correlations of 
mean diurnal IOPs within-subject will be modeled using an unstructured covariance matrix.  The 
mathematical model is analogous to the model in the primary efficacy endpoint. 
If there are convergence issues, covariance matrix structures other than unstructured will be tried 
in the following order: (1) heterogeneous Toeplitz (TOEPH), (2) heterogeneous autoregressive of 
order 1 (ARH(1)), (3) heterogeneous compound symmetry (CSH), and (4) compound symmetry 
(CS).  The first covariance structure that converges will be used as the primary analysis.  Least 
squares mean diurnal IOP values at Month 3 for each treatment arm and the difference between 
least squares treatment group means and its 95% confidence interval will be reported. 
Noninferiority of DE-117 to Timolol is achieved for this endpoint if the upper limit of the 95% 
confidence interval for the difference between DE-117 and Timolol (DE-117 minus Timolol) in 
the mean diurnal IOP at Month 3 is ≤ 1.5 mmHg.  Superiority of DE-117 to Timolol is achieved 
for this endpoint if the upper limit of the 95% confidence interval is < 0 mmHg. 
This key secondary endpoint analysis will be repeated on pediatric subjects. 
8.1.1.1.2.2. 
IOP at Nine Timepoints in Study Eyes with Baseline Mean Diurnal 
IOP < 25 mmHg 
The second key secondary endpoint is IOP at each scheduled timepoint (08:00, 10:00, and 16:00) 
at each of three follow-up visits, Week 1, Week 6, and Month 3, in the study eyes with mean 
diurnal IOP < 25 mmHg at the Baseline Visit.  If noninferiority of DE-117 to Timolol for the 
primary endpoint and the first key secondary endpoint is achieved, the following null (versus 
alternative) hypothesis will be tested for the second key secondary endpoint: 


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H0 S2: µT2 – µC2 > Δ,  for at least one timepoint 
versus 
HA S2: µT2 –  µC2 ≤  Δ at all nine timepoints 
where µT2 and µC2 denote the mean IOP values in the DE-117 arm and the Timolol arm, 
respectively, and Δ denotes the noninferiority margin of 1.5 mmHg or 1.0 mmHg as specified 
below. 
The same MMRM used in the analysis of the primary efficacy endpoint will be used for the 
analysis of the second key secondary endpoint.  Noninferiority of DE-117 to Timolol for this 
endpoint (i.e., for subjects with baseline mean diurnal IOP < 25 mmHg) is achieved if the upper 
limit of the two-sided 95% confidence interval for the difference in the mean IOP (DE-117 
minus Timolol) is ≤ 1.5 mmHg at all nine timepoints and ≤ 1.0 mmHg at a majority (five or 
more) of the nine timepoints.  Superiority of DE-117 to Timolol for this endpoint (i.e., for 
subjects with baseline mean diurnal IOP < 25 mmHg) is achieved if the upper limit of the  
two-sided 95% confidence interval for the difference in the mean IOP (DE-117 minus Timolol) 
is < 0 mmHg at all nine timepoints. 
8.1.1.1.2.3. 
Mean Diurnal IOP at Week 1 
The third key secondary endpoint is mean diurnal IOP in the study eye at Week 1.  If 
noninferiority of DE-117 to Timolol for the primary and the first two key secondary endpoints is 
achieved, then the following null (versus alternative) hypothesis will be tested for the third key 
secondary endpoint: 
H0S3: µT3 = µC3  versus HAS3: µT3 ≠ µC3 
where µT3 and µC3 denote the mean diurnal IOP at Week 1 in the DE-117 and Timolol arm, 
respectively.  The primary analysis of this key secondary endpoint will be performed using a 
MMRM analogous to the model used for the first key secondary efficacy endpoint (mean diurnal 
IOP at Month 3). 
For the primary and key secondary efficacy endpoints, the testing sequence and multiplicity 
adjustment details are provided in Section 6.4. 
This key secondary endpoint analysis will be repeated on pediatric subjects. 
8.1.1.2. 
Sensitivity Analyses 
For the primary endpoint and the key secondary endpoints, sensitivity analyses will be performed 
to assess the robustness of the results from the primary analysis.  The sensitivity analyses consist 
of two types: (1) assessment based on the PPS and (2) a pattern-mixture model (PMM) approach 
(Table 8).  Unless otherwise specified, for subjects who receive IOP-lowering rescue therapy, 
any IOP values collected after the receipt of rescue therapy will be censored (i.e., treated as 
missing) in the analyses. 
 


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Table 8: 
Overview of Primary and Sensitivity Analysis Methods 
Primary or Sensitivity 
Analysis 
Statistical Method 
Analysis 
Population 
Handling of Missing 
Data 
Primary Analysis 
MMRM 
FAS 
Observed cases 
Sensitivity Analyses 
MMRM 
PPS 
Observed cases 
PMM with delta-adjustment 
FAS 
MI 
Abbreviations: FAS = full analysis set; MI = multiple imputation; MMRM = mixed-effects model for repeated 
measures; PMM = pattern-mixture model; PPS = per protocol set. 
To assess the sensitivity to departure from MAR assumption, a PMM with delta-adjustment will 
be applied, as follows: 
a. Use Markov chain Monte Carlo (MCMC) to create monotone missingness first.  Then 
obtain standard multiple imputations under MAR assumptions for missing IOP values 
using monotone regression.  The missing data are filled in and 50 complete datasets 
are created.  The seed that will be used in the SAS program is 13546. 
b. For each IOP value that had been missing because of (1) censoring after having 
received IOP-lowering rescue therapy; or because of (2) early study discontinuation 
due to lack of efficacy or AE, regardless of treatment arm, adjust these values by 
adding delta to the imputed values, where delta = 1.0 mmHg.  The seed that will be 
used in the SAS program is 13546. 
c. Each of the 50 complete datasets will then be analyzed separately using the same 
MMRM as used for the primary analysis. 
d. The estimates obtained from the MMRM analysis of each complete dataset are 
combined for inference purposes. 
e. Repeat step b, c, d, with delta = 2.0, 3.0, 4.0, and 5.0 mmHg.  The larger the value of 
delta that is required to reverse the conclusion of the primary analysis, the more 
robust the conclusion is considered to be. 
The main part of the SAS code for the specified MMRM analysis and PMM are provided in 
Appendix A and Appendix B, respectively. 
For the primary endpoint, in addition to the two types of sensitivity analyses described above, if 
the overall rate of study drug discontinuation due to lack of efficacy or AE is greater than 10% 
and the difference between the rate in the DE-117 and Timolol arms is greater than 5 percentage 
points, a trimmed mean analysis (Permutt et al., 2017) will be conducted as a sensitivity analysis. 
8.1.2. 
Analyses of Other Secondary Efficacy Endpoints 
Other secondary endpoints to be assessed include: 
 Change and percent change from baseline in IOP at each timepoint/post-baseline visit 
 Change and percent change from baseline in mean diurnal IOP at each post-baseline visit 
 Having a mean diurnal IOP reduction ≥ 20%, ≥ 25%, or ≥ 30% from Baseline (Visit 2) at 
each post-baseline visit 
 Having a mean diurnal IOP ≤ 18mmHg at each post-baseline visit 


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For continuous secondary endpoints (change and percent change from baseline in IOP/mean 
diurnal IOP) at Week 1 (Visit 3), Week 6 (Visit 4), and Month 3 (Visit 5), both an analysis using 
a MMRM will be performed and descriptive summaries will be generated.  The MMRM will be 
analogous to the MMRM used in the analysis of the primary endpoint.  For both the analysis 
using MMRM and descriptive summaries of the IOP or mean diurnal IOP (raw) scores, IOP 
values obtained after using rescue therapy will be censored (i.e., treated as missing). 
For the following binary secondary endpoints, the responder rates will be analyzed using the 
Pearson’s chi-square test for a 2×2 contingency table; differences between the DE-117 and 
Timolol arms will be reported along with corresponding p-values: 
 Having a mean diurnal IOP reduction ≥ 20%, ≥ 25%, or ≥ 30% from 
Baseline (Visit 2) at each post-baseline visit 
 Having a mean diurnal IOP ≤ 18mmHg at each post-baseline visit 
The above secondary efficacy endpoint analyses will be repeated on pediatric subjects. 
8.1.3. 
Subgroup Analyses 
The homogeneity of treatment effects among prospectively defined subgroups was assessed 
using MMRM analyses of IOP (at each visit and timepoint) and mean diurnal IOP (at each visit) 
for the following subgroups: 
 Age (< 18, ≥ 18 and < 65, or ≥ 65 years) 
 Sex (males or females) 
 Race (White or Black)  
 Primary ocular diagnosis [OAG (including pigmentary glaucoma and 
pseudoexfoliative glaucoma), OHT, or JOAG] 
 Prior use of IOP-lowering medication (ß-adrenergic antagonist, prostamide or 
prostaglandin analogue, α-adrenergic agonist, carbonic anhydrase inhibitors, or none) 
 Mean diurnal IOP at baseline (< 25 or ≥ 25 mmHg) 
 Lens status (phakic or pseudophakic/aphakic)  
Other subgroup analyses may be performed as deemed necessary. 
8.2. 
Efficacy Analyses for Open-Label Period 
For efficacy measures during open-label period, no inferential analysis will be performed. 
Summary statistics will be provided on the following variables for open-label and entire study 
periods separately for all subjects who entered the open-label treatment period. 
 Raw scores, change from baseline, and percent change from baseline in IOP at each 
timepoint/post-baseline visit 
 Raw scores, change from baseline, and percent change from baseline in mean diurnal 
IOP at each post-baseline visit 


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9. 
SAFETY ANALYSES 
The safety-related measures collected in this study include AEs, best-corrected visual acuity,  
slit-lamp biomicroscopy (severity scores for 12 parameters), ophthalmoscopy (cup-to-disc ratio, 
glaucomatous optic nerve severity score, and assessments of retina, macula, choroid, and 
vitreous), and eyelid sulcus/eyelid/eyelash/iris color.  In the event that a subject took both 
DE-117 and Timolol during double-masked period of the study, the subject will be summarized 
with those receiving DE-117. 
All the safety-related measures will be summarized descriptively by actual treatment received on 
the Safety population. 
9.1. 
Adverse Events 
AEs, SAEs, SARs, serious SARs, and significant AEs (AEs leading to study drug 
discontinuation and AEs leading to death) will be tabulated by type of AEs by treatment arm 
using actual treatment received for all AEs, ocular AEs, and non-ocular AEs separately. 
Besides the overall AE summary, AEs, SAEs, SARs, serious SARs will be tabulated by SOC and 
preferred term for all AEs, ocular AEs, and non-ocular AEs separately.  A subject who 
experienced multiple AEs within a SOC or preferred term will be counted only once for that 
SOC or preferred term.  Non-serious AEs (including number of events) and ESIs will also be 
summarized by SOC and preferred term. 
All the AE summaries will be performed for double-masked, open-label, and entire study periods 
separately.  For double-masked period summaries, overall AE summary, summary of AE by 
SOC and PT, SAEs, SARs, and serious SARs will also be tabulated on pediatric subjects 
separately.  For open-label and entire study period summaries, tabulations by treatment received 
during double-masked period will be provided as well as overall summary for subjects exposed 
to DE-117.  So, for subjects who exposed to the Timolol arm during the double-masked period, 
their AE summaries under the Overall DE-117 column will be those AEs that started during the 
open-label treatment period. 
AEs, SAEs, SARs, serious SARs, ocular AEs, AEs leading to death, AEs leading to study drug 
discontinuation, non-TEAEs, and ESIs, if any, will be listed separately. 
9.1.1. 
Ocular Inflammation 
Subjects who developed AEs during the study with one of the following preferred terms will be 
included in the ocular inflammation summary: 
 Anterior chamber cell 
 Anterior chamber flare 
 Eye inflammation 
 Anterior chamber inflammation  
 Iridocyclitis  
 Iritis 


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 Uveitis 
Other preferred terms might be added upon review of the AE data before database lock. 
Ocular inflammation leading to study drug discontinuation, requiring steroid treatment, or 
requiring NSAIDs treatment will be summarized at the subject level by frequency and 
percentage separately. 
Ocular inflammation start time (in terms of study day) and duration of the AE will be 
summarized at the eye level using mean, standard deviation, median, minimum, and maximum 
by study eye and fellow eye separately.  To allow for the computation of simple descriptive 
statistics, only subjects who develop ocular inflammation during the study will be used for the 
ocular inflammation start time summary, and only subjects who develop these AEs during the 
study and later resolved will be used in the duration of AE analysis. 
The aforementioned summaries will be performed at the eye level.  All ocular inflammation AEs 
will be provided in a listing. 
9.1.2. 
Macular Edema 
Subjects who developed AEs during the study with one of the following preferred terms will be 
included in the macular edema summary: 
 Macular edema 
 Cystoid macular edema 
Macular edema start time (in terms of study day) and duration of the AE will be summarized 
using mean, standard deviation, median, minimum, and maximum by study eye and fellow eye 
separately.  To allow for the computation of simple descriptive statistics, only subjects who 
develop macular edema during the study will be used for the macular edema start time summary, 
and only subjects who develop these AEs during the study and later resolved will be used in the 
duration of AE analysis. 
Change from baseline in BCVA at the onset of macular edema, when macular edema is resolved, 
and at the last visit will be summarized using mean, standard deviation, median, minimum, and 
maximum by study eye and fellow eye separately.  Pseudophakic eyes or phakic eyes at baseline 
who developed macular edema during the study will be summarized by frequency and 
percentages separately. 
The aforementioned summaries will be performed at the eye level.  All macular edema AEs will 
be provided in a listing. 
9.1.3. 
Cosmetic Change(s) 
Subjects who developed AEs during the study with one of the following preferred terms will be 
included in the cosmetic change summary: 
 Blepharal pigmentation  
 Eyelash changes 
 Eyelash hyperpigmentation  


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 Eyelash thickening  
 Growth of eyelashes  
 Lid sulcus deepened 
 Trichiasis  
 Iris hyperpigmentation 
Other preferred terms might be added upon review of the AE data before database lock. 
Cosmetic change(s) start time (in terms of study day) will be summarized using mean, standard 
deviation, median, minimum, and maximum by study eye and fellow eye separately.  To allow 
for the computation of simple descriptive statistics, only subjects who develop cosmetic 
change(s) during the study will be used for the cosmetic change start time summary. 
The aforementioned summaries will be performed at the eye level.  All cosmetic change AEs 
will be provided in a listing. 
9.2. 
Best-Corrected Visual Acuity 
BCVA (logMAR scores) and changes from baseline will be summarized by treatment, analysis 
visit, and study period (double masked and open-label) for study eyes and fellow 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 treatment, analysis visit and study period (double masked and open-label) for 
study eyes and fellow eyes, separately.  In addition, any clinically significant worsening 
(increase) from baseline will be summarized and listed. 
9.4. 
Ophthalmoscopy 
Cup-to-disc ratio will be summarized with n, mean, standard deviation, median, minimum and 
maximum by treatment, analysis visit, and study period (double masked and open-label) for 
study eyes and fellow eyes separately.  In addition, subjects with at least 0.2 increase in cup/disc 
ratio from baseline will be listed. 
Glaucomatous optic nerve findings will be assessed as 0 = none, 1 = mild, 2 = moderate, or  
3 = severe.  Frequency and percentage of rating scores will be summarized by treatment and 
analysis visit for study eyes and fellow eyes, separately.  In addition, subjects with any 
worsening (increase) of ≥ 2 units from baseline will be listed. 
Retina/Macula/Choroid and vitreous will be assessed as normal or abnormal.  Shift from baseline 
at Month 3 will be summarized by treatment on study eyes and fellow eyes separately.  In 
addition, subjects with change from baseline from normal to abnormal in these parameters will 
be listed. 


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9.5. 
Eyelid Sulcus, Eyelid, Eyelash, and Iris Color 
For changes from baseline in eyelid pigmentation, eyelid hair growth, eyelash length, eyelash 
thickness, eyelash pigmentation, eyelash number, and iris color/pigmentation, frequency and 
percentage of subjects with No change, Increased, or Decreased will be summarized by 
treatment, analysis visit, and study period (double masked and open-label) for study eyes and for 
fellow eyes.  For changes from baseline in eyelid sulcus, count and percentage of changes (Yes) 
will be summarized by treatment and analysis visit (Month 3, Month 6, Month 9, and Month 12) 
for study eyes and for fellow eyes.  In addition, any changes from baseline in eyelid sulcus will 
be listed. 
9.6. 
Vital Signs 
Resting blood pressure (systolic and diastolic) and pulse rate and their change from baseline will 
be summarized by treatment, analysis visit, and study period (double masked and open-label). 
A listing for vital signs will be provided. 


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10. 
ADDITIONS AND CHANGES TO THE PROTOCOL-SPECIFIED 
ANALYSES 
10.1. 
Full Analysis Set Definition 
The full analysis set definition has been updated to add the requirement that baseline IOP data 
has to be present: 
The Full Analysis Set (FAS) will include all randomized subjects who received at least one dose 
of study medication and provided Baseline IOP data (at any timepoint) and at least one  
post-baseline IOP measurement (at any timepoint).  Efficacy analyses will be performed using 
the FAS and summarized by treatment as randomized. 
10.2. 
Key Secondary Endpoint 
An additional key secondary endpoint (IOP at each scheduled timepoint [08:00, 10:00, and 
16:00] at Week 1 [Visit 3], Week 6 [Visit 4], and Month 3 [Visit 5] in the study eyes with mean 
diurnal IOP < 25 mmHg at the Baseline Visit) was added based on analysis results of a recently 
completed study in Asia.  This key secondary endpoint was not in the clinical study protocol, but 
instead it was added in the SAP.  All endpoints for this study are presented in Section 2.2. 
10.3. 
Sensitivity Analysis of the Primary and Secondary Efficacy 
Endpoints 
Protocol Amendment 1 (Version 1.1) Section 14.5, Handling of Missing Values, specified a 
sensitivity analysis of the primary efficacy endpoints and the secondary binary IOP endpoints 
(Month 3) in which missing values would be imputed using the last-observation-carried-forward 
(LOCF) approach.  The LOCF approach is removed from the sensitivity analyses because the 
PMM generalizes the MMRM to include mixed missing data mechanisms beyond the MAR 
assumption of the MMRM.  Thus, the PMM is sufficient to evaluate the robustness of the results 
from the MMRM. 


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11. 
REFERENCES 
1. 
Permutt, T., Li, F. (2017).  Trimmed means for symptom trials with dropouts. Pharm Stat. 
16(1):20-8. doi: 10.1002/pst.1768. PubMed PMID: 27523396. 
 
 
 


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12. 
APPENDICES 


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