Clinical trial NCT04742283
Conditions: Primary Open Angle Glaucoma Ocular Hypertension
Keywords: Glaucoma
Sponsor: Santen Inc.
Start date: 2020-12-17; Completion date: 2021-12-07
Enrollment: 323 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Reduction of elevated pressure in the eye (Intraocular pressure, or 'IOP') with eye drop medications has been shown to be effective in delaying or preventing the progression of glaucoma, and it is the only proven method for reducing the risk of glaucomatous visual field loss.

This study is being conducted to determine how well DE-126 ophthalmic solution works (efficacy) in safely lowering IOP when dosed as topical eyedrops. This study will evaluate the safety and efficacy of DE-126, ophthalmic solution in subjects with Primary Open Angle Glaucoma (POAG) or Ocular Hypertension (OHT).

The IOP will be measured at 3 different times throughout the day, over 4 total visits during a 3-month treatment period (with up to 4 extra weeks observation if the patient must stop taking current eye drops to lower IOP). Safety assessments will be done throughout the study, including ocular signs and symptoms, and vital signs. While the most important time-point to measure IOP in this study and evaluate efficacy will be at the final study visit (month 3), IOP values will also be evaluated at other visits throughout the 3-month treatment period.

Detailed description:

Arms: arm 1: DE-126 Ophthalmic Solution 0.002% is administered once daily (QD) arm 2: Timolol Maleate Ophthalmic Solution 0.5% is administered twice daily (BID)
Interventions: intervention 1: DE-126 Ophthalmic Solution 0.002% QD intervention 2: Timolol Maleate Ophthalmic Solution 0.5% BID
Intervention descriptions: intervention 1: DE-126 Ophthalmic Solution QD evening and Vehicle QD Morning intervention 2: Timolol Maleate Ophthalmic Solution BID (morning and evening)

Protocol documents:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:   
ANGEL-2: A Phase IIb, Randomized, Double-Masked, Active-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety of 
DE-126 Ophthalmic Solution 0.002% Compared with Timolol Maleate 
Ophthalmic Solution 0.5% in Subjects with Primary Open Angle 
Glaucoma or Ocular Hypertension. 
 
NCT Number:  
NCT04742283  
 
Date of the document: 
 18Feb2021 
 
 
 


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DE-126 PROTOCOL 
STUDY 012604IN 
TITLE:  ANGEL-2: A Phase IIb, Randomized, Double-Masked, Active-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety of DE-126 
Ophthalmic Solution 0.002% Compared with Timolol Maleate Ophthalmic Solution 
0.5% in Subjects with Primary Open Angle Glaucoma or Ocular Hypertension 
PROTOCOL NUMBER: 012604IN 
COMPOUND NUMBER: DE-126  
STUDY PHASE: Phase IIb 
SPONSOR: SANTEN INCORPORATED 
LEGAL REGISTERED ADDRESS: 6401 Hollis Street, Suite 125, Emeryville, CA 94608 
REGULATORY AGENCY IDENTIFIER NUMBER(S): IND Number: 112026 
PROTOCOL VERSION/DATE: ORIGINAL 16OCT2020 
AMENDMENT 1: 18FEB2021 
I have read the 012604IN protocol and agree to conduct the study as outlined.  I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.  I will not initiate the study until I have obtained written approval by the appropriate 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and have complied 
with all financial and administrative requirements of the governing body of the clinical 
institution and Santen as the Sponsor.  I will obtain written informed consent from each study 
subject prior to performing any study-specific procedures.  I understand that my electronic 
signature on an electronic case report form (eCRF) indicates that the data therein has been 
reviewed and accepted by me as the Investigator. 
 
INVESTIGATOR: 
Date:  
 
_________________________________ 
 
Signature: 
 
_________________________________ 
 
Name:  
 
_________________________________ 
 
Address:  
 
_________________________________ 
 
 
_________________________________ 
 
Phone: 
_________________________________ 
This study will be conducted in accordance with applicable Good Clinical Practices (GCP), United 
States Code of Federal Regulations, International Conference on Harmonization (ICH) guidelines, and 
the Declaration of Helsinki. 


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1. PROTOCOL SUMMARY 
1.1. 
Synopsis 
Name of Sponsor/Company: 
Santen Inc. 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608, USA 
Name of Investigational Product: DE-126 Ophthalmic Solution 
Name of Active Ingredient: 
Propan-2-yl 4-{(3S,5aR,6R,7R,8aS)-6- [(1E,3R)-4-(2,5-difluorophenoxy)-3- hydroxybut-1-en- 
1-yl]-7-hydroxyoctahydro- 2H-cyclopenta[b]oxepin-3-yl}butanoate 
Title of Study: ANGEL-2: A Phase IIb, Randomized, Double-Masked, Active-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety of DE-126 Ophthalmic 
Solution 0.002% Compared with Timolol Maleate Ophthalmic Solution 0.5% in Subjects with 
Primary Open Angle Glaucoma or Ocular Hypertension 
Protocol Number: 012604IN 
Number of Subjects (planned): Approximately 294 adult subjects (147 in each treatment 
arm) with Primary Open-Angle Glaucoma (POAG) or Ocular Hypertension (OHT) will be 
randomized in this study 
Number of Sites (planned): Approximately 45 sites in the United States  
Study Period: Approximately 19 weeks 
Phase of Development: Phase IIb 
Study objectives and endpoints: 
 
Study Objectives 
Corresponding Study Endpoints 
Primary Efficacy Objective 
To investigate whether the IOP lowering 
efficacy of DE-126 ophthalmic solution 
0.002% dosed once daily (QD, in the evening 
at 20:00) is non-inferior to that of Timolol 
maleate 0.5% dosed twice daily (BID, 8:00 
and 20:00) in subjects with POAG or OHT 
after treatment for 3 months.  If  
non-inferiority is met, superiority will be 
tested. 
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 2 
(Visit 3), Week 6 (Visit 4), and Month 3 
(Visit 5). 


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Secondary Efficacy Objectives 
 To compare the mean diurnal IOP 
between DE-126 ophthalmic 
solution 0.002% and Timolol 
maleate ophthalmic solution 0.5% 
after 3 months of treatment.  If  
non- inferiority is met, superiority 
will be tested. 
 To evaluate the changes and 
percent changes in IOP from 
baseline at all post-baseline visits. 
 To evaluate proportions of subjects 
achieving target pressure reductions 
expressed as either in percent 
reductions of ≥ 20%, ≥ 25%,  
or ≥ 30% or in achieving a target 
IOP value of IOP ≤ 18 mmHg. 
 
Secondary Efficacy Endpoints 
Key Secondary Efficacy Endpoint 
 Mean diurnal IOP in the study eye 
at Month 3 (Visit 5) 
Other Secondary Efficacy Endpoints 
 Mean diurnal IOP in the study eye 
at Week 2 (Visit 3) and  
Week 6 (Visit 4) 
 Change and percent change from 
Baseline (Visit 2, Day 1) in IOP 
in the study eye at each timepoint 
of each post-baseline visit 
 Change and percent change from 
Baseline (Visit 2, Day 1) in mean 
diurnal IOP in the study eye at 
each post-baseline visit 
 Having a mean diurnal IOP 
reduction ≥ 20%, ≥ 25%, or 
 ≥ 30% from Baseline (Visit 2,  
Day 1) in the study eye at each 
post-baseline visit 
 Having a mean diurnal IOP  
≤ 18mmHg in the study eye at 
each post-baseline visit 
Safety Objectives 
To evaluate the safety of DE-126 ophthalmic 
solution 0.002% as compared to Timolol 
maleate ophthalmic solution 0.5% in subjects 
with POAG or OHT. 
Safety Endpoints 
 Adverse Events (AEs) and serious 
AEs (SAEs), including both 
ocular and  
non-ocular AEs 
 Visual acuity: measured by best 
corrected visual acuity (BCVA) 
 Slit-lamp biomicroscopy 
 Ophthalmoscopy 
 Vital signs (blood pressure and 
pulse rate) 


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Exploratory Objectives 
To explore Quality of Life in subjects with 
POAG or OHT when given DE-126 or 
Timolol for 3 months. 
Exploratory Endpoints 
 Glaucoma Quality of Life-15 (GQL-15) 
questionnaire at Baseline (Visit 2, Day 1) 
and Month 3 (Visit 5). 
Duration of Treatment: 3 months 
Methodology: 
This is a Phase IIb, randomized, double-masked, active-controlled, parallel-group and 
multicenter study assessing the efficacy and safety of DE-126 ophthalmic solution 0.002% 
compared with Timolol maleate ophthalmic solution 0.5% in subjects with POAG or OHT. 
Subjects diagnosed with POAG 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 treatment for 3 months. 
Approximately 294 adult subjects with POAG or OHT who meet all eligibility criteria will be 
randomized in a 1:1 ratio to receive either: 
 DE-126 Ophthalmic Solution 0.002% QD (20:00) and Vehicle QD (08:00), or 
 Timolol Maleate Ophthalmic Solution 0.5% BID (20:00 and 08:00) 
 
Study Design: Please see Figure 1. 
 
This study will consist of a Screening Period of up to 35 days including a washout period of up 
to 28 days (+ 7 days window) and a 3-month Double-Masked Treatment Period. 
At the Screening visit (Visit 1), subjects will be screened against the inclusion and exclusion 
criteria.  Eligible subjects will be instructed to discontinue use of all IOP-lowering 
medications, if any, during a washout period as follows (up to +7 days as a window is 
allowed): 
 Miotics: 7 days 
 Oral/topical Carbonic Anhydrase Inhibitors (CAIs): 7 days 
 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandin Analogs (PGA): 28 days 
 Rho kinase inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will 
be used. 


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Please note: Subjects are only allowed to be treated with a maximum of two active ingredients 
for IOP reduction prior to screening. 
During the required washout period, subjects who discontinue their current treatment may, if 
the Investigator deems it necessary, be treated with a short-acting IOP lowering agent, topical 
CAI, e.g., brinzolamide or dorzolamide eye drops, one drop twice daily.  Topical CAI 
treatment must be stopped 1 week before the randomization at Visit 2 (Baseline, Day 1). 
An interim safety visit during the washout period (mid-washout visit; Optional Visit 1a) may 
be performed during the washout period if, in the Investigator’s opinion, a subject’s IOP may 
be of concern during the washout period.  If subjects are treated with a topical CAI during the 
washout period, mid-washout visit (Optional Visit 1a) is recommended to be performed. 
Final eligibility for randomization will be determined at Visit 2 (Baseline, Day 1) after all 
necessary washout from prior IOP-lowering medications have been completed.   
At Visit 2 (Baseline, Day 1), baseline IOP will be measured for both eyes at 08:00 (±60 min), 
10:00 (±60 min), and 16:00 (±60 min).  The study eye will be the eye that qualifies per 
eligibility criteria at Visit 2 (Baseline, Day 1).  If both eyes meet the eligibility criteria, the eye 
with the higher mean diurnal IOP at Visit 2 (Baseline, Day 1) 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.  Both eyes should be treated with the study medication 
for the duration of the study, even if only one eye is eligible per IOP inclusion criteria. 
Please note: Visit 1 (Screening) and Visit 2 (Eligibility/Baseline, Day 1) may be combined into 
one visit for treatment-naïve subjects as long as the additional requirements of Visit 2 
(Eligibility/Baseline, Day 1) are fulfilled on the day of this combined visit; in particular, full 
diurnal IOP measurements (at 08:00, 10:00, 16:00) must be taken. 
Double-Masked Treatment Period (3 months): 
Approximately 294 eligible adult subjects will be randomized to receive either DE-126 
ophthalmic solution 0.002% QD in the evening and vehicle QD in the morning or Timolol 
maleate ophthalmic solution 0.5% BID in a 1:1 ratio.  Subjects will be treated for 3 months 
with scheduled visits at Visit 2 (Baseline, Day 1), 3 (Week 2), 4 (Week 6), and 5 (Month 3).  
Subjects will be contacted approximately 2 weeks post last study drug administration by a 
phone call to confirm AE. 
In the evening of Visit 2 (Baseline, Day 1), subjects will receive their first dose of study 
medication (study eye drops) as per their assigned/randomized study treatment at  
20:00 (±60 min).  The next day, subjects will subsequently dose with their assigned study 
medication at 08:00 (±60 min), and 20:00 (±60 min).  For the DE-126/Vehicle arm, the  
08:00 (±60 min) instillation will be DE-126 vehicle and the 20:00 (±60 min) instillation will 
be DE-126 ophthalmic solution 0.002%.  At each scheduled follow-up visit, subjects will 
receive their morning dose of study medication/eye drops following the 08:00 (±60 min) IOP 
measurement at the investigative site (the doctor’s office). 
IOP will be measured at 08:00 (±60 min), 10:00 (±60 min), and 16:00 (±60 min) at Visit 3 
(Week 2), Visit 4 (Week 6), and Visit 5 (Month 3).  At these scheduled visits, BCVA and  
slit-lamp biomicroscopy will be performed just prior to the 08:00 (±60 min) IOP measurement. 
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 5 (Month 3).  After 
the 16:00 (±60 min) IOP measurement at Visit 5 (Month 3), ophthalmoscopy with the pupil 


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dilated will be performed.  Subjects will be contacted approximately 2 weeks post last study 
drug administration by a phone call to confirm AE. 
Pharmacogenomics/Genomics: 
Subjects who consent to the optional pharmacogenomics/genomics (PGx) laboratory study 
will provide a blood sample for future testing.  The earliest this sample is to be collected at 
Visit 3 (Week 2), but it may also be collected at any later time during the study after Visit 2 
(Eligibility/Baseline) or at a separate post-study visit, if necessary.  The purpose of this 
exploratory research is to identify possible genetic markers associated with the study 
medication(s) and/or ocular conditions. 
Masking: 
This is a double-masked study.  The subjects, Investigators, Examiners, and Santen personnel 
involved in the conduct of the study will be masked to the study treatment.  An authorized 
unmasked study staff member at the investigator site who is not the Investigator or Examiner 
will dispense and collect study medication(s) and will query about dosing compliance. 
Subjects will be instructed not to show the eye drop bottles or discuss the eye drops to either 
the Investigator or the Examiner or other study subjects.  The active control treatment (Timolol 
Maleate) bottles will be over-labeled and packaged in the same secondary package  
(e.g., cardboard carton) as the investigational treatment (DE-126). Subjects in DE-126/Vehicle 
arm will receive a kit containing 2 bottles labeled “morning” for the morning dose and  
2 bottles labeled “evening” for the evening dose. Subjects on Timolol arm will receive a kit 
containing 2 bottles labeled morning/evening for the BID dosing. 
Each eligible subject will receive a numbered study medication kit assigned by Central 
randomization via Interactive Response Technology (Medidata Rave RTSM) at Visit 2 
(Baseline, Day 1) and at Visit 4 (Week 6). 
Inclusion Criteria: Please see Section 5.1 Subject Inclusion Criteria 
Exclusion Criteria: Please see Section 5.2 Subject Exclusion Criteria 
Investigational product, dosage, and mode of administration:  
Subjects will be randomly assigned in a 1:1 ratio to the DE-126/Vehicle arm and Timolol 
Maleate arms to receive either DE-126/Vehicle or Timolol Maleate, as described below: 
Investigational Product: 
DE-126 Ophthalmic Solution contains 0.002% DE-126. Other ingredients include  
 
 
Vehicle: 
The vehicle is identical to the investigational product but does not contain the active ingredient 
DE-126. 
Active Control: 
Timolol maleate ophthalmic solution 0.5% contains the active ingredient, Timolol 5 mg/ml, and 
the preservative BAK 0.01%.  Other ingredients include monobasic and dibasic sodium 
phosphate and purified water.  The pH is adjusted to 6.5 to 7.5 with sodium hydroxide. 


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Each subject will be instructed to instill one drop of study medication in each eye at 20:00 and 
at 08:00 starting the evening of Visit 2 (Baseline, Day 1) through the morning of Visit 5  
(Month 3). 
Route of Administration of Investigational Product: Topical ocular 
Duration of the Study: The study duration includes up to a 5- weeks Screening Period, a  
3-month Double-Masked Treatment Period, and up to a 2- weeks Follow-up Period. 
Statistical Methods: 
The sample size calculation is based on a two-sided Type I error rate of 5% and a  
non-inferiority margin of 1.5 mmHg.  Assuming a between-treatment difference of 0 mmHg,  
a standard deviation (SD) of 4.0 mmHg, and a correlation coefficient of 0.6 among repeated 
measures, approximately 280 adult subjects in total (140 subjects per treatment arm) will 
provide 70% power to demonstrate non-inferiority of DE-126 0.002% to Timolol 0.5%.  
Assuming a drop-out rate of 5%, the final needed sample size will be 294 in total,  
i.e. 147 subjects/arm. 
For the primary efficacy endpoint, a mixed-effects model for repeated measures (MMRM) will 
be fitted and 95% confidence interval for least square mean difference in IOP in the study eye 
between the DE-126/Vehicle arm and the Timolol Maleate arm at each scheduled time point of 
each post-baseline visit up to Month 3 will be estimated.  Non-inferiority is achieved if the 
upper limit of the two-sided  
95% confidence interval for the difference in the mean IOP (DE-126 0.002% - Timolol Maleate 
0.5%) is ≤ 1.5 mmHg at all nine time points and ≤ 1.0 mmHg in majority (5 or more) of the  
9 time points.  If non-inferiority is achieved for the primary endpoint, superiority will be tested. 
For the key secondary efficacy endpoint, a MMRM will be fitted on observed cases up to 
Month 3 on the mean diurnal IOP in the study eye.  The least square mean diurnal IOP of each 
treatment arm and 95% confidence interval for the difference between DE-126/Vehicle and 
Timolol at Month 3 will be estimated.  If  
non-inferiority in the primary endpoint is achieved, then the key secondary endpoint will be 
tested at the 0.05 significance level (2-sided).  Non-inferiority is achieved if the upper limit of 
the two-sided 95% confidence interval for the difference in the mean diurnal IOP (0.002%  
DE-126 - Timolol Maleate) at Month 3 is ≤ 1.5 mmHg.  If non-inferiority is achieved for the 
key secondary endpoint, superiority will be tested. 
All safety outcome measures will be summarized descriptively.  Incidences of AEs will be 
tabulated by the system organ classes and preferred terms specified in the Medical Dictionary 
for Regulatory Activities (MedDRA).  Separate summaries will be provided for ocular and 
non-ocular AEs. 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ............................................................................................4 
1.1. 
Synopsis ........................................................................................................................4 
2. 
INTRODUCTION ......................................................................................................18 
2.1. 
Study Rationale ...........................................................................................................18 
2.2. 
Background .................................................................................................................18 
2.3. 
Benefit/Risk Assessment ............................................................................................20 
3. 
STUDY OBJECTIVES AND PURPOSE ..................................................................22 
3.1. 
Primary Objective .......................................................................................................22 
3.2. 
Secondary Objectives .................................................................................................22 
3.3. 
Safety Objective ..........................................................................................................22 
3.4. 
Exploratory Objective .................................................................................................22 
4. 
STUDY DESIGN .......................................................................................................23 
4.1. 
Overall Study Design ..................................................................................................23 
4.2. 
Number of Subjects ....................................................................................................25 
4.3. 
Treatment Assignment ................................................................................................25 
4.4. 
Schedule of Events and Procedures ............................................................................25 
5. 
STUDY POPULATION .............................................................................................29 
5.1. 
Subject Inclusion Criteria ...........................................................................................29 
5.2. 
Subject Exclusion Criteria ..........................................................................................30 
6. 
STUDY INTERVENTION ........................................................................................33 
6.1. 
Study Medication ........................................................................................................33 
6.1.1. 
Investigational Product ...............................................................................................33 
6.1.2. 
Vehicle ........................................................................................................................33 
6.1.3. 
Active Control ............................................................................................................33 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................33 
6.2.1. 
Study Medication Packaging and Labeling ................................................................33 
6.2.2. 
Study Medication Storage ...........................................................................................34 
6.2.3. 
Study Medication Preparation ....................................................................................34 
6.2.4. 
Study Medication Administration...............................................................................34 
6.2.5. 
Study Medication Accountability ...............................................................................34 
6.2.6. 
Study Medication Handling and Disposal ..................................................................34 


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6.2.7. 
Study Supplies ............................................................................................................35 
6.3. 
Concomitant Medications or Therapies ......................................................................35 
6.3.1. 
Prohibited Medications or Therapies ..........................................................................35 
6.4. 
Treatment Compliance ................................................................................................36 
6.5. 
Randomization and Masking ......................................................................................37 
7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL FROM STUDY ......................38 
7.1. 
Subject Early Discontinuation/Withdrawal from the Study .......................................38 
7.2. 
Lost to Follow-up .......................................................................................................38 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................40 
8.1. 
Visit Details ................................................................................................................40 
8.1.1. 
Visit 1 (Screening) ......................................................................................................40 
8.1.2. 
Optional Visit 1a .........................................................................................................42 
8.1.3. 
Visit 2 (Baseline, Day 1) ............................................................................................42 
8.1.4. 
Visit 3 (Week 2, Day 14 ±3) .......................................................................................43 
8.1.5. 
Visit 4 (Week 6, Day 42 ±3) .......................................................................................44 
8.1.6. 
Visit 5 (Month 3, Day 90 ±7) / Study Exit/ Early Termination ..................................46 
8.1.7. 
Follow-up (2 Weeks +7 days Post Last Study Drug Administration) ........................47 
8.2. 
Study Termination ......................................................................................................47 
8.3. 
Efficacy Parameter ......................................................................................................47 
8.4. 
Safety Parameters .......................................................................................................47 
8.4.1. 
Ocular Assessments ....................................................................................................47 
8.4.2. 
Non-ocular Assessments .............................................................................................48 
8.5. 
Other Assessments ......................................................................................................48 
8.5.1. 
Demographic and Other Assessments ........................................................................48 
8.5.2. 
Pharmacogenomics/Genomics ....................................................................................48 
8.5.3. 
Glaucoma Quality of Life (GQL-15) Questionnaire ..................................................48 
8.6. 
Assessment of Safety ..................................................................................................48 
8.6.1. 
Adverse Events and Serious Adverse Events .............................................................48 
8.6.1.1. 
Definition of Adverse Events .....................................................................................48 
8.6.1.2. 
Assessment of Adverse Events ...................................................................................49 
8.6.1.3. 
Reporting Adverse Events ..........................................................................................49 
8.6.2. 
Serious Adverse Events ..............................................................................................50 


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8.6.2.1. 
Assessment of Serious Adverse Events ......................................................................50 
8.6.2.2. 
Reporting Serious Adverse Events .............................................................................51 
8.6.2.3. 
Expedited Reporting of Serious Adverse Events ........................................................51 
8.6.3. 
Events of Special Interest ...........................................................................................51 
8.6.4. 
Pregnancy Testing, Monitoring, and Reporting .........................................................52 
8.6.4.1. 
Pregnancy Testing ......................................................................................................52 
8.6.4.2. 
Pregnancy Monitoring and Reporting Procedures ......................................................52 
8.6.5. 
Time Period and Frequency for Collecting AE and SAE Information .......................53 
8.6.6. 
Method of Detecting AEs and SAEs ..........................................................................54 
8.6.7. 
Follow-up of Adverse Events .....................................................................................54 
8.6.8. 
Manual Back-Up Reporting Procedures .....................................................................55 
8.6.9. 
Regulatory Reporting Requirements for SAEs ...........................................................55 
9. 
STATISTICAL CONSIDERATIONS .......................................................................56 
9.1. 
Interim Analysis ..........................................................................................................56 
9.2. 
Final Analysis .............................................................................................................56 
9.3. 
General Considerations ...............................................................................................56 
9.3.1. 
Sample Size ................................................................................................................56 
9.3.2. 
Statistical Hypotheses and Level of Significance .......................................................56 
9.3.3. 
Multiple Comparisons/Multiplicity ............................................................................57 
9.4. 
Study Populations .......................................................................................................58 
9.4.1. 
Safety Population ........................................................................................................58 
9.4.2. 
Full Analysis Set .........................................................................................................58 
9.4.3. 
Per-Protocol Set ..........................................................................................................58 
9.5. 
Handling of Missing Values .......................................................................................58 
9.6. 
Demographic and Baseline Characteristics ................................................................58 
9.7. 
Efficacy Analyses .......................................................................................................59 
9.7.1. 
Analysis of Primary Efficacy Endpoint ......................................................................59 
9.7.2. 
Analysis of Secondary Efficacy Endpoints ................................................................59 
9.7.2.1. 
Key Secondary Efficacy Endpoint ..............................................................................59 
9.7.2.2. 
Other Secondary Efficacy Endpoints ..........................................................................59 
9.8. 
Safety Analyses ..........................................................................................................60 
9.9. 
Exploratory Analyses ..................................................................................................60 


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10. 
SUPPORTING DOCUMENTAITON AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................61 
10.1. 
Study Monitoring ........................................................................................................61 
10.2. 
Audits and Inspections ................................................................................................62 
10.3. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................62 
10.4. 
Quality Control and Quality Assurance ......................................................................62 
10.4.1. 
Quality Control ...........................................................................................................62 
10.4.2. 
Quality Assurance .......................................................................................................62 
10.5. 
Ethics ..........................................................................................................................62 
10.5.1. 
Ethics Review .............................................................................................................62 
10.5.2. 
Ethical Conduct of the Study ......................................................................................63 
10.6. 
Written Informed Consent ..........................................................................................63 
10.7. 
Data Handling and Recordkeeping .............................................................................63 
10.7.1. 
Inspection of Records .................................................................................................63 
10.7.2. 
Retention of Records ..................................................................................................63 
10.7.3. 
Source Documents ......................................................................................................64 
10.7.4. 
Source Data .................................................................................................................64 
10.7.5. 
Data Collection ...........................................................................................................64 
10.8. 
Study and Site Closure................................................................................................65 
10.9. 
Publication Policy .......................................................................................................65 
11. 
REFERENCES ...........................................................................................................66 
11.1. 
Literature .....................................................................................................................66 
11.2. 
Study Reports..............................................................................................................67 
12. 
APPENDICES ............................................................................................................68 
12.1. 
Appendix A - Obligations of Investigators .................................................................68 
12.2. 
Appendix B - Elements of Informed Consent ............................................................70 
12.3. 
Appendix C - Procedures for Assessments .................................................................72 
12.3.1. 
Refraction ...................................................................................................................72 
12.3.2. 
Demographics, Medication/Therapy, and Medical History .......................................72 
12.3.3. 
Pregnancy Test ............................................................................................................73 
12.3.4. 
Vital signs (Blood pressure/Pulse rate) .......................................................................73 
12.3.5. 
Best-Corrected Visual Acuity .....................................................................................73 
12.3.5.1. 
ETDRS Visual Acuity Scoring ...................................................................................73 


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12.3.6. 
Slit-Lamp Biomicroscopy ...........................................................................................74 
12.3.7. 
Intraocular Pressure ....................................................................................................78 
12.3.7.1. 
Goldmann Applanation Tonometer Calibration .........................................................79 
12.3.8. 
Gonioscopy .................................................................................................................79 
12.3.9. 
Pachymetry (Central Corneal Thickness) ...................................................................79 
12.3.10. 
Visual Field .................................................................................................................80 
12.3.11. 
Ophthalmoscopy (Fundus) Examination ....................................................................80 
12.3.12. 
Blood Sample for Pharmacogenomics/genomics Study .............................................80 
12.4. 
Appendix D- Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................81 
12.5. 
Appendix E- Adverse Event Case Report Form Items and Terms .............................86 
12.6. 
Appendix F – The Glaucoma Quality of Life-15 Questionnaire ................................88 
12.7. 
Appendix G - Protocol Amendment 1 Summary of Changes ....................................89 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................15 
Table 3: 
Schedule of Events and Procedures ............................................................................26 
Table 4: 
LogMAR Scoring Grid for ETDRS Eye Chart...........................................................74 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................23 
 
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations and Definition of Terms 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Definition 
ACE 
Angiotensin-Converting Enzyme 
AE 
Adverse Event 
AGIS 
Advanced Glaucoma Intervention Study 
ARB 
Angiotensin II Receptor Blockers 
ATC 
Anatomical Therapeutic Chemical 
BAK 
Benzalkonium Chloride 
BCVA 
Best-Corrected Visual Acuity 
BID 
Twice a Day 
CAI 
Carbonic Anhydrase inhibitor 
CV 
Curriculum Vitae 
D 
Diopter 
dB 
Decibel 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMGT 
Early Manifest Glaucoma Trial 
ESI 
Events of Special Interest 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GQL 
Glaucoma Quality of Life 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 


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Table 2: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Definition 
IUDs 
Intrauterine Devices 
LASIK 
Laser-Assisted-in-Situ Keratomileusis 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
Medidata Rave RTSM 
Medidata Rave Randomization & Trial Supply Management 
µg 
Microgram 
µm 
Micrometer 
mg 
Milligram 
MIGS 
Minimally Invasive Glaucoma Surgery  
min 
Minute 
mL 
Milliliter 
mmHg 
Millimeters of Mercury 
MMRM 
Mixed-effects Model for Repeated Measures 
N 
Number of subjects 
OAG 
Open-Angle Glaucoma 
OCT 
Optical Coherence Tomography 
OD 
Right Eye 
OHT 
Ocular Hypertension 
OHTS 
Ocular Hypertension Treatment Study 
OS 
Left Eye 
OU 
Both Eyes 
PCR 
Polymerase Chain Reaction 
PGx 
Pharmacogenomic/genomics 
PGA 
Prostaglandin Analogue 
PMM 
Pattern Mixture Model 
POAG 
Primary Open-Angle Glaucoma 
PPS 
Per-Protocol Set 
PRK 
Refractive Keratectomy 
PT 
Preferred Term 
QD 
Once a day 


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Table 2: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Definition 
RK 
Radial Keratotomy 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SUN 
Standardization of Uveitis Nomenclature 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 


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2. 
INTRODUCTION 
2.1. 
Study Rationale 
This Phase IIb study (012604IN) will assess the safety and efficacy of DE-126 ophthalmic 
solution 0.002% QD against Timolol maleate ophthalmic solution 0.5% BID in subjects with 
POAG or OHT after 12 weeks of treatment.  The efficacy and safety profiles for DE-126 have 
been explored in early clinical studies.  Four clinical studies were conducted in the U.S. and 
Japan with DE-126 in healthy adult subjects, or subjects with POAG or OHT to evaluate the 
safety and efficacy of DE-126.  As a result, DE-126 ophthalmic solution in concentration of 
0.002% appeared to be tolerated and effective.  This data, along with the novel mechanism of 
action of DE-126, support the initiation of the clinical study presented in this protocol. 
2.2. 
Background 
Glaucoma is a group of diseases of the optic nerve, often associated with elevated IOP.  When 
left untreated, glaucoma can lead to retinal ganglion cell death and optic nerve damage that result 
in progressive and irreversible loss of vision.  Glaucoma is the leading cause of irreversible 
blindness in the world (King et al., 2013).  While people of all ages can be diagnosed with 
glaucoma, it primarily affects adults who are 40 years of age or greater, and the prevalence 
increases substantially with increasing age group.  In 2013, the global prevalence of glaucoma 
for the population 40 to 80 years of age was 3.54%, or 64.3 million, and the prevalence was 
estimated to increase to 76.0 million by 2020 and 111.8 million by 2040 (Tham et al., 2014). 
Although currently there is no cure for open-angle glaucoma, results from multiple studies, 
including the Advanced Glaucoma Intervention Study (AGIS) (AGIS_Investigators, 2000), the 
Ocular Hypertension Treatment Study (OHTS) (Kass et al., 2002), and the Early Manifest 
Glaucoma Trial (EMGT) (Leske et al., 2003), have demonstrated that treating elevated IOP with 
topical ocular hypotensive agents is effective in delaying or preventing disease progression.  The 
lowering of IOP is currently the only method for reducing the risk of glaucomatous visual field 
loss and remains the primary goal of therapy. 
Topical hypotensive agents are typically the first-line treatment option for patients with OAG or 
OHT; there are several classes and they are differentiated by their mechanisms of action (MOAs) 
at the cellular/molecular level: 
1. Prostanoid FP receptor agonists (FP agonists) (all FP agonists approved for the reduction 
of elevated IOP in patients with Open-Angle Glaucoma (OAG) or OHT are PGAs or 
prostamides) 
2. Beta-adrenergic antagonists (beta blockers) 
3. CAIs 
4. Alpha-adrenergic agonists 
5. Rho kinase (ROCK) inhibitors 
6. Parasympathomimetics 
Some classes of ocular hypotensive medications lower IOP primarily by reducing aqueous 
humor production (beta blockers, CAIs, and alpha-adrenergic agonists), and some lower IOP 


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mainly by increasing aqueous humor outflow (FP agonists, ROCK inhibitors, and 
parasympathomimetics).  Of those medications that primarily increase aqueous humor outflow, 
ROCK inhibitors, and parasympathomimetics mainly increase trabecular outflow and FP 
agonists primarily increase uveoscleral outflow.  Additional distinctions exist among the MOAs, 
and thus the pharmacodynamic effects of these medications can differ substantially.  
Of the available topical hypotensive agents, FP agonists are the most frequently prescribed 
first-line topical therapies (Cheema et al., 2016; European_Glaucoma_Society, 2017), as they 
lower IOP in most patients and have minimal systemic side effects. 
First line treatment with PGAs or β-blockers is very effective in IOP reduction; however,  
mono-therapy is often insufficient to achieve target IOP.  Therefore, adjunctive therapy or 
combination therapy with a drug of other classes is often chosen as an alternative.  Limited 
treatment options for non- or low-responders are also an issue.  To address these issues, a first 
line treatment with more potent IOP reduction than existing PGAs or β-blockers, or an ocular 
hypotensive agent with a novel mechanism of action is still needed. 
To address these needs, Santen is developing an ophthalmic topical formulation of sepetaprost 
(code number: DE-126) for the reduction of elevated IOP in patients with OHT or OAG. 
The ocular hypotensive effects of PGAs have been fully investigated in many animal models.  
Although current PGAs, such as latanoprost, are thought to lower IOP mainly via the prostanoid 
FP receptor, a novel mechanism of action via EP3 receptor has been reported recently (Ota et al., 
2006).  The prostanoid EP3 and FP receptors have distinct cellular distributions in the tissues 
involved in the uveoscleral and conventional pathways which regulate IOP (Schlotzer-Schrehardt 
et al., 2002).  Based on these reports, it was hypothesized that compounds which stimulate both 
prostanoid FP and EP3 receptors simultaneously can achieve more profound IOP reduction than 
PGAs alone, and it was demonstrated compounds targeted both FP/EP3 receptor exhibit more 
potent IOP reduction than latanoprost (Data on file).  Among such dual FP and EP3 receptor 
agonists tested, DE-126 was chosen for its high agonistic activities for both FP and EP3 
receptors. 
DE-126 is unique with a significantly different agonistic profile compared to selective FP 
agonists.  DE-126 is rapidly hydrolyzed by ocular esterases to the active free acid ONO-AG-367, 
a highly selective and potent agonist for not only the prostanoid FP receptor, but also the 
prostanoid EP3 receptor.  In efficacy studies with monkeys and dogs, DE-126 showed more 
potent and longer-lasting reduction of IOP than approved PGAs or the fixed combination of PGA 
and β-adrenergic blocker.  In toxicology studies, DE-126 was well tolerated both systemically 
and locally in rodent and non-rodent species for up to 13 weeks. 
Prior to the licensing agreement with Santen, three clinical studies (ONO-9054IOU001, 
ONO-9054IOU002, ONO-9054IOU003) were conducted by ONO in the U.S. with DE-126 in 
healthy adult subjects, or subjects with POAG or OHT to evaluate the safety and efficacy of  
DE-126.  As a result, DE-126 ophthalmic solution in concentrations of up to 0.003% appeared to 
be tolerated and effective. 
After the licensing agreement, a Phase IIb Study 012601IN (Refer to 012601IN CSR), also 
known as a dose-finding study, was conducted in the US and Japan to assess the safety and 
efficacy of four concentrations of DE-126 ophthalmic solution (0.0005%, 0.001%, 0.002%, and 
0.003%) when compared to placebo and latanoprost 0.005% in subjects with POAG or OHT.  


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Based on the primary and other efficacy endpoints at Month 3, DE-126 0.002% was the optimal 
dose from among the four concentrations assessed with respect to IOP lowering, and the 
magnitude of the effect for this concentration was similar to that observed for latanoprost 
0.005%.  All four DE-126 concentrations were well-tolerated.  Most AEs were mild in severity.  
The most frequently observed AE was conjunctival hyperemia.  No DE-126 dose-related trend 
was observed with related to conjunctival hyperemia incidence.  AE incidence was lower with 
DE-126 concentration 0.0005%, 0.001% and 0.002% compared with latanoprost 0.005% and 
DE-126 0.003%.  No safety issues were identified by ocular safety assessments.  One serious AE 
(SAE) was reported (left hand weakness) while the patient was receiving placebo. Three patients 
experienced AEs that led to discontinuation. For further information, refer to the current 
investigator’s brochure for DE-126. 
DE-126 with a novel mechanism of action could be a new hypotensive agent for patients with 
OHT or OAG. 
2.3. 
Benefit/Risk Assessment 
Topical PGAs, such as latanoprost, are increasingly chosen over topical beta blockers and other 
medications as first-line therapy for patients with POAG or OHT (AAO-PPP et al., 2015).  While 
PGAs typically reduce IOP via the FP receptor, DE-126 (Sepetaprost), a novel prodrug that is 
rapidly hydrolyzed by esterases to its active metabolite, targets both the FP and EP3 receptors 
simultaneously; preliminary data suggest that this mechanism can enhance IOP reduction.  In 
Phase I and II studies, DE-126 demonstrated good tolerability and was efficacious in patients 
with POAG and OHT (Berlin et al., 2015; Miller Ellis et al., 2017; Suto et al., 2015).  The effects 
of DE-126 in IOP lowering appear to persist longer than those of latanoprost (Miller Ellis et al., 
2017). 
In 012601IN study, in both Japan- and US-based patients, DE-126 0.002% was identified as the 
optimal dose among the four concentrations assessed with respect to IOP lowering and safety 
profile.  The magnitude of IOP reduction was similar to that observed for latanoprost 0.005% at 
Month 3 and significantly greater than that of placebo at Week 6. Most AEs were mild in 
severity; AE incidence was lower with DE-126 concentrations 0.0005%, 0.001%, and 0.002% 
compared with latanoprost 0.005% or DE-126 0.003%. 
The most common adverse reaction from the previous Phase IIb 012601IN study was 
conjunctival hyperemia.  Since DE-126 is a potent dual agonist for both Prostaglandin F2α 
receptor and EP3 receptor, we have observed some similar side effects of Prostaglandin F2α 
analog (i.e., latanoprost).  It has been reported that latanoprost cause changes to pigmented 
tissues.  The most frequently reported changes have been increased pigmentation of the iris, 
periorbital tissue (eyelid) and eyelashes, and growth of eyelashes. 
DE-126 should be used with caution in patients with a history of intraocular inflammation 
(iritis/uveitis) and should generally not be used in patients with active intraocular inflammation. 
Macular edema, including cystoid macular edema, has been reported during treatment with 
latanoprost.  These reports have mainly occurred in aphakic patients, in pseudophakic patients 
with a torn posterior lens capsule, or in patients with known risk factors for macular edema. 
DE-126 should be used with caution in patients who do not have an intact posterior capsule or 
who have known risk factors for macular edema. 


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In summary, DE-126 is anticipated to provide clinically meaningful decrease in IOP in patients 
with open angle glaucoma or ocular hypertension.  The adverse reactions observed in patients 
receiving DE-126 were generally well-tolerated.  No serious suspected adverse reaction has been 
reported.  The severity and the frequency of the reported ocular AEs were not unexpected for a 
topical ophthalmic medication.  Consequently, benefit-risk balance continued to be favorable 
after taking into consideration the safety data from nonclinical assessment and clinical trials.  
Santen will continue to actively characterize the benefit: risk profile of DE-126. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AE of DE-126 may be found in the Investigator’s Brochure. 


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3. 
STUDY OBJECTIVES AND PURPOSE 
3.1. 
Primary Objective 
To investigate whether the IOP lowering efficacy of DE-126 ophthalmic solution 0.002% dosed 
once daily (QD, in the evening at 20:00) is non-inferior to that of Timolol maleate ophthalmic 
solution 0.5% dosed twice daily (08:00 and 20:00) in subjects with POAG or OHT after 
treatment for 3 months.  If non-inferiority is met, superiority will be tested. 
3.2. 
Secondary Objectives 
To compare the mean diurnal IOP between DE-126 ophthalmic solution 0.002% and Timolol 
maleate ophthalmic solution 0.5% after 3 months of treatment.  If non- inferiority is met, 
superiority will be tested. 
To evaluate the changes and percent changes in IOP from baseline at all post-baseline visits. 
To evaluate proportions of subjects achieving target pressure reductions expressed as either in 
percent reductions of ≥ 20%, ≥ 25%, or ≥ 30% or in achieving a target IOP value of IOP  
≤ 18 mmHg. 
3.3. 
Safety Objective 
To evaluate the safety of DE-126 ophthalmic solution 0.002% as compared to Timolol maleate 
ophthalmic solution 0.5% in subjects with POAG or OHT. 
3.4. 
Exploratory Objective 
To explore Quality of Life in subjects with POAG or OHT (using the Glaucoma Quality of Life 
(GQL)–15 Questionnaire) when given DE-126 or Timolol for 3 months. 
 


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4. 
STUDY DESIGN 
4.1. 
Overall Study Design 
This is a Phase IIb, randomized, double-masked, active-controlled, parallel-group, and 
multicenter study assessing the efficacy and safety of DE-126 ophthalmic solution 0.002% 
compared with Timolol maleate ophthalmic solution 0.5% in subjects with POAG or OHT. 
Subjects diagnosed with POAG 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 treatment for 3 months. 
Approximately 294 adult subjects with POAG or OHT who meet all eligibility criteria will be 
randomized in a 1:1 ratio to receive either: 
 DE-126 Ophthalmic Solution 0.002% QD (20:00) and Vehicle QD (08:00), or 
 Timolol Maleate Ophthalmic Solution 0.5% BID (20:00 and 08:00) 
In the Double-Masked Treatment Period, Timolol maleate ophthalmic solution 0.5% will be used 
as active control. 
 
Figure 1: 
Study Design 
   
 
 
See the study design diagram in Figure 1.  This study will consist of a Screening Period of up to 
35 days including a washout period of up to 28 days (+ 7 days window) and a 3-month Double-
Masked Treatment Period. 
At the Screening visit (Visit 1), subjects will be screened against the inclusion and exclusion 
criteria.  Eligible subjects will be instructed to discontinue use of all IOP-lowering medications, 
if any, during a washout period as follows (up to +7 days as a window is allowed):  


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 Miotics: 7 days 
 CAIs: 7 days 
 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 PGA: 28 days 
 Rho kinase inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will be 
used. 
Please note: Subjects are only allowed to be treated with a maximum of two active ingredients 
for IOP reduction prior to screening. 
During the required washout period, subjects who discontinue their current treatment may, if the 
Investigator deems it necessary, be treated with a short-acting IOP lowering agent, topical CAI, 
e.g., brinzolamide or dorzolamide eye drops, one drop twice daily.  Topical CAI treatment must 
be stopped 1 week before the randomization at Visit 2 (Baseline, Day 1).  An interim safety visit 
during the washout period (mid-washout visit; Optional Visit 1a) may be performed during the 
washout period if, in the Investigator’s opinion, a subject’s IOP may be of concern during the 
washout period.  If subjects are treated with a topical CAI during the washout period, mid-
washout visit (Optional Visit 1a) is recommended to be performed. 
Final eligibility for randomization will be determined at Visit 2 (Baseline, Day 1) after all 
necessary washout from prior IOP-lowering medications have been completed.   
At Visit 2 (Baseline, Day 1), baseline IOP will be measured for both eyes at 08:00 (±60 min), 
10:00 (±60 min), and 16:00 (±60 min).  The study eye will be the eye that qualifies per eligibility 
criteria at Visit 2 (Baseline, Day 1).  If both eyes meet the eligibility criteria, the eye with the 
higher mean diurnal IOP at Visit 2 (Baseline, Day 1) 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.  Both eyes should be treated with the study medication for the 
duration of the study, even if only one eye is eligible per IOP inclusion criteria. 
Please note: Visit 1 (Screening) and Visit 2 (Eligibility/Baseline, Day 1) may be combined into 
one visit for treatment-naïve subjects as long as the additional requirements of Visit 2 
(Eligibility/Baseline, Day 1) are fulfilled on the day of this combined visit; in particular, full 
diurnal IOP measurements (at 08:00, 10:00, 16:00) must be taken. 
Double-Masked Treatment Period (3 months): 
Approximately 294 eligible adult subjects will be randomized to receive either DE-126 
ophthalmic solution 0.002% QD in the evening and vehicle QD in the morning or Timolol 
maleate ophthalmic solution 0.5% BID in a 1:1 ratio.  Subjects will be treated for 3 months with 
scheduled visits at Visit 2 (Baseline, Day 1), 3 (Week 2), 4 (Week 6), and 5 (Month 3).  Subjects 


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will be contacted approximately 2 weeks post last study drug administration by a phone call to 
confirm AE.  
In the evening of Visit 2 (Baseline, Day 1), subjects will receive their first dose of study 
medication (study eye drops) as per their assigned/randomized study treatment at  
20:00 (±60 min).  The next day, subjects will subsequently dose with their assigned study 
medication at 08:00 (±60 min), and 20:00 (±60 min).  For the DE-126/Vehicle arm, the  
08:00 (±60 min) instillation will be DE-126 vehicle and the 20:00 (±60 min) instillation will be 
DE-126 ophthalmic solution 0.002%.  At each scheduled follow-up visit, subjects will receive 
their morning dose of study medication/eye drops following the 08:00 (±60 min) IOP 
measurement at the investigative site (the doctor’s office). 
IOP will be measured at 08:00 (±60 min), 10:00 (±60 min), and 16:00 (±60 min) at Visit 3 
(Week 2), Visit 4 (Week 6), and Visit 5 (Month 3).  At these scheduled visits, BCVA and  
slit-lamp biomicroscopy will be performed just prior to the 08:00 (±60 min) IOP measurement. 
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 5 (Month 3).  After the 
16:00 (±60 min) IOP measurement at Visit 5 (Month 3), ophthalmoscopy with the pupil dilated 
will be performed. Subjects will be contacted approximately 2 weeks post last study drug 
administration by a phone call to confirm AE. 
Pharmacogenomics/genomics: 
Subjects who consent to the optional PGx laboratory study will provide a blood sample for future 
testing. The earliest this sample is to be collected at Visit 3 (Week 2) but it may also be collected 
at any later time during the study after Visit 2 (Eligibility/Baseline) or at a separate post-study 
visit, if necessary.  The purpose of this exploratory research is to identify possible genetic 
markers associated with the study medication(s) and/or ocular conditions. 
4.2. 
Number of Subjects 
Approximately 294 subjects from approximately 45 sites in the U.S. are planned to be enrolled in 
this study. 
4.3. 
Treatment Assignment 
Subjects are randomized to one of two following treatment arms in a 1:1 ratio during the  
Double-Masked Treatment Period: 
 DE-126 ophthalmic solution 0.002% QD (20:00) and Vehicle QD (08:00) 
 Timolol maleate ophthalmic solution 0.5% BID (20:00 and 08:00) 
4.4. 
Schedule of Events and Procedures 
The schedule of events and procedures is provided in Table 3. 


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Table 3: 
Schedule of Events and Procedures 
 
Washout Period 
Double-Masked Treatment Period 
Follow-up Period 
Visit 1 
Screening * 
Optional 
Visit 1a 
Visit 2 
Eligibility/Baseline 
* 
Visit 3 
Week 2 
Visit 4 
Week 6 
Visit 5 Month 3 
Exit or Early 
Termination a 
2 weeks of post-Last 
Study Drug 
Administration 
Study day 
D-28 
D1 
D14 
D42 
D90 
Study Exit + D14 
Visit window in days 
+7 
NA 
±3 
±3 
±7 
+7 
Signed and dated informed consent b 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria b 
X 
 
X 
 
 
 
 
Demographics and Medical History,  
including prior PGA c 
X 
 
 
 
 
 
 
Other prior or Concomitant Medications/ and 
Therapies/Procedures 
X 
X 
X 
X 
X 
X 
 
Dosing Compliance Check 
 
 
 
X 
X 
X 
 
AEs d 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test e 
X 
 
X 
 
X 
X 
 
Vital Signs (blood pressure/pulse rate) f 
X 
 
X (08:00) 
 
 
X (08:00) 
 
Refraction g 
X 
 
 
 
 
 
 
BCVA g 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
 
Slit-lamp Biomicroscopy h 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
 
 
IOP i 
X 
X 
08:00 
08:00 
08:00 
08:00 
 
10:00 
10:00 
10:00 
10:00 
 
16:00 
16:00 
16:00 
16:00 
 
Pachymetry j 
X 
 
 
 
 
 
 
Instill study medication after IOP measurement at 
site by unmasked site staff and record dosing 
 
 
 
X (08:00) 
X (08:00) 
X (08:00) 
 
Gonioscopy k 
X 
 
 
 
 
 
 
Visual Field l 
X 
 
 
 
 
 
 


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Table 3: 
Schedule of Events and Procedures (Continued) 
 
Washout Period 
Double-Masked Treatment Period 
Follow-up Period 
Visit 1 
Screening 
Optional 
Visit 1a 
Visit 2 
Eligibility/Baseline 
Visit 3 
Week 2 
Visit 4 
Week 6 
Visit 5 Month 3 
Exit or Early 
Termination a 
2 weeks of post-Last 
Study Drug 
Administration 
Study day 
D-28 
D1 
D14 
D42 
D90 
Study Exit + D14 
Visit window in days 
+7 
NA 
±3 
±3 
±7 
+7 
Ophthalmoscopy m 
X 
 
X (16:00) 
 
 
X (16:00) 
 
Blood Sampling for PGx n 
 
 
 
X 
 
Dispense Study Medication & Diary 
 
 
X 
 
X 
 
 
Collect Study Medication & Diary 
 
 
 
 
X 
X 
 
Phone call o 
 
 
 
X 
X 
X 
X 
GQL-15 questionnaire p 
 
 
X 
 
 
X 
 
* Visit 1 (Screening) and Visit 2 (Eligibility/Baseline, Day 1) may be combined into one visit for treatment-naïve subjects as long as the additional requirements of Visit 2 
(Eligibility/Baseline, Day 1) are fulfilled on the day of this combined visit; in particular, full diurnal IOP measurements (at 08:00, 10:00, 16:00) must be taken.  
a Optional at unscheduled visit, required for early terminated subjects. 
b Informed Consent Form must be signed and dated before study procedures are performed. Informed consent for the optional PGx laboratory research study may be obtained at 
any visit prior to the study exit. 
c 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. 
d AE will be recorded starting after the signing of the informed consent form until 2 weeks post Last Study Drug Administration. Regardless of the source of the reported 
occurrence of an AE in a subject, the masked investigator will assess the causality of the AE. 
e A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
f Vital signs (resting blood pressure and pulse rate) will be collected in sitting position anytime at Visit 1 (Screening), and approximately at 08:00 for Visit 2 (Baseline, Day 1), and 
Visit 5 (Month 3)/exit or early termination before the morning dose. 
g Refraction will be performed at the screening visit anytime. 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. 
h Slit-lamp Biomicroscopy examination must be completed before IOP is measured at 08:00. Aqueous flare and cell evaluation will be performed before fluorescein instillation. 
i IOP measurements using Goldmann applanation tonometer will be performed at 08:00 (±60 min), 10:00 (±60 min), and 16:00 (±60 min) at all visits except for Visit 1 
(Screening), and Optional Visit 1a (mid-washout). 
j Pachymetry will be performed after IOP measurement at Visit 1 (Screening). 
k 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. If needed, Gonioscopy will be performed after IOP measurement at Visit 1 (Screening). 
l 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. 


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m Ophthalmoscopy with pupil dilated will be performed at Visit 1 (Screening) anytime, Visit 2 (Baseline), and Visit 5 (Month 3)/exit or early termination at the 16:00 (±60 min) 
after IOP measurements.   
n Blood sampling for the PGx laboratory research study may be performed at any visit after PGx informed consent obtained, subject randomized, and study drug dosing has begun. 
The earliest this sample is to be collected at Visit 3 (Week 2) but it may also be collected at any later time during the study after Visit 2 (Eligibility/Baseline) or at a separate 
post-study visit, if necessary. 
o At Visit 3, 4, and 5, subject will be reminded to take evening dose on the day before each visit. At Follow-up Period, subject will be contacted by a phone call to confirm AE after 
2 weeks post last study drug administration.  
p GQL-15 questionnaire will be administered by subject. 


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5. 
STUDY POPULATION 
Subjects must meet all eligibility (inclusion and exclusion) criteria. 
5.1. 
Subject Inclusion Criteria 
At Visit 1 (Screening), the subjects must meet all of the following inclusion criteria: 
1. Provide signed written informed consent on the IRB/EC approved ICF. 
2. Be 18 years of age or older on the date of signing the ICF and be able and willing to 
comply with all treatment and follow-up study procedures. 
3. If a subject is a female of childbearing potential (i.e., not post-menopausal [within  
12 months since the last menses] or not surgically sterile [less than 6 months from date of 
surgery]), she must have a negative urine pregnancy test and must use at least one of the 
following acceptable contraceptive methods during the study (as well as for 4 weeks 
following last dose in study). 
 Abstinence 
 Hormonal contraceptive method (including oral or transdermal contraceptives, 
injectable progesterone, progestin subdermal implants, progesterone-releasing 
intrauterine devices [IUDs]) initiated at least 28 days prior 
 Placement of a copper-containing IUD 
 Condom with spermicidal foam/gel/film/cream/suppository 
4. The male partner of the female subject of childbearing potential should use or practice an 
acceptable contraceptive method, such as abstinence, condom or vasectomy (surgery at 
least 6 months prior to signing the study ICF and beginning screening), or other 
contraception deemed adequate by the investigator during the study. 
5. Male subjects, with a female partner of childbearing potential, should use or practice an 
acceptable contraceptive method, such as abstinence, condom or vasectomy (surgery at 
least 6 months prior to signing the study ICF), or other contraception deemed adequate by 
the investigator during the study. 
6. Must have a diagnosis of POAG or OHT in both eyes, or one eye with OAG and the 
other with OHT. 
7. BCVA of +0.60 logMAR (Snellen equivalent 20/80) or better in each eye. 
8. Central corneal thickness ≥ 480 µm and ≤ 600 µm in each eye. 
9. Anterior chamber angle grade ≥ 2 (Shaffer scale) in each eye. 
In addition to continuing to meet inclusion criterion 7  (BCVA), the subject must meet the 
following criteria at Visit 2 (Baseline, Day 1): 
10. Completed the required wait/washout period (if required per protocol). 


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11. At all-time points of IOP measurements (08:00, 10:00, and 16:00) at Visit 2 (Baseline, 
Day 1), have IOP of ≥ 22 mmHg in at least one eye (the same eye), and ≤ 34 mmHg in 
both eyes. 
5.2. 
Subject Exclusion Criteria 
At Visit 1 (Screening) and Visit 2 (Baseline, Day 1), subjects with any of the following ocular 
conditions in either eye or with any of the following non-ocular conditions or characteristics are 
not eligible to participate in the study: 
General 
1. Females who are pregnant, nursing, or planning a pregnancy. 
2. Subjects with known or suspected drug or alcohol abuse. 
3. Participation in other investigational drugs (oral or topical therapy) or device clinical 
trials within 28 days prior to Visit 2 (Baseline, Day 1) and/or participation in other 
investigational drugs (intravitreal injection therapy) within 3 months or 5 half-lives 
(whichever is longer) prior to Day 1 or planning to participate in other investigational 
drug or device clinical trials during a time which would overlap with the duration of the 
study.  This includes both ocular and no-ocular clinical trials.  Exposure to investigational 
biologics should be discussed with the medical monitor. 
Medications / Therapies 
4. Subjects who cannot safely discontinue use of ocular hypotensive medications during the 
wait/washout period. 
5. Subjects who will be required to initiate or modify any systemic or topical medication 
known to affect IOP (e.g., β-adrenergic antagonists, α-adrenergic agonists, calcium 
channel blockers, angiotensin-converting enzyme [ACE] inhibitors, and angiotensin II 
receptor blockers [ARBs]).  Subjects using the above medications must be on a stable 
dose use for at least 28 days prior to Visit 2 (Baseline, Day 1) and the duration of the 
study. 
6. Intended or current use of the following prohibited medications/therapies during the 
study duration: 
 All ocular medications other than sodium chloride/potassium chloride ophthalmic 
solution, cataract treatment agents (e.g., glutathione, pirenoxine), Vitamin B12 
formulation (e.g., cyanocobalamine), over-the-counter dry eye artificial tears/drops, 
and study medications. 
 All systemic medications for ocular hypotensive (e.g., oral or intravenous CAI, oral 
glycerol). 
 Any ocular, periocular, inhaled, nasal, or systemic corticosteroids (excluding joint 
injections). 
 Lacrimal/punctual occlusion via plug (s) or cautery. 
7. History of ocular surgery specifically intended to lower IOP (e.g., laser trabeculoplasty, 
filtering surgery, tube shunt, MIGS, or trabeculotomy) in either eye. Please note that laser 
iridotomy in history is allowed. 


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8. History of keratorefractive surgery (e.g., radial keratotomy [RK], photorefractive 
keratectomy [PRK], laser-assisted-in-situ keratomileusis [LASIK]) in either eye. 
9. Use of contact lenses within 1-2 weeks prior to Visit 2 (Baseline, Day 1) until end of 
treatment in either eye (1 week for soft contact lens wearers, and/or 2 weeks for rigid 
contact lens wearers). 
10. Any ocular surgery within 180 days prior to Visit 2 (Baseline, Day 1) and throughout the 
study in either eye. 
Diseases 
11. Presence of advanced glaucoma (e.g., visual field mean deviation worse than -12 dB) in 
either eye. 
12. Presence of any corneal abnormality or other conditions interfering with or preventing 
reliable Goldmann applanation tonometry (e.g., Fuch’s dystrophy or significant corneal 
surface abnormality) in either eye. 
13. Presence of any active severe external ocular disease, inflammation, or infection of the 
eye and/or eyelids in either eye. 
14. Presence of any lid structural abnormalities such as Ectropion or entropion at Visit 1 
(Screening). 
15.  History of iritis and/or uveitis, corneal inflammatory conditions, and/or viral infection, 
such as herpes simplex virus (HSV), in either eye; history of adenovirus infection is not 
an exclusion criterion if no associated inflammation has been observed within 6 months 
prior to Visit 1 (Screening). 
16. Aphakia, pseudophakia with a torn posterior lens capsule, history or presence of macular 
edema or known risk factors (e.g., retinal vein occlusion, diabetic retinopathy, uveitis, 
age-related macular degeneration) for macular edema in either eye. 
17. History of severe ocular trauma in either eye. 
18. Any condition that prevents clear visualization of the fundus in either eye. 
19. History of retinal detachment, proliferative diabetic retinopathy, or any retinal disease 
that may be progressive during the time course of the study in either eye. 
20. Presence or history of any disease or condition that in the opinion of the study 
investigator may put the subject at significant risk may confound study results or may 
interfere significantly with the subject’s participation in the study (e.g., recurrent corneal 
erosion syndrome, uncontrolled cardiovascular disease, etc.). 
21. Subjects with a history or presence of contraindications to prostaglandins, beta-blockers, 
or any other components (e.g., Benzalkonium Chloride [BAK]) of the study medication 
or other study-related procedures /medication.  Specifically, contraindications to beta-
blockers include e.g. 
 chronic obstructive pulmonary disease (e.g., chronic bronchitis, emphysema) 
 bronchial asthma 


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 second or third degree atrioventricular block  
 uncontrolled congestive heart failure 
22. Any decision by the Investigator or Medical Monitor to terminate a subject in screening 
or declare any subject ineligible for any sound medical reason. 
23. Use of marijuana and/or marijuana derivatives within 28 days prior to Visit 2 (Baseline, 
Day 1); including, but not limited to, cannabidiol topical eye drops. 


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6. 
STUDY INTERVENTION 
6.1. 
Study Medication 
6.1.1. 
Investigational Product 
DE-126 Ophthalmic Solution contains 0.002% DE-126.  Each 5 mL bottle of DE-126 
Ophthalmic Solution 0.002% contains 50 μg of DE-126.
 
6.1.2. 
Vehicle 
The vehicle is identical to the investigational product but does not contain the active ingredient 
in DE-126. 
6.1.3. 
Active Control 
The active control used in this clinical study, Timolol Maleate Ophthalmic Solution 0.5%, is 
supplied as a sterile, isotonic, buffered aqueous solution. 
Timolol Maleate Ophthalmic Solution 0.5% contains the active ingredient, Timolol 5 mg/ml, and 
the preservative BAK 0.01%.  Other ingredients include monobasic and dibasic sodium 
phosphate and purified water.  The pH is adjusted to 6.5 to 7.5 with sodium hydroxide. 
6.2. 
Preparation/Handling/Storage/Accountability  
6.2.1. 
Study Medication Packaging and Labeling 
DE-126 ophthalmic solution, 0.002%, and DE-126 vehicle ophthalmic solution will be supplied 
as 
 
Timolol Maleate Ophthalmic Solution 0.5% will be supplied as a 5 mL solution in a 5 mL white 
low density polyethylene bottle. 
Each eye drop bottle will be placed in a unit carton.  Four DE-126 eye drop bottles/unit cartons 
of study medication will be placed in one DE-126 kit.  Two Timolol eye drop bottles/unit cartons 
of study medication will be placed in one Timolol kit.  The eye drop bottles, unit cartons, and the 
kit will be labeled with the protocol number, kit number, storage conditions, and dosing 
instructions. 
Kits dispensed at Visit 2 (Baseline, Day 1) and Visit 4 (Week 6) will contain “morning” eye drop 
bottles and “evening” eye drop bottles of DE-126 study medication, or “morning/evening” 
Timolol maleate eye drop bottles of Timolol maleate study medication. 
An authorized unmasked study staff member, other than the Investigator or Examiner, will 
dispense and collect study medications.  When collecting the study medications, the kit 
containing all the used and unused eye drop bottles will be sealed. 


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6.2.2. 
Study Medication Storage 
All study medication will be provided by Santen and will be stored in an appropriate secure area 
at the investigational site. 
Study medications should be stored under refrigeration at 2° to 8°C (36° to 46°F), protected from 
light, and stored upright.  During the refrigeration storage, the Investigator (or his/her designee) 
will verify and record that the temperature was maintained at 2° to 8°C (36° to 46°F) using 
temperature recorder.  In the event of a temperature excursion or any study medications damaged 
during storage, the Investigator (or his/her designee) will notify Santen (or designee) and will not 
dispense the study medications until obtaining authorization from Santen (or designee). 
Subjects will be reminded to store all dispensed eye drop bottles under refrigeration, protected 
from light, and kept in unit cartons in an upright position. Study medications should not be 
frozen. 
6.2.3. 
Study Medication Preparation 
The study medications will arrive at the site prepared for instillation. 
6.2.4. 
Study Medication Administration 
During the Double-Masked Treatment Period, subjects will instill one drop of study medication 
in each eye at approximately 20:00 (±60min) and 08:00 (±60min) daily for 3 months.  
6.2.5. 
Study Medication Accountability 
The Principal Investigator is responsible for ensuring that an inventory is conducted upon receipt 
of the clinical supplies.  The temperature chart recorder from the shipment will be deactivated, 
and the Investigator (or his/her designee) will verify that the temperature was maintained at  
2° to 8°C (36° to 46°F) during transit.  In the event of a temperature excursion or any study 
medications damaged during transit, the Investigator (or his/her designee) will notify Santen  
(or designee) and will not dispense the study medications until obtaining authorization from 
Santen (or designee).  The receipt of clinical supplies form should be completed, signed, dated, 
and returned as directed.  A copy must be maintained at the site for the Investigator’s records. 
The Investigator (or his/her designee) will keep a current record of the inventory, storage 
conditions and dispensing of all study medications.  This record will be made available to Santen 
(or designee) for the purpose of accounting for all clinical supplies.  Any significant discrepancy 
and/or deficiency must be recorded with an explanation. 
All supplies sent to the investigational site must be accounted for and in no case will study 
medications be used in any unauthorized situation.  It is the responsibility of the Investigator to 
ensure that any used and unused supplies are available to Santen (or designee) for accountability 
purposes throughout the study. 
6.2.6. 
Study Medication Handling and Disposal 
The used study medication kits will be stored at room temperature and the unused study 
medication kits will be refrigerated until final study medication accountability has been 
completed by Santen (or designee).  Following final study medication accountability and 


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reconciliation by Santen (or designee), all used and unused study medication will be returned to 
the assigned central drug depot, or destroyed at the site at the direction of Santen. 
6.2.7. 
Study Supplies 
Customized blood sample collection kits for the PGx and urine pregnancy kit will be provided by 
Santen (or designee). 
6.3. 
Concomitant Medications or Therapies 
Medication or therapy considered necessary for the subject’s welfare may be given at the 
discretion of the Investigator. Subjects may continue participation in the study if the instituted 
medication or therapy will not interfere with the evaluation of the study medication. Whenever 
possible, medications should be administered in dosages that remain constant throughout the 
study. Any treatment other than the study medication during the study duration will be 
considered as a concomitant treatment. The information of concomitant treatment must be 
recorded in the subject’s source documents and on the eCRF.  
 Concomitant medication: name of medication, route of administration, treated eye(s) 
(if applicable), dose, frequency, indication, start date, and stop date. 
 Concomitant therapy: name of therapy, treated eye(s) (if applicable), indication, start 
date, and stop date. 
6.3.1. 
Prohibited Medications or Therapies 
 All ocular medications other than sodium chloride/potassium chloride ophthalmic 
solution, cataract treatment agents (e.g., glutathione, pirenoxine), Vitamin B12 
formulation (e.g., cyanocobalamine), over-the-counter dry eye artificial tears/drops, 
and study medications during the study duration. 
 If artificial sodium chloride/potassium chloride ophthalmic solution, cataract 
treatment agents, Vitamin B12 formulation, over-the-counter dry eye artificial 
tears/drops are concomitantly used, there must be an interval of at least 10 
minutes between use of the study medication and these ocular medications (the 
study medication to be given first). 
 All systemic medications for ocular hypotensive (e.g., oral or intravenous CAI, oral 
glycerol) during the study duration. 
 Any ocular, periocular, inhaled, nasal, or systemic corticosteroids (excluding joint 
injection), etc. during the study duration. 
 Lacrimal/punctual occlusion via plug (s) or cautery during the study duration. 
 Initiate or modify any systemic or topical medication known to affect IOP  
(e.g., β-adrenergic antagonists, α-adrenergic agonists, calcium channel blockers, ACE 
inhibitors, and ARB) within the first 28 days prior to Visit 2 (Baseline, Day 1) and 
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 Contact lenses within 1-2 weeks prior to Visit 2 (Baseline, Day 1) until end of 
treatment in either eye (1 week for soft contact lens wearers, and/or 2 weeks for rigid 
contact lens wearers). 
 Any ocular surgery or ocular laser treatment within 180 days prior to Visit 2 
(Baseline, Day 1) and throughout the study in either eye. 
 Participation in other investigational drugs (oral or topical therapy) or device clinical 
trials within 28 days prior to Visit 2 (Baseline, Day 1) and/or participation in other 
investigational drugs (intravitreal injection therapy) within 3 months or 5 half-lives 
(whichever is longer) prior to Day 1 or planning to participate in other investigational 
drug or device clinical trials during a time which would overlap with the duration of 
the study.  This includes both ocular and no-ocular clinical trials.  Exposure to 
investigational biologics should be discussed with the medical monitor. 
The decision to administer a prohibited medication or therapy should be made with the safety of 
the subject as the primary consideration.  Whenever possible, Medical Monitor or designee 
should be notified before any prohibited medication or therapy is administered.  There may be 
additional prohibited therapies not mentioned above.  Medical Monitor or designee should be 
contacted if the permissibility of a specific medication or therapy is in question. 
6.4. 
Treatment Compliance 
To obtain reliable efficacy and safety data, the following precautions will be taken to ensure 
compliance with the treatment regimen during the study: 
 Subjects will receive verbal and written instructions for proper instillation of the 
study medication, the dosing regimen, and the conditions of the study medication 
storage.  
 Subject will record daily medication instillation into paper subject diary. 
 Subjects will be reminded at study visits to consistently dose at the same time of the 
day 
 Twice daily at 08:00 and 20:00 [±60min] through Visit 2 (Baseline, Day 1) to 
Visit 5 (Month 3). 
 Subjects will be reminded of the evening instillation of the study drug on the day 
before Visit 3 (Week 2) through Visit 5 (Month 3)/Early Termination respectively. 
 Subjects will be reminded that the morning instillation of the study drug at each visit 
through Visit 3 (Week 2) to 5 (Month 3) will be done at the site. 
 Subjects will be queried regarding compliance with the protocol’s dosing regimen at 
Visit 3 (Week 2) through Visit 5 (Month 3)/Early Termination. 
 Subjects will be counseled on proper dosing procedures and dosing schedule if the 
subject’s compliance is not 100%. 
 A subject’s dosing compliance for a specific period is determined by the total number 
of days that subject followed the proper dosing procedures and dosing schedule.  
Stoppage of study medication use, overdosing of study medication, incorrect time of 


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study medication administration, will be noted as non-compliance.  The subject’s 
dosing compliance will be recorded in the subject’s source documents at Visit 3 
(Week 2) through Visit 5 (Month 3)/Early Termination.  
 Subjects may be discontinued from the study at the discretion of the Investigator if 
the subject cannot be brought into compliance. 
6.5. 
Randomization and Masking 
A stratified permuted-block randomization will be employed to randomize eligible subjects in a 
1:1 ratio to either DE-126/Vehicle arm or Timolol Maleate arm.  The randomization will be 
stratified by mean diurnal IOP in the study eye at baseline visit (Visit 2): <25 mmHg vs.  
≥25 mmHg. 
The randomization schedule will be generated and implemented using central randomization via 
Interactive Response Technology (Medidata Rave RTSM).  Each randomized subject will 
receive numbered study medication kits as assigned by Medidata Rave RTSM. 
This is a double-masked study.  The subjects, Investigators, Examiners, and Santen personnel 
involved in the conduct of the study will be masked to the study treatment.  An authorized 
unmasked study staff member at the investigative site who is not the Investigator or Examiner 
will dispense and collect study medication(s) and will query about dosing compliance. 
Subjects will be instructed not to show the eye drop bottles or discuss the eye drop to either the 
Investigator or the Examiner or other study subjects.  The active control treatment (Timolol 
Maleate) containers will be over-labeled and packaged in the same secondary package  
(e.g., cardboard kit carton) as the investigational treatment (DE-126).  Subjects on  
DE-126/Vehicle arm will receive a kit containing 2 bottles labeled “morning” for the morning 
dose and 2 bottles labeled “evening” for the evening dose.  Subjects on Timolol arm will receive 
a kit containing 2 bottles labeled morning/evening for the BID dosing.  
Each eligible subject will receive a numbered study medication kit assigned by Central 
randomization via Interactive Response Technology (Medidata Rave RTSM) at Visit 2 
(Baseline, Day 1) and at Visit 4 (Week 6). 
In case of a medical emergency, the Principal Investigator may reveal the treatment information 
by unmasking through Medidata Rave RTSM to know which treatment the subject has received.  
The Principal Investigator (or his/her designee) should contact Santen, or Santen’s designee, 
before taking this measure, if there is sufficient time. Santen, or Santen’s designee, must be 
informed of all instances where the code is broken and of the reasons for such instances. 
Additionally, the AE or SAE for which study treatment was unmasked should be reported to 
Santen Pharmacovigilance. 


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7. 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL FROM STUDY 
7.1. 
Subject Early Discontinuation/Withdrawal from the Study 
An early termination occurs when a subject who provides written informed consent ceases 
participation in the study, regardless of circumstances, before the completion of the study.  
Subjects may be voluntarily discontinued from study medication or withdrawn from the study at 
any time for any reason.  In addition, the Principal Investigator or Medical Monitor or designee 
may discontinue the study drug administration or terminate a subject’s study participation due to 
any of the following reasons: 
 AE (e.g., not compatible with study continuation) 
 Non-compliance with study drug 
 Lack of efficacy (e.g., IOP exceeds 34 mmHg in either eye after randomization) 
 Progressive disease 
 Protocol deviation (e.g., not fulfilling eligibility criteria) 
 Pregnancy 
 Voluntary withdrawal by subject at any time for any reason 
 Lost to follow-up (e.g., no contact is possible) 
 Death 
 Other 
If the study drug administration is discontinued prior to Visit 5, they should be encouraged to 
still participate in all follow-up study visits until Visit 5 on an observational basis. 
If the study drug administration is discontinued prior to Visit 5, then to the extent possible, all 
procedures for Early Termination will be performed on the day of early drug discontinuation as 
per Table 3.  Subjects who are discontinued from the study early will not be replaced. 
7.2. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  The following actions must be taken if a 
subject fails to return to the clinic for a required study visit: 
 The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study. 
 Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and, 
if necessary, a certified letter to the subject’s last known mailing address or local 


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equivalent methods).  These contact attempts should be documented in the subject’s 
medical record. 
 Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or discontinuation of the study is handled as indicated in 
Section 10.8. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Visit Details 
The Schedule of Events and Procedures Table 3 provides a high-level overview of the visits.  
The sections below provide visit guidance/details by visit.  
8.1.1. 
Visit 1 (Screening) 
 Explain the purpose and conduct of the study to the subject and obtain written 
individual informed consent.  Informed consent for the optional PGx consent may 
sign at screening yet laboratory research study must be obtained after subject Visit 2 
(Baseline, Day 1) at any visit.  Ensure the subject understands that if he/she does not 
wish to provide a blood sample for the PGx laboratory research study that their 
decision will have no influence on their participation in the main study. 
 Prepare the list of screening/registration of subjects. 
 Obtain demographics. 
 Obtain medications, procedures/therapies, and medical history including all lifetime 
ocular medical history to the extent possible, non-ocular medical history within  
5 years, diagnosis, ocular surgical history, current ocular, and systemic conditions. 
 Obtain urine and perform a urine pregnancy test, if the subject is a female of child-
bearing potential. 
 Query the subject regarding AEs 
 As per Schedule of Events and Procedures (Table 3), perform the following 
procedures or assessments (all ophthalmic procedures to be performed in both eyes): 
 Vital signs (blood pressure/pulse rate)  
 Refraction  
 BCVA (before IOP measurement) 
 Slit-lamp biomicroscopy (before IOP measurement) 
 IOP 
 Pachymetry (after IOP measurement)  
 Gonioscopy (only if no gonioscopy was performed within 3 months [90 days] 
prior to screening and documented in the subject’s records). If needed, 
gonioscopy will be performed after IOP measurement. 
  
 Visual field (only if no visual field test was performed within 3 months [90 days] 
prior to screening and documented in the subject’s records). If needed, visual field 
test will be performed before IOP, pachymetry, and gonioscopy (if applicable). 
 Ophthalmoscopy with pupil dilation (after IOP measurement) 


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 Determine if the subject meets eligibility criteria. 
 If the subject meets eligibility criteria and is still willing to continue the study, 
discontinue current IOP-lowering medications, if any, according to the following 
schedule (up to +7 days as a window is allowed): 
 Miotics: 7 days 
 Oral/topical CAIs: 7 days 
 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandin Analogs: 28 days 
 Rho kinase inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will 
be used. Please note: Subjects are only allowed to be treated with a maximum of 
two active ingredients for IOP reduction prior to screening. 
 During the required washout period, subjects who discontinue their current treatment 
may, if the Investigator deems it necessary for safety, be treated with a topical CAI, 
e.g., brinzolamide or dorzolamide eye drops, one drop twice daily. Topical CAI 
treatment must stop 7 days before the randomization at Visit 2 (Baseline, Day 1). 
 An interim safety visit, mid-washout visit (Optional Visit 1a), may be performed 
during the washout period if, in the Investigator’s opinion, a subject’s IOP causes any 
safety concerns during the washout period. If subjects are to be treated with topical 
CAI in the week before Visit 2 (Baseline, Day 1), mid washout visit (Optional Visit 
1a) is recommended to be performed. 
 The eligibility visit (Visit 2 (Baseline, Day 1)) will be scheduled at the end of the 
washout period for those subjects on prior IOP-lowering medications. 
 Subjects who have not used an IOP-lowering medication for the last 28 days, 
including treatment-naïve subjects, may be combined Visit 1 (Screening) and Visit 2 
(Eligibility/Baseline, Day 1) into one visit. Subjects must fulfill on the day of this 
combined visit; in particular, full diurnal IOP measurements (at 08:00, 10:00, 16:00) 
must be taken. 
 If a subject does not require washout from an IOP-lowering medication, but they 
use contact lenses in either eye, they will need a wait period of ≥ 1-2 weeks  
(1 week for soft contact lens wearers, and 2 weeks for rigid contact lens wearers) 
with no contact use before their Visit 2 (Baseline, Day 1). 
 Schedule the eligible subject to return for Visit 2 (Baseline, Day 1) after the required 
wait/washout period. 


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 A subject who does not meet eligibility criteria or will not otherwise continue in the 
study is considered a screen failure. 
8.1.2. 
Optional Visit 1a 
 Optional Visit 1a is an interim safety visit (referred to as mid-washout visit) that may 
be performed during the washout period if, in the Investigator’s opinion, a subject’s 
IOP causes any safety concern during washout period. 
 Update concomitant medications and procedures/therapies. 
 Query the subject regarding AEs. 
 As per Schedule of Events and Procedures (Table 3), perform the following 
procedures or assessments (all ophthalmic procedures to be performed in both eyes): 
 BCVA (before IOP measurement) 
 Slit-lamp biomicroscopy (before IOP measurement) 
 IOP 
8.1.3. 
Visit 2 (Baseline, Day 1) 
 Update concomitant medications and procedures/therapies. 
 Confirm the subject has complied with the required wait/washout period for ocular 
hypotensive medication(s), or contact lenses use, if required. 
 Query the subject regarding AEs. 
 As per Schedule of Events and Procedures (Table 3), perform the following 
procedures or assessments immediately before the 08:00 (±60 min) IOP measurement 
(all ophthalmic procedures to be performed in both eyes): 
 BCVA (before the 08:00 (±60 min) IOP measurement). 
▪ If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Slit-lamp biomicroscopy (before the 08:00 (±60 min) IOP measurement). 
 Perform vital signs (blood pressure/pulse rate) measurements (before the 08:00 
(±60 min) IOP measurement). 
 Obtain urine and perform a urine pregnancy test, if the subject is a female of  
childbearing potential (before the 08:00 (±60 min) IOP measurement). 
 Perform IOP measurement at 08:00 (±60 min). 
 If subject meets the 08:00 IOP eligibility requirements, schedule additional IOP 
measurements at 10:00. 
 Perform IOP measurement at 10:00 (±60 min). 
 If subject meets the 08:00 and 10:00 IOP eligibility requirements, schedule additional 
IOP measurements at 16:00. 


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 Perform GQL-15 questionnaire at any time during this visit prior to 16:00 IOP 
measurement. 
 Perform IOP measurement at 16:00 (±60 min). 
 Perform pupil dilation in both eyes after the 16:00 (±60 min) IOP measurement. 
 Perform ophthalmoscopy with pupil dilation in both eyes immediately after the  
16:00 (±60 min) IOP measurement. 
 Perform final review of eligibility criteria after the 16:00 (±60 min) IOP 
measurement.  The subject will then be randomized, via Medidata Rave RTSM. 
 A subject who does not meet eligibility criteria or will not otherwise continue in the 
study is considered a screen failure. 
 After the subject has been randomized to a treatment arm, and assigned a treatment 
kit by Medidata Rave RTSM, an authorized unmasked study staff member, other than 
the Investigator or Examiner, must: 
 Dispense the assigned kit to the subject which will contain the following:  
▪ Two bottles of study drug labeled “morning” and 
▪ Two bottles of study drug labeled “evening” 
OR 
▪ Two bottles of study drug labeled morning/evening. 
 Give the subject verbal and written instructions for proper instillation of the study 
medication, the dosing regimen, and study medication storage.  
 Provide paper subject diary to subject and provide instructions to record daily 
medication instillation.  
 Instruct the subject not to show or discuss their study medication with other study 
staff including the Investigator or Examiner, or other study subjects. 
 Instruct the subject to instill the study medicine daily in both eyes, starting from this 
evening (“evening” dose) (20:00).  
 Schedule the subject to return on Visit 3 (Week 2, Day 14 ±3). 
 Inform the subjects they will be reminded of the evening instillation of the study 
medication by a phone call a few days before Visit 3 (Week 2). 
 Remind the subjects that the morning dose of Visit 3 (Week 2) will be done at the 
site. 
8.1.4. 
Visit 3 (Week 2, Day 14 ±3) 
 Update concomitant medications and procedures/therapies. 
 An authorized unmasked study staff member, other than the Investigator or Examiner 
should query the subject regarding dosing compliance, check the subject paper diary 


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of daily medication recording, and ensure subject has sufficient study medication to 
complete dosing through Visit 4 (Week 6). 
 Query the subject regarding AEs. 
 As per Schedule of Events and Procedures (Table 3), perform the following 
procedures or assessments immediately before the 08:00 (±60 min) IOP measurement  
(all ophthalmic procedures to be performed in both eyes): 
 BCVA (before the 08:00 (±60 min) IOP measurement) 
▪ If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Slit-lamp biomicroscopy (before the 08:00 (±60 min) IOP measurement) 
 Perform IOP measurement at 08:00 (±60 min). 
 Instill study medication/eye drop after the 08:00 IOP measurement in both eyes. 
Authorized unmasked study staff should make sure the instillation is performed. 
Record the morning medication in the subject diary.  
 Perform IOP measurement at 10:00 (±60 min), and 16:00 (±60 min). 
 If the subject provided written consent to provide a blood sample for a future PGx 
laboratory research study, collect the sample at this visit or subsequent visit prior to 
exit from the study. 
 Note: If a blood sample cannot be collected at this visit, it may be collected at any 
one of the following visits, for example, Visit 4, 5, or unscheduled or early 
termination visit, provided the subject has written consent prior to collection of 
the sample. 
 Schedule the subject to return on Day 42±3 for Visit 4 (Week 6). 
 Remind the subject to continue dosing according to the written instructions. 
 Inform the subjects they will be reminded of the evening instillation of the study 
medication by a phone call a few days before Visit 4 (Week 6). 
 Remind the subjects that the morning dose of Visit 4 (Week 6) will be done at the 
site. 
 Remind the subject to bring all used and unused study medication and subject diary at 
Visit 4 (Week 6). 
8.1.5. 
Visit 4 (Week 6, Day 42 ±3) 
 Update concomitant medications and procedures/therapies. 
 An authorized unmasked study staff member, other than the Investigator or Examiner 
should query the subject regarding dosing compliance and check the subject paper 
diary of daily medication recording. 
 Query the subject regarding AEs. 


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 As per Schedule of Events and Procedures (Table 3), perform the following 
procedures or assessments immediately before the 08:00 (±60 min) IOP measurement  
(all ophthalmic procedures to be performed in both eyes): 
 BCVA (before the 08:00 (±60 min) IOP measurement) 
▪ If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Slit-lamp biomicroscopy (before the 08:00 (±60 min) IOP measurement) 
 Obtain urine and perform a urine pregnancy test if the subject is a female of 
childbearing potential (before the 08:00 (±60 min) IOP measurement). 
 Perform IOP measurement at 08:00 (±60 min). 
 Instill study medication/eye drop after the 08:00 IOP measurement in both eyes. 
Authorized unmasked study staff should make sure the instillation is performed. 
Record the morning medication in subject diary. 
 Perform IOP measurement at 10:00 (±60 min), and 16:00 (±60 min). 
 An authorized unmasked study staff member, other than the Investigator or Examiner, 
must: 
 Collect all used and unused bottles of study medication. 
 Collect the paper subject diary. 
 Dispense the assigned kit (from Medidata Rave RTSM) to the subject which will 
contain the following:  
▪ Two bottles of study drug labeled “morning” and 
▪ Two bottles of study drug labeled “evening” 
OR 
▪ Two bottles of study drug labeled morning/evening. 
 Instruct the subject not to show or discuss their study medication with other study 
staff including the Investigator or Examiner, or other study subjects. 
 Provide paper subject diary to subject and provide instructions to record daily 
medication instillation. 
 If the subject provided written consent to provide a blood sample for a future PGx 
laboratory research study, the sample may be collected at this visit or subsequent visit 
prior to exit from the study, if not collected at the previous visit. 
 Schedule the subject to return on Day 90±7 for Visit 5 (Month 3). 
 Remind the subject to continue dosing according to the written instructions. 
 Inform the subjects they will be reminded of the evening instillation of the study 
medication by a phone call a few days before Visit 5 (Month 3). 


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 Remind the subjects that the morning dose of Visit 5 (Month 3) will be done at the 
site. 
 Remind the subject to bring all used and unused study medication and subject diary at 
Visit 5 (Month 3). 
8.1.6. 
Visit 5 (Month 3, Day 90 ±7) / Study Exit/ Early Termination 
 Update concomitant medications and procedures/therapies. 
 An authorized unmasked study staff member, other than the Investigator or Examiner 
should query the subject regarding dosing compliance and check the subject paper 
diary of daily medication recording. 
 Query the subject regarding AEs. 
 As per Schedule of Events and Procedures (Table 3), perform the following 
procedures or assessments immediately before the 08:00 (±60 min) IOP measurement  
(all ophthalmic procedures to be performed in both eyes): 
 BCVA (before the 08:00 (±60 min) IOP measurement) 
▪ If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Slit-lamp biomicroscopy (before the 08:00 (±60 min) IOP measurement) 
 Perform vital signs (blood pressure/pulse rate) measurements (before the 08:00 
(±60 min) IOP measurement). 
 Obtain urine and perform a urine pregnancy test, if the subject is a female of  
childbearing potential (before the 08:00 (±60 min) IOP measurement). 
 Perform IOP measurement at 08:00 (±60 min). 
 Instill study medication/eye drop after the 08:00 IOP measurement in both eyes. 
Authorized unmasked study staff should make sure the instillation is performed. 
Record the morning medication in subject diary. 
 Perform IOP measurement at 10:00 (±60 min), and 16:00 (±60 min). 
 Perform pupil dilation in both eyes after the 16:00 (±60 min) IOP measurement. 
 Perform ophthalmoscopy with pupil dilation in both eyes immediately after the  
16:00 IOP measurement. 
 Perform GQL-15 questionnaire at any time during this visit. 
 An authorized unmasked study staff member, other than the Investigator or Examiner, 
must: 
 Collect all used and unused bottles of study medication. 
 Collect the paper subject diary. 


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 If the subject provided written consent to provide a blood sample for a future PGx 
laboratory research study, the sample must be collected at this visit, if not collected at 
the previous visits. 
 Exit the subject from the study. 
 Inform the subjects they will be contacted to confirm AEs by phone call 
approximately 2 weeks post last study drug administration. 
Note: 
 If the study drug administration is discontinued prior to Visit 5, then to the 
extent possible, all procedures for Study Exit/Early Termination as per Table 3 
will be performed on the day of early termination. Subjects who are 
discontinued from the study early will not be replaced. 
 If subject requires an unscheduled visit, procedures and assessments will be 
performed as needed. 
8.1.7. 
Follow-up (2 Weeks +7 days Post Last Study Drug Administration) 
 After 2 weeks post last study drug administration, a follow-up phone call visit will be 
conducted. 
8.2. 
Study Termination 
Santen may stop this study at any time by appropriate notification. 
8.3. 
Efficacy Parameter 
The IOP (mmHg) measured in the study eye (identified by the IOP values at baseline visit) is the 
efficacy measure for this study.  The IOP at each scheduled time point (08:00, 10:00, and 16:00) 
will be evaluated at each post-baseline visit.  Besides observed IOP measurements, change and 
percent change from baseline in IOP at each scheduled time point as well as the change and 
percent change from baseline in mean diurnal IOP will also be derived and evaluated. 
8.4. 
Safety Parameters 
In addition to observed values, changes from baseline will be evaluated at relevant post baseline 
visits.  For a safety outcome measure, the baseline value will be the last observation of that 
outcome measure prior to the first dose of study medication. 
8.4.1. 
Ocular Assessments 
Ocular assessments include: 
 BCVA 
 Slit-lamp biomicroscopy findings: anterior chamber cells, anterior chamber flare, lid 
hyperemia, lid edema, conjunctival hyperemia, conjunctival chemosis, corneal 
edema, corneal staining, keratic precipitate, lens, anterior synechiae of iris, posterior 
synechiae of iris, iris color abnormalities, eyelash abnormalities, and eyelid 
abnormalities 


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 Ophthalmoscopy variables: glaucomatous optic nerve 
8.4.2. 
Non-ocular Assessments 
Non-Ocular assessments include: 
 Vital Signs (blood pressure and pulse rate) 
8.5. 
Other Assessments 
8.5.1. 
Demographic and Other Assessments 
Subject demographics, medical history, concomitant medications, and exposure to study 
medication will be summarized. 
8.5.2. 
Pharmacogenomics/Genomics 
For future exploratory research, blood sample will be collected from the participants who have 
consented to participate in the collection.  
8.5.3. 
Glaucoma Quality of Life (GQL-15) Questionnaire 
The GQL-15 (Section 12.6, Appendix F) is a 15-item questionnaire assessing the quality of life 
in glaucoma patients by measuring the severity of visual disability.  The GQL-15 will be 
completed by the subject at Baseline (Visit 2, Day 1) and Month 3 (Visit 5).  The GQL-15 
questionnaire will be used as an exploratory outcome in this study. 
8.6. 
Assessment of Safety 
8.6.1. 
Adverse Events and Serious Adverse Events 
8.6.1.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the study 
intervention.  An AE does not necessarily have a causal relationship with the study medication.  
For this study, the investigational products are DE-126, DE-126 vehicle, and Timolol.  
Regardless of relationship to the study medication, an AE can be a clinically relevant unintended 
sign (including an abnormal laboratory finding), symptom, or disease. 
Any significant change in a subject’s condition from the time that written informed consent is 
obtained, regardless of causality, is to be considered an AE.  A clinically significant worsening in 
severity, intensity, or frequency of a pre-existing condition may indicate an AE. 
An elective surgical procedure scheduled or planned prior to study entry that does not require 
overnight hospitalization is not considered an AE, and the underlying diagnosis for the procedure 
should be captured in the medical history as a pre-existing condition.  The surgical procedure 
should also include the term “elective” in all reports.  An elective or planned hospitalization must 
be reported as an SAE. 
The lack of efficacy of the study medication for the condition being investigated is not 
considered an AE unless a clinically significant change is assessed by the Investigator. 


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8.6.1.2. 
Assessment of Adverse Events 
Investigators will seek information on AEs at each subject contact.  Subjects should be asked 
using a general, non-direct question if there has been any change in their general health.  Direct 
questioning and examination should then be performed as appropriate. 
Severity of the AE should be assessed according to the following criteria: 
Mild: No interference with the subject’s daily activities; no medical intervention/therapy 
required. 
Moderate: Possible interference with the subject’s daily activities; no or minimal 
medical intervention/therapy required. 
Severe: Considerable interference with the subject’s daily activities; medical 
intervention/therapy required. 
Regardless of severity, some events may also meet regulatory serious criteria.  Refer to 
definitions and reporting of serious adverse events (SAEs) in Section 12.4, Appendix D. 
An Investigator who is medically qualified must make the determination of relationship (related 
or not related) to the investigational product for each AE or SAE.  When determining 
relationship to study medication, the Investigator will consider any investigational products that 
a subject could be exposed to in this clinical trial.  The Investigator should decide whether there 
is a reasonable possibility that the study medication caused the event, taking into account the 
following: a) evidence, b) science-based rationale, c) medical and clinical judgment,  
d) mechanisms of action, e) biologic plausibility, f) confounding risk factors (i.e., medical 
history, concomitant medications), g) temporal relationship, h) dechallenge/rechallenge, and  
i) lack of alternative explanation. 
 The event may be recorded as Related to investigational product or  
 Reporting the event as Not Related to study medication be considered 
8.6.1.3. 
Reporting Adverse Events  
AEs, whether spontaneously reported by the subject or noted by authorized study personnel, will 
be recorded in the subject’s medical record and on the appropriate AE eCRF.  Each recorded AE 
will be described by its duration (represented in dates), affected eye(s) (if applicable), maximum 
severity of the AE, seriousness criteria, suspected relationship to the study medication, actions 
taken with the study medication, and the study participation, outcome of the AE, and any other 
attributable causes of the AE. 
Regardless of relationship to the clinical study, AEs that occur at any time after the subject has 
provided written informed consent until subject withdrawal or the scheduled exit visit, must be 
recorded.  To improve the quality and precision of acquired AE data, Investigators should 
observe the following guidelines: 
 Whenever possible, use recognized medical terms when recording.  Do not use 
colloquialisms and/or abbreviations. 
 If known, record the diagnosis (i.e., disease or syndrome) rather than component 
signs and symptoms and /or laboratory or test findings (e.g., record congestive heart 


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failure rather than dyspnea, rales, and cyanosis, and enlarged heart on chest x-ray).  
However, other events that are considered unrelated to an encountered syndrome or 
disease should be recorded as individual AEs (e.g., if congestive heart failure and 
severe headache are observed at the same time and are clinically unrelated, each event 
should be recorded as an individual AE). 
 If the diagnosis is not known, then record the leading component sign, symptom, or 
test finding and describe the other clinically related findings in the narrative 
description of the case.  A suspected diagnosis can be used and described as such 
(e.g., record suspected or probable myocardial infarction); this has to be updated in 
the clinical database once the diagnosis is confirmed. 
AEs occurring secondary to other events (e.g., sequelae) should be identified by the 
primary cause.  A primary AE, if clearly identifiable, generally represents the most 
accurate clinical term.  If a primary AE is recorded, events occurring secondary to the 
primary event should be described in the narrative description of the case.  For 
example: 
The subject developed orthostatic hypotension and subsequently fainted and fell to 
the floor wherein she experienced a head trauma and neck pain. 
The primary AE in this example is orthostatic hypotension.  The fall, head trauma, 
and neck pain should be described in the narrative description of the case.  
 For intermittent events (e.g., intermittent headache), the event onset date should be 
recorded as the date the subject first started to experience the event and resolution 
date should reflect when the last occurrence resolved or stopped.  Separate AEs for 
each event should not be recorded.  For example, if a subject experienced headache 
on 14SEP2015 lasting for three hours, then subsequently experienced intermittent 
episodes of headache every day for approximately 3 hours until 21SEP2015, then the 
AE date of onset is 14SEP2015 and the resolution date is 21SEP2015. 
 For intermittent events, record the maximum severity of the individual events.  For 
example, if a subject complains of intermittent headaches for one week and the 
severity of each headache ranges from mild to moderate, then the severity would be 
moderate. 
 For intermittent hospitalizations occurring for a primary AE (e.g., in a subject with 
multiple sclerosis, commonly known for its relapsing and remitting course, in some 
cases leading to multiple hospital confinements), the subsequent hospitalizations 
should be described in the narrative description of the case. 
 If treatment was initiated, include the treatment and duration of the medication(s) in 
the eCRF. 
8.6.2. 
Serious Adverse Events 
8.6.2.1. 
Assessment of Serious Adverse Events 
An AE is considered serious if it fulfills one or more of the following criteria: 
 Death (i.e., the AE caused or led to death). 


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 It was 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. 
 Sight threatening event: A sight-threatening event is any event that places the 
subject at immediate risk of permanently losing vision in either eye as a direct 
result of the event. 
8.6.2.2. 
Reporting Serious Adverse Events 
The SAE eCRF must be completed with as much information as is available within 24 hours of 
knowledge of the event. 
To improve the quality and precision of acquired SAE data, Investigators should observe the 
following guidelines: 
 Death: Death is an outcome of an event.  The event that resulted in the death should 
be recorded and reported as the SAE. 
 Hospitalizations for Surgical or Diagnostic Procedures: The illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself.  The procedure should be captured in the case narrative as part of the action 
taken in response to the illness. 
Depending on the nature and seriousness of the AE, Santen may request additional 
documentation, for example, copies of the ophthalmic and medical records as well as results of 
laboratory tests.  If the subject was hospitalized, a copy of the discharge summary may be 
requested. 
8.6.2.3. 
Expedited Reporting of Serious Adverse Events 
Santen (or designee) will provide the Principal Investigator with a reporting cover letter and a 
masked expedited safety report for expedited reporting of SAEs to the IRB or IEC.  The 
Principal Investigator is responsible for receiving and reviewing expedited safety reports, 
submitting expedited safety reports to the IRB or IEC, and maintaining copies of expedited 
safety reports in the study records. 
8.6.3. 
Events of Special Interest 
The following are considered Events of Special Interests (ESIs) and should be reported on the 
appropriate eCRF with as much information as available within 24 hours of knowledge of the 
event:  


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 Pregnancy: 
 There are no controlled data with the investigational product in human pregnancy. 
It is required that females of childbearing potential use effective contraception 
during the study and recommended for 4 weeks for female subjects of 
childbearing potential and 12 weeks for male subjects capable of fathering 
children after the completion of the study.  Any pregnancy occurring during study 
treatment should be reported and the subject will be discontinued from the study.  
The subject should be followed until the end of pregnancy or until the end of the 
study, whichever is longer. 
 Medication administration errors 
 Study medication administration errors determined to be significant by the 
Investigator will be reported and evaluated as ESIs.  Examples of study 
medication administration errors may include, but are not limited to: incorrect 
dose of study medication and administration of study medication from an 
incorrect kit.  An AE does not necessarily need to have occurred to count as a 
study medication administration error.  A medication administration error is an 
unintended failure in the process of treatment with a medicinal product that leads 
to, or has the potential to lead to harm of the subject. 
8.6.4. 
Pregnancy Testing, Monitoring, and Reporting 
8.6.4.1. 
Pregnancy Testing 
If the subject is a female of childbearing potential, urine samples will be collected for pregnancy 
tests as specified in Schedule of Events and Procedures (Table 3).  Urine samples will be 
analyzed at the site with results available prior to administration of Study Medication. 
8.6.4.2. 
Pregnancy Monitoring and Reporting Procedures 
A urine pregnancy test will be conducted using a commercially available test kit at Visit 1 
(Screening), Visit 2 (Baseline, Day 1), Visit 4 (Week 6) and Visit 5 Study Exit/Early 
Termination for all females of childbearing potential. 
Although not considered an AE or SAE, pregnancy is an ESI and requires careful monitoring and 
follow up.  If pregnancy is reported by a study subject (or in the partner of a study subject), the 
investigator must:  
 Inform Santen within 24 hours of learning of the pregnancy. 
 If the pregnancy has occurred in a study subject, discontinue further study medication 
administration and/or withdraw the subject from the study. 
 Report pregnancy information on the eCRF following instructions. 
 Follow the pregnancy until outcome is known.  Santen will request specific follow-up 
on a case-by-case basis. 
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Female subjects who become pregnant: The investigator will collect pregnancy information on 
any female subject who becomes pregnant while participating in this study.  Information will be 
recorded on the appropriate form and submitted to Santen within 24 hours of learning of a 
subject's pregnancy.  The subject will be followed to determine the outcome of the pregnancy.  
The investigator will collect follow-up information on the subject and the neonate and the 
information will be forwarded to Santen.  Generally, follow-up will not be required for longer 
than 6 to 8 weeks beyond the estimated delivery date.  Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure.  While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an ESI.  Abnormal 
pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs and will be reported as such.  Any post-study 
pregnancy-related SAE considered reasonably related to the study medication by the investigator 
will be reported to Santen.  While the investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of an SAE through spontaneous 
reporting.  Any female subject who becomes pregnant while participating in the study will 
discontinue study medicaiton and be withdrawn from the study. 
Male subjects with partners who become pregnant: The investigator will attempt to collect 
pregnancy information on any male subject’s female partner who becomes pregnant while the 
male subject is in this study.  After obtaining the necessary signed informed consent from the 
pregnant female partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to Santen within 24 hours of learning of the partner’s pregnancy. 
The female partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to Santen.  Generally, the 
follow-up will be no longer than 6 to 8 weeks following the estimated delivery date.  Any 
termination of the pregnancy will be reported regardless of fetal status (presence or absence of 
anomalies) or indication for the procedure. 
8.6.5. 
Time Period and Frequency for Collecting AE and SAE Information 
AEs and SAEs will be monitored for and collected at the time points specified in  Schedule of 
Events and Procedures (Table 3), from the signing of the ICF until the subject withdrawal or the 
scheduled exit visit. (Note: Although AEs will be monitored for and collected prior to study 
medication administration, the statistical data analysis will determine and summarize treatment-
emergent AEs, i.e., those AEs that began or worsened in severity after the first study medication 
administration.) 
All SAEs will be recorded and reported to Santen or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Section 12.4, Appendix D.  The 
investigator will submit any updated SAE data to Santen within 24 hours of it being available. 
Investigators are not obligated to monitor for new AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event to be reasonably 
related to the study medication or study participation, the investigator must promptly notify 
Santen. 


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8.6.6. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in  
Section 12.4, Appendix D.  During the double-masked period, regardless of the source of the 
reported occurrence of an AE in a subject, the masked investigator will assess the causality of the 
AE. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
8.6.7. 
Follow-up of Adverse Events 
All reported AEs (related and unrelated) should be followed until resolution or until the subject’s 
participation in the study ends.  Subjects with the following types of events should be followed 
by the Investigator until the event is determined to be resolved, irreversible, chronic, stable, the 
subject withdraws consent, or no further information can be reasonably obtained. 
Independent of whether a subject has already had their scheduled study exit visit or not, any 
ongoing following types of event should be followed by the investigator until the event is 
determined to be resolved, irreversible, stable, the subject withdraws consent, or no further 
information is available. 
 On-going SAEs 
 On-going ESIs, including pregnancy and medication errors resulting in AE’s 
 Early termination and withdrawal from the study due to study medication related AEs 
 The other types of related AEs should be also followed by the same manner as SAEs 
in principle, and this follow up should be continued, as needed, up until the time 
database lock.  Generally, the status/resolution of the AE should be confirmed via an 
on-site visit, frequency as per investigator's judgement.  However, in cases where the 
investigator considers an on-site visit is not necessary, such as with an AE based on 
subjective symptoms, the Investigator may confirm the outcome of the AE by 
telephone, email, etc. 
 The other types of unrelated AE should be followed until resolution or the scheduled 
exit visit 
If the information requested by Santen is not part of the eCRF, or when database lock has already 
been completed, the site’s response to follow-up requests should be emailed, faxed, or reported 
in writing to Santen Global Pharmacovigilance of Emergency Contact Information. 
In addition, on a case by case basis, Santen (or designee) may request follow up beyond the 
scheduled exit visit. 
The follow-up information on an individual SAE or AE (or ESI) will be entered into the eCRF 
prior to database lock.  If the information requested by Santen is not part of the eCRF, or when 
database lock has already been completed, the site’s response to follow-up requests should be 
emailed to globalPVAmericas@santen.com or reported in writing and fax to +1-415-276-5882 
(in the US). 


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8.6.8. 
Manual Back-Up Reporting Procedures 
This study is utilizing an EDC system for data entry.  In the event that the EDC system is 
unavailable for electronic reporting, the manual back-up reporting procedures below should be 
followed. 
 Complete an AE Form, SAE Form, Pregnancy Form, Medication Error Form, or ESI 
Form as appropriate. 
 Attach a cover sheet with your contact information and address to Santen (or its 
designee) (Table 1). 
 Email (preferred) or Fax the cover sheet and the completed form(s) to Santen  
(or its designee) (Table 1) at ‘globalPVAmericas@santen.com’ or fax number  
+1-415-276-5882 (in the US). 
When the EDC system becomes available, the EDC system should be updated with all 
previously reported information. 
8.6.9. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to Santen of an SAE is essential so that legal obligations 
and ethical responsibilities towards the safety of subjects and the safety of a study intervention 
under clinical investigation are met. 
Santen has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a study intervention under clinical investigation.  Santen will comply 
with country-specific regulatory requirements relating to safety reporting to the regulatory 
authority, IRB/IEC, and investigators. 
Santen will prepare investigator safety reports for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Santen policy and forward 
them to investigators as necessary.  An investigator who receives an investigator safety report 
describing an SAE or other specific safety information (e.g., summary or listing of SAEs) from 
Santen will review and then file it along with the Investigational Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 


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9. 
STATISTICAL CONSIDERATIONS 
This section outlines topics related to the statistical methods used in the design and analysis of 
the study. A more detailed description of all the analyses and methods is provided in the SAP. 
9.1. 
Interim Analysis 
There is no planned interim analysis for this study. 
9.2. 
Final Analysis 
An unmasked final analysis will be performed after all subjects completed Month 3 or 
discontinued prematurely.  The analysis will evaluate the efficacy and safety of DE-126 
Ophthalmic Solution 0.002% once daily compared with Timolol Maleate Ophthalmic  
Solution 0.5% twice daily. 
9.3. 
General Considerations 
Descriptive statistics, unless otherwise noted, will include the number of subjects (N), mean, SD, 
median, minimum, and maximum for continuous variables and N and percent for categorical 
variables. 
The study eye will be defined as the eye that qualifies per inclusion criteria at Visit 2 (Baseline, 
Day 1).  For example, IOP must be ≥ 22 mmHg at all IOP measurement time-points (08:00, 
10:00, and 16:00).  See Section 5.1  and Section 5.2 for all inclusion/exclusion criteria.  If both 
eyes qualify, the eye with the higher mean diurnal IOP at Visit 2 (Baseline, Day 1) will be the 
study eye.  If both eyes have the same mean diurnal IOP at baseline, then the right eye will be 
designated as the study eye. 
Additional considerations will be described in SAP which will be finalized prior to unmasking 
the data. 
9.3.1. 
Sample Size 
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 between-treatment difference of 0 mmHg,  
SD of 4.0 mmHg and a correlation coefficient of 0.6 among repeated measures, approximately 
280 adult subjects in total (140 subjects per treatment arm) will provide 70% power to 
demonstrate non-inferiority of DE-126 Ophthalmic Solution 0.002% to Timolol maleate 
ophthalmic solution 0.5%.  Assuming a drop-out rate of 5%, the final needed sample size will be 
294 in total, i.e. 147 subjects/arm. 
9.3.2. 
Statistical Hypotheses and Level of Significance 
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 2, Week 6, and Month 3 visits. 
For the primary endpoint, a MMRM will be used to test the following hypotheses: 
H0: µT – µC > Δ versus HA: µT – µC ≤ Δ  


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Where µT and µC denote the mean values of the primary endpoint in DE-126/Vehicle arm and 
Timolol Maleate arm, respectively, and Δ denotes the non-inferiority margin of 1.5 mmHg. 
Treatment difference between the DE-126/Vehicle arm and Timolol Maleate arm at each 
specified time point of each post-baseline visit up to Month 3 will be reported along with 95% 
confidence intervals.  Non-inferiority is established if the upper limit of the two-sided 95% 
confidence interval for the difference in the mean IOP (DE-126/Vehicle - Timolol Maleate) is  
≤ 1.5 mmHg at all nine time points and ≤ 1.0 mmHg in majority (5 or more) of the time points. 
If the upper limit of the 95% confidence interval for the difference is < 0 at all nine time points, 
superiority of DE-126 ophthalmic solution 0.002% to Timolol maleate ophthalmic solution 0.5% 
will be claimed for the primary endpoint. 
If non-inferiority in the primary endpoint is achieved, then the key secondary endpoint will be 
tested: Mean diurnal IOP in the study eye at Month 3. 
The corresponding hypothesis is: 
H0S: µTs – µCs  > Δ versus HAS: µTs– µCs ≤  Δ 
Where µTs and µCs denote the mean diurnal IOP at Month 3 in DE-126/Vehicle arm and Timolol 
Maleate arm, respectively; and Δ denotes the non-inferiority margin of 1.5 mmHg.   
Non-inferiority is established if the upper limit of the two-sided 95% confidence interval for the 
difference between DE-126/Vehicle arm and Timolol Maleate arm (DE-126/Vehicle – Timolol 
Maleate) in the mean diurnal IOP at Month 3 is ≤ 1.5 mmHg.  If the upper limit of the  
95% confidence interval for the difference is < 0 mmHg, superiority of DE-126 ophthalmic 
solution 0.002% to Timolol maleate ophthalmic solution 0.5% for the key secondary endpoint 
will be claimed. 
9.3.3. 
Multiple Comparisons/Multiplicity 
Fixed sequence procedure will be applied to control the overall Type I error rate across the four 
hypotheses in the primary and key secondary endpoints at the 0.05 level.  Fixed sequence 
procedure tests hierarchically ordered hypotheses at level 0.05 until the first non-rejection. 
The fixed sequence for the four hypotheses in this study is as follows: 
1. Hypothesis of non-inferiority of DE-126 ophthalmic solution 0.002% to Timolol maleate 
ophthalmic solution 0.5% for the primary endpoint, IOP at each scheduled timepoint 
(08:00, 10:00, and 16:00) at Week 2, Week 6, and Month 3. 
2. Hypothesis of non-inferiority of DE-126 ophthalmic solution 0.002% to Timolol maleate 
ophthalmic solution 0.5% for the key secondary endpoint, mean diurnal IOP at Month 3. 
3. Hypothesis of superiority of DE-126 ophthalmic solution 0.002% to Timolol maleate 
ophthalmic solution 0.5% for the key secondary endpoint, mean diurnal IOP at Month 3. 
4. Hypothesis of superiority of DE-126 ophthalmic solution 0.002% to Timolol maleate 
ophthalmic solution 0.5% for the primary endpoint, IOP at each scheduled timepoint 
(08:00, 10:00, and 16:00) at Week 2, Week 6, and Month 3. 


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9.4. 
Study Populations 
9.4.1. 
Safety Population 
The Safety Population will include all randomized subjects who received at least one dose of the 
study medication.  The safety analysis will be performed on the Safety Population by actual 
treatment received. 
9.4.2. 
Full Analysis Set 
The FAS will include all randomized subjects who received at least one dose of study medication 
and provided at least one post-baseline IOP measurement.  The efficacy analysis will be 
performed on the FAS or a subset of the FAS by planned treatment. 
9.4.3. 
Per-Protocol Set 
The PPS is a subset of the FAS, restricted to the subjects who fulfill the protocol in the terms of 
the eligibility, interventions, and outcome assessment.  It will be the analysis population for 
some sensitivity analyses.  More details will be provided in SAP. 
9.5. 
Handling of Missing Values 
The primary analysis of continuous IOP endpoints will be performed using the MMRM analysis 
on observed cases.  As sensitivity analyses, a PMM approach may be applied to evaluate the 
impact of missing data on the primary analysis results. 
For medical events including AEs and medical history, completely or partially missing onset and 
resolution dates will be imputed in a conservative fashion to be detailed in the SAP.  Similar 
rules will be followed to impute the completely or partially missing start and end dates of  
non-study medications. 
Unless specified otherwise, descriptive summaries will be based on observed cases.  
More details on handling of missing data will be provided in the SAP. 
9.6. 
Demographic and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized with descriptive statistics 
by treatment. 
Concurrent diseases will be coded using the latest version of MedDRA.  Subjects with any 
concurrent diseases will be tabulated by primary SOC and PT specified in the MedDRA. 
Subjects using any prior medications that has been used for glaucoma or OHT within 28 days 
before Screening (Visit 1) will be tabulated by Anatomical Therapeutic Chemical (ATC) levels 
and PT specified in the latest version of World Health Organization Drug Dictionary Enhanced 
(World Health Organization Drug Dictionary, 2011). 


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9.7. 
Efficacy Analyses  
Unless specified otherwise, for subjects who discontinue from the study medication per protocol 
before the Study Exit, the IOP data collected after the study medication discontinuation with any 
use of non-study IOP lowering medication or surgery will be censored from all efficacy analyses. 
9.7.1. 
Analysis of 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 2 (Visit 3), Week 6 (Visit 4), and Month 3 (Visit 5). 
A MMRM will be carried out on observed cases up to Month 3.  At each scheduled time point of 
each visit, least square mean IOP of each treatment arm and 95% confidence interval for the 
difference in least square means between DE-126/Vehicle arm and Timolol Maleate arm will be 
estimated.  Non-inferiority is established if the upper limit of the 95% confidence interval for the 
difference is ≤ 1.5 mmHg for all nine time points and ≤ 1.0 mmHg for at least 5 out of the 9 time 
points. 
The primary analysis will be based on the FAS.  The same analysis will be repeated on the PPS 
population as a sensitivity analysis.  More details on the model specifications will be provided in 
the SAP. 
9.7.2. 
Analysis of Secondary Efficacy Endpoints 
9.7.2.1. 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is mean diurnal IOP in the study eye at Month 3 (Visit 5). 
A MMRM will be carried out on observed cases up to Month 3.  The least square mean diurnal 
IOP of each treatment arm and 95% confidence interval for the difference in least square means 
between DE-126/Vehicle arm and Timolol Maleate arm at Month 3 will be estimated.  If  
non-inferiority in the primary endpoint is achieved, then the key secondary endpoint will be 
tested at the 0.05 significance level (2-sided). 
The primary analysis will be based on the FAS.  The same analysis will be repeated on the PPS 
population as a sensitivity analysis.  More details on the model specifications will be provided in 
the SAP. 
9.7.2.2. 
Other Secondary Efficacy Endpoints 
Other secondary endpoints to be assessed include: 
 Mean diurnal IOP in the study eye at Week 2 (Visit 3) and Week 6 (Visit 4) 
 Change and percent change from Baseline (Visit 2, Day 1) in IOP in the study eye at 
each timepoint of each post-baseline visit 
 Change and percent change from Baseline (Visit 2, Day 1) in mean diurnal IOP in the 
study eye at each post-baseline visit 
 Having a mean diurnal IOP reduction ≥ 20%, ≥ 25%, or ≥ 30% from Baseline  
(Visit 2, Day 1) in the study eye at each post-baseline visit 


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 Having a mean diurnal IOP ≤ 18mmHg in the study eye at each post-baseline visit 
The continuous secondary endpoints will be analyzed using MMRM on observed cases. More 
details on the model specifications will be provided in the SAP. 
The binary secondary endpoints will be analyzed using the Pearson’s chi-square test for a  
2×2 contingency table.  The Fisher’s Exact test may be conducted as a sensitivity analysis. 
Subgroup analyses by the two randomization strata (baseline IOP in the study eye  
<25 mmHg vs. ≥25 mmHg) be performed for secondary endpoints using descriptive statistics. 
9.8. 
Safety Analyses 
All safety outcome measures will be summarized descriptively for the Safety Population.  The 
safety outcome measures include AEs, BCVA, slit-lamp biomicroscopy, ophthalmoscopy, and 
vital signs (blood pressure and pulse rate). 
AEs will be coded using the latest version of MedDRA.  Subjects with any AEs will be tabulated 
by primary SOC and PT specified in the MedDRA.  Similarly, subjects with any ocular and non-
ocular AEs will be tabulated separately.  AEs, ocular, and non-ocular will also be summarized by 
relationship to treatment and maximum severity.  In addition, SAEs and discontinuations due to 
AEs will be summarized. 
Safety parameters listed in Section 8.4.1 and Section 8.4.2 will be summarized using descriptive 
statistics by actual treatment received. Changes from baseline in these safety parameters will also 
be summarized by treatment. 
9.9. 
Exploratory Analyses 
The GQL-15 total score and each domain score will be summarized descriptively by actual 
treatment received.  The 4 domains are central and near vision, outdoor mobility, peripheral 
vision, and dark adaption and glare. 


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10. 
SUPPORTING DOCUMENTAITON AND OPERATIONAL 
CONSIDERATIONS 
The Principal Investigator will allow representatives of Santen’s monitoring team (or designee), 
the governing IRB or IEC, and other applicable regulatory agencies to inspect all study records, 
eCRFs, recruitment materials, and corresponding portions of the subject’s medical records at 
regular intervals throughout the study.  These inspections are for the purpose of verifying 
adherence to the protocol, completeness, and exactness of the data being entered onto the eCRF, 
and compliance with the International Conference on Harmonization (ICH)- Good Clinical 
Practice (GCP) or other regulatory agency regulations. 
10.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of Santen (or 
designee) will evaluate the investigational study site to: 
 Determine the adequacy of the study facilities. 
 Review with the Principal Investigator and his/her designee their responsibilities with 
regard to protocol procedures adherence, and the responsibilities of Santen  
(or designee). 
During the study, Santen (or designee) will have regular contact with the investigational site, for 
the following: 
 Provide information and support to the Investigator(s). 
 Confirm that facilities remain acceptable. 
 Assess adherence to the protocol and ICH-GCP. 
 Perform investigational product accountability checks and quality control procedures. 
 Ensure the on-going implementation of accurate data entry in the eCRF. 
 Perform source data verification, including a comparison of the data in the eCRFs 
with the subject’s medical records and other records relevant to the study.  This will 
require direct access to all original records for each subject (e.g., clinic charts). 
 Record and report any protocol deviations not previously sent to Santen. 
 Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to Santen and those SAEs that met criteria for reporting 
have been forwarded to the IRB or IEC. 
 Confirm sites have a complete record of all study International New Drug Application 
(IND) Safety Reports and filed them with the IRB or IEC. 
Santen (or designee) may remotely access the eCRFs at any time during the study for centralized 
monitoring. Santen (or designee) will be available between visits if authorized study staff need 
study related information or support. 


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10.2. 
Audits and Inspections 
The Principal Investigator will allow Santen (or designee), the governing IRB or IEC, and 
applicable regulatory agencies to audit and inspect any aspect of the study, including all study 
records, eCRFs, recruitment materials, and corresponding portions of the subject’s charts and 
medical records at any time during the study.  These study records must be retained at the study 
site and made available for audits and inspections.  The purpose of these audits and inspections is 
to verify adherence to the protocol, completeness, and accuracy of the eCRF data, and 
compliance with ICH-GCP guidelines and applicable regulatory requirements. 
The Principal Investigator (or his/her designee) will notify Santen (or designee) should the site 
be audited or inspected by the governing IRB or IEC, and applicable regulatory agencies. Santen 
(or designee) will also notify the investigational site of any known pending site audits or 
inspections planned by Santen (or designee), governing IRB or IEC, and regulatory agencies. 
10.3. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) 
The Principal Investigator must obtain IRB/IEC approval for the study.  Initial IRB/IEC 
approval, and all materials approved by the IRB/IEC for this study including the subject consent 
form, written information provided to subjects, and recruitment materials must be maintained by 
the Principal Investigator and made available for inspection. 
10.4. 
Quality Control and Quality Assurance 
10.4.1. 
Quality Control 
Santen (or designee) will provide instructional material to the study sites, as appropriate; 
including but not limited to instruction on the protocol, the eCRFs completion guidelines, and 
study procedures.  Santen (or designee) will communicate regularly with site personnel via mail, 
email, telephone, and/or fax; and make periodic visits to the study site.  During those visits, 
Santen  
(or designee) will perform source data verification with the subject’s medical records and other 
records relevant to the study.  Upon receiving the eCRFs, Santen (or designee) will review and 
evaluate eCRF data and use standard system edits and may use centralized monitoring to detect 
errors in data collection. 
10.4.2. 
Quality Assurance 
Santen (or designee) may conduct a quality assurance audit at any time.  See Section 10.2. 
10.5. 
Ethics 
10.5.1. 
Ethics Review 
The final study protocol and the final version of the ICF, for the main study and the ICF for the 
PGx study, assent form, and other study related material, as appropriate, must be approved in 
writing by an IRB or IEC as appropriate.  If an IRB or IEC does not approve the collection of 
blood samples for optional future PGx research, this will not affect the approvals for conducting 


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the main study.  The Principal Investigator must submit written IRB or IEC approval to Santen 
(or designee) before study initiation.  Refer to Section 12.1, Appendix A for a list of obligations 
of Investigators. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local regulations and guidelines.  In addition, the IRB or IEC must 
approve all advertising used to recruit subjects for the study.  The protocol must be re-approved 
by the IRB or IEC upon receipt of amendments. 
The Principal Investigator is also responsible for providing the IRB or IEC with progress reports 
and notifications of any reportable serious adverse drug reactions from the investigational 
product. 
10.5.2. 
Ethical Conduct of the Study 
This study will be conducted in compliance with IRB or IEC, and regulatory requirements.  This 
study will also be conducted in compliance with the protocol, GCP guidelines, International ICH 
guidelines, and the Declaration of Helsinki. 
10.6. 
Written Informed Consent 
The Principal Investigator at each center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk, and possible benefit of the 
study and participation in the collection of blood samples for future PGx research studies.  If the 
subject does not wish to provide a blood sample for the biomarker research study this will not 
affect the subject’s enrollment in this clinical trial.  Subjects must also be notified that they are 
free to withdraw from either study at any time.  Subjects should be given the opportunity to ask 
questions and allowed time to consider the information provided.  Before participating in any 
study-related activity, voluntary informed consent must be documented by the use of a written 
ICF approved by the IRB or IEC and signed and dated by the subject or the subject’s legally 
authorized representative at the time of consent.  The original signed and dated ICF will be 
retained with the study records, and a copy of the signed ICF will be given to the subject or the 
subject’s legally authorized representative.  See Section 12.2, Appendix B. 
10.7. 
Data Handling and Recordkeeping 
10.7.1. 
Inspection of Records 
The Principal Investigator will allow Santen (or designee), the governing IRB or IEC, and 
applicable regulatory agencies to inspect any aspect of the study, including all study records, 
eCRFs, and corresponding portions of the subject’s charts and medical records at any time 
during the study.  The purpose of these inspections is to verify adherence to the protocol, 
completeness, and accuracy of the eCRF data, and compliance with ICH-GCP guidelines and 
applicable regulatory requirements. 
10.7.2. 
Retention of Records 
All records relating to the conduct of this study are to be retained by the Principal Investigator 
until notified by Santen (or designee) that the records may be destroyed. 


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10.7.3. 
Source Documents 
The Principal Investigator must maintain detailed source documents on all study subjects who 
provide informed consent.  Source documents include subject medical records, hospital charts, 
clinic charts, medication dosing diaries, study files, as well as the results of diagnostic tests  
(e.g., visual field test printouts). 
The following minimum information should be entered into the subject’s medical record: 
 The date the subject entered the study and the subject number 
 The study protocol number and the name of Santen 
 The date that informed consent was obtained 
 Evidence that the subject meets study eligibility requirements (e.g., medical history, 
study procedures, and/or evaluations) 
 The dates of all study-related subject visits (scheduled and unscheduled) 
 Evidence that required procedures and/or evaluations were completed 
 Use of any concomitant medications 
 Documentation of study medication accountability 
 Occurrence and status of any AEs 
 The date the subject exited the study and a notation as to whether the subject 
completed or terminated early from the study, including the reason for early 
termination 
 If unmasking at the site occurred, proper documentation and notifications were made 
10.7.4. 
Source Data 
Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data should be accurate, legible, 
contemporaneous, original, attributable, complete and consistent.  Source data is documented in 
source documents which may be both electronic and on paper. 
The Investigator(s) should be aware about the location of the source data and consistent in 
recording them.  The intended location should be clearly defined prior to subject enrollment.  
One way of achieving this is to generate a source data location list.  The source data location list 
will be prepared by the site and will be signed and dated by the Principal Investigator.  The list 
will be filed in the Investigator’s trial master file. 
10.7.5. 
Data Collection 
The Principal Investigator must maintain detailed records on all subjects who provide informed 
consent.  Data for screened and randomized subjects will be entered into eCRFs. eCRFs should 
be completed within 3 business days of each subject visit as much as possible.  A review of the 
eCRFs will be completed remotely by Santen (or designee).  At designated intervals, a study 
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will monitor the subject data recorded in the eCRF against source documents at the study site. 
Santen (or designee) will review and evaluate eCRF data and use standard system edits, and may 
use centralized monitoring evaluations, to detect errors in data collection.  At the end of the 
study, a copy of the completed eCRFs will be sent to the site to be maintained as study records. 
10.8. 
Study and Site Closure 
Santen’s designee reserves the right to close the study site or terminate the study at any time for 
any reason at the sole discretion of Santen. Study sites will be closed upon study completion. A 
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by Santen or investigator may include but are not 
limited to: 
 Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, Santen's procedures, or GCP guidelines 
 Inadequate recruitment of subjects by the investigator 
 Discontinuation of further development of the investigational product 
10.9. 
Publication Policy 
The existence of this clinical study is confidential, and it should not be discussed with persons 
outside of the study.  Additionally, the information in this document and regarding this study 
contains trade secrets and commercially sensitive information that is confidential and may not be 
disclosed unless such disclosure is required by federal or state law or regulations.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who 
have a need to know, but all such persons must be instructed not to further disseminate this 
information to others.  These restrictions of disclosure will apply equally to all future 
information supplied that is indicated as confidential.  Information pertaining to this study will 
be published on www.clinicaltrials.gov. 
The data generated by this clinical study are the property of Santen and should not be disclosed 
without the prior written permission of Santen.  These data may be used by Santen now and in 
the future for presentation or publication at Santen’s discretion or for submission to 
governmental regulatory agencies.  Santen reserves the right of prior review of any publication 
or presentation of data from this study. 
In signing this protocol, the Principal Investigator agrees to the release of the data from this 
study and acknowledges the above publication policy. 


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11. 
REFERENCES 
11.1. 
Literature 
1. 
AAO-PPP, American_Academy_of_Ophthalmology, Preferred_Practice_Pattern. (2015).  
Primary Open-Angle Glaucoma. American Academy of Ophthalmology. 
 
2. 
AGIS_Investigators. (2000).  The Advanced Glaucoma Intervention Study (AGIS): 7. 
The Relationship Between Control of Intraocular Pressure and Visual Field Deterioration. 
American Journal of Ophthalmology. 130(4):429-40. 
 
3. 
Berlin, M. S., Rowe-Rendleman, C., Ahmed, I., Ross, D. T., Fujii, A., Ouchi, T., Quach, 
C., Wood, A., Ward, C. L. (2015).  EP3/FP dual receptor agonist ONO-9054 
administered morning or evening to patients with open-angle glaucoma or ocular 
hypertension: results of a randomised crossover study. Br J Ophthalmol. 100(6):843-7. 
doi: 10.1136/bjophthalmol-2015-307000. PubMed PMID: 26453641; PubMed Central 
PMCID: PMCPMC4893083. 
 
4. 
Cheema, A., Chang, R. T., Shrivastava, A., Singh, K. (2016).  Update on the Medical 
Treatment of Primary Open-Angle Glaucoma. Asia Pac J Ophthalmol (Phila). 5(1):51-8. 
doi: 10.1097/APO.0000000000000181. PubMed PMID: 26886120. 
 
5. 
European_Glaucoma_Society. (2017).  European Glaucoma Society Terminology and 
Guidelines for Glaucoma, 4th Edition - Chapter 3: Treatment principles and options 
Supported by the EGS Foundation: Part 1: Foreword; Introduction; Glossary; Chapter 3 
Treatment principles and options. Br J Ophthalmol. 101(6):130-95. doi: 
10.1136/bjophthalmol-2016-EGSguideline.003. PubMed PMID: 28559477; PubMed 
Central PMCID: PMCPMC5583689. 
 
6. 
Kass, M., Heuer, D., Higginbotham, E., Johnson, C., Keltner, J., Miller, J., Parrish, R., 
Wilson, M., Gordon, M. (2002).  The Ocular Hypertension Treatment Study: A 
Randomized Trial Determines That Topical Ocular Hypotensive Medication Delays or 
Prevents the Onset of Primary Open-Angle Glaucoma. Arch Ophthalmol. 120:701-13. 
 
7. 
King, A., Azuara-Blanco, A., Tuulonen, A. (2013).  Glaucoma. BMJ. 346:f3518. doi: 
10.1136/bmj.f3518. PubMed PMID: 23757737. 
 
8. 
Leske, M., Heijl, A., Hussein, M., Bengtsson, B., Hyman, L., Komaroff, E. (2003).  
Factors for Glaucoma Progression and the Effect of Treatment: The Early Manifest 
Glaucoma Trial. Arch Ophthalmol. 121(1):48-56. 
 
9. 
MedDRA.  Medical Dictionary for Regulatory Activities. 14.1. 
 
 
 
 


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10. 
Miller Ellis, E., Berlin, M. S., Ward, C. L., Sharpe, J. A., Jamil, A., Harris, A. (2017).  
Ocular hypotensive effect of the novel EP3/FP agonist ONO-9054 versus Xalatan: results 
of a 28-day, double-masked, randomised study. Br J Ophthalmol. 101(6):796-800. doi: 
10.1136/bjophthalmol-2016-309023. PubMed PMID: 27649982; PubMed Central 
PMCID: PMCPMC5583686. 
 
11. 
Ota, T., Aihara, M., Saeki, T., Narumiya, S., Araie, M. (2006).  The effects of 
prostaglandin analogues on prostanoid EP1, EP2, and EP3 receptor-deficient mice. Invest 
Ophthalmol Vis Sci. 47(8):3395-9. doi: 10.1167/iovs.06-0100. PubMed PMID: 
16877408. 
 
12. 
Schlotzer-Schrehardt, U., Zenkel, M., Nusing, R. (2002).  Expression and Localization of 
FP and EP Prostanoid Receptor Subtypes in Human Ocular Tissues. Investigative 
Ophthalmology & Visual Science. 43(5):1475-87. 
 
13. 
Suto, F., Rowe-Rendleman, C. L., Ouchi, T., Jamil, A., Wood, A., Ward, C. L. (2015).  A 
Novel Dual Agonist of EP3 and FP Receptors for OAG and OHT: Safety, 
Pharmacokinetics, and Pharmacodynamics of ONO-9054 in Healthy Volunteers. Invest 
Ophthalmol Vis Sci. 56(13):7963-70. doi: 10.1167/iovs.15-18166. PubMed PMID: 
26720443. 
 
14. 
Tham, Y., Li, X., Wong, T., Quigley, H., Aung, T., Cheng, C. (2014).  Global Prevalence 
of Glaucoma and Projections of Glaucoma Burden through 2040. Ophthalmology. 
121(11):2081-90. 
 
15. 
World Health Organization Drug Dictionary, E. World Health Organization Drug 
Dictionary Enhanced (WHO-DDE), September 2011 Version2011. 
 
11.2. 
Study Reports 
1. Data on File: ONO-9054IOU001. A Double-masked, Placebo-controlled, Single-dose 
Escalation Study To Evaluate The Safety, Tolerability, And Pharmacokinetics Of  
ONO-9054 In Healthy Adult Subjects 
2. Data on File: ONO-9054IOU002. A Double-Masked, Placebo-Controlled,  
Dose-Escalation Stusy And Double-Masked, Two-sequence, Crossover Study To 
Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics of  
ONO-9054 In Patients With Ocular Hypertension Or Mild Openangle Glaucoma 
3. Data on File: ONO-9054IOU003. A 28-Day, Double-masked, Randomized,  
Parallel-group, Active-controlled Study of ONO-9054 Ophthalmic Solution in Subjects 
With Ocular Hypertension or Open-angle Glaucoma 
4. 012601IN - A Phase IIb, Randomized, Observer-Masked, Placebo- and Active-
Controlled, Parallel-Group, Multinational and Multicenter Study Assessing the Safety 
and Efficacy of DE-126 Ophthalmic Solution in Subjects with Primary Open-Angle 
Glaucoma or Ocular Hypertension – Angel Study 


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12. 
APPENDICES 
12.1. 
Appendix A - Obligations of Investigators 
In summary, the Principal Investigator has agreed to the following obligations: 
 Obtaining informed consent from every subject before the subject’s participation in 
any study-related activity and maintaining records of consent as part of the study 
records. 
 Obtaining approval from the IRB or IEC before involving any subject in any study-
related activity; submitting verification of the approval to Santen; submitting periodic 
progress reports (at least annually) and final report to IRB or IEC. 
 Approving the protocol and conducting the study according to the protocol and 
applicable regulations; informing Santen of all deviations from the protocol. 
 Informing the IRB or IEC of all protocol amendments/modifications; sending Santen 
a copy of the letter from the IRB or IEC approving the amendment/modification. 
 Reporting to Santen any AEs and reporting to the IRB or IEC any reportable AEs that 
occur in the course of the investigation. 
 Keeping careful and accurate records of all clinical study data (study records must be 
considerably more exact and complete than those kept in ordinary medical practice); 
maintaining records of all materials submitted to the IRB or IEC and of all action by 
the IRB or IEC regarding the study. 
 Making study records available for inspection by Santen and representatives of 
regulatory agencies and the IRB or IEC; keeping records until notified by Santen that 
they may be destroyed.  
 Maintaining proper control and documentation of all test and control articles. 
 Submitting the following records and reporting to Santen. See I, II, and III as listed 
below. 
I. 
Before the Beginning of the Study Providing Santen the following: 
 A signed Form FDA 1572, Statement of Investigator, if applicable. 
 A signed Financial Disclosure Form. 
 A current curriculum vitae (CV) if not submitted to Santen previously or if 
updated. 
 CVs for all Sub-Investigators. 
 A letter from the IRB or IEC indicating that the protocol was approved, including 
the name and address of the IRB or IEC. 
 A copy of the consent form approved by the IRB or IEC. 
 A list of current members of the IRB or IEC. 
 A copy of the source data location list. 


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 A copy of delegation list/log. 
 A copy of training log. 
II. 
While the Study is in Progress 
 Acknowledgment of receipt of the test and control articles; documentation of 
disposition of all test and control articles. 
 eCRFs for each subject enrolled in the study. 
 Information regarding all deviations from the protocol. 
 Information regarding all AEs occurring to a subject while enrolled in the study. 
 Annual progress report (if study is on-going for more than one year). Letter from 
the IRB or IEC indicating approval of the annual progress report. 
III. 
Once the Study is Completed 
 Disposition of all used and/or unused test and control articles, as well as 
documentation of all and drug accountability. 
 Providing Santen a final study report. 
 
 


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12.2. 
Appendix B - Elements of Informed Consent 
I. 
Elements of Informed Consent  
The following information must be provided to each subject in obtaining informed consent as 
required by ICH-GCP and/or local regulations.  If written consent is being obtained, the 
subject (or subject’s legal representative) should be provided with a copy of the signed 
written ICF. 
A. The trial involves research. 
B. The purpose of the trial. 
C. Name of the Investigator (s) and IRB/IEC 
D. The trial treatment(s) and the probability for random assignment to each treatment. 
E. The trial procedures to be followed, including all invasive procedures. 
F. The subject's responsibilities. 
G. Those aspects of the trial that are experimental. 
H. The reasonably foreseeable risks or inconveniences to the subject and, when 
applicable, to an embryo, fetus, or nursing infant. 
I. 
The reasonably expected benefits. When there is no intended clinical benefit to the 
subject, the subject should be made aware of this. 
J. 
The alternative procedure(s) or course(s) of treatment that may be available to the 
subject, and their important potential benefits and risks. 
K. The compensation and/or treatment available to the subject in the event of trial-
related injury. 
L. The anticipated prorated payment, if any, to the subject for participating in the 
trial. 
M. The anticipated expenses, if any, to the subject for participating in the trial. 
N. That the subject's participation in the trial is voluntary and that the subject may 
refuse to participate or withdraw from the trial, at any time, without penalty or loss 
of benefits to which the subject is otherwise entitled. 
O. That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) 
will be granted direct access to the subject's original medical records for 
verification of clinical trial procedures and/or data, without violating the 
confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations and that, by signing a written informed consent form, the subject or the 
subject's legally acceptable representative is authorizing such access. 
P. That records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available. If the results of the trial are published, the subject’s identity will remain 
confidential. 


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Q. That the subject or the subject's legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the 
subject's willingness to continue participation in the trial. 
R. The person(s) to contact for further information regarding the trial and the rights of 
trial subjects, and whom to contact in the event of trial-related injury. 
S. The foreseeable circumstances and/or reasons under which the subject's 
participation in the trial may be terminated. 
T. The expected duration of the subject's participation in the trial. 
U. The approximate number of subjects involved in the trial. 
V. Clinical trial information has been or will be available on 
http://www.clinicaltrials.gov. 
II. 
Additional Elements of Informed Consent for Optional Future 
Pharmacogenomics/genomics Laboratory Research Study  
The following information must be provided to each subject in obtaining informed consent 
for the future PGx laboratory research study: 
1. The location of storage of their sample. 
2. The duration of storage of their sample. 
3. What group(s) within Santen will be using their sample in research study. 
4. What use restrictions are assigned to their sample. 
5. Destruction of their sample if they withdraw prior to its use, and retention of the sample 
data if they withdraw after its use. 
The informed consent requirements in this protocol are not intended to preempt any applicable 
local laws which require additional information to be disclosed for informed consent to be 
legally effective. 
Nothing in this protocol is intended to limit the authority of a physician to provide emergency 
medical care to the extent the physician is permitted to do so under applicable local laws. 
 
 


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12.3. 
Appendix C - Procedures for Assessments 
12.3.1. 
Refraction 
Refraction will be performed for each eye at Visit 1 (Screening).  At Visit 2 (Baseline, Day 1) to 
5 (Month 3) Exit/Early Termination, if the prescription is not up to date within 12 months at the 
screening visit.  Refraction will be performed at study visits after Screening if more than  
10 letters lost compared to the screening visit. 
12.3.2. 
Demographics, Medication/Therapy, and Medical History 
Demographics, Medication/Therapy, and Medical History will be obtained through subject 
interviews at Visit 1 (Screening) to determine if the subject meets eligibility criteria. 
 
Demographics 
Demographics include age, sex, race, prostaglandin analogs naïve status, and ethnicity.  They 
must be confirmed and recorded in the source documents. 
Medical and Surgical History 
Followings must be confirmed. 
 Non-ocular medical history including diagnosis and relevant treatments within  
5 years before the date of Visit 1 (Screening) 
 All lifetime ocular medical history including diagnosis and relevant treatments 
 All current ocular and systemic conditions 
Following details must be recorded in the source documents. 
 Diagnosis and treatment(s), affected eye(s) (if applicable), start date, and resolved 
date. 
Medications 
Followings must be confirmed. 
 Prior medications that have been used for POAG or OHT within 28 days before the 
date of Visit 1 (Screening) 
 All current concomitant medications (including over-the-counter) 
Following details must be recorded in the source documents. 
 Name of medication, route of administration, treated eye(s) (if applicable), dose, 
frequency, indication, start date and stop date 
Therapies 
Followings must be confirmed. 
 Prior therapies that have been used for POAG or OHT within 28 days before the date 
of Visit 1 (Screening) 


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 All current concomitant therapies 
Following details must be recorded in the source documents. 
 Name of therapy, treated eye(s) (if applicable), indication, start date and stop date 
Surgical procedures occurring during the study 
Following details must be recorded in the source documents. 
 Name of surgical procedure, treated eye(s) (if applicable), indication, start date and 
stop date 
12.3.3. 
Pregnancy Test 
A urine pregnancy test will be conducted using a commercially available test kit at Visit 1 
(Screening), Visit 2 (Baseline, Day 1), Visit 4 (Week 6) and Visit 5 (Month 3) Exit/Early 
Termination for all females of childbearing potential. A female is considered of childbearing 
potential unless she is post-menopausal (at least 12 months since last menses occurred), is 
without a uterus or without both ovaries, or has had a bilateral tubal ligation.  To perform the 
pregnancy test, follow instructions provided by the manufacturer of the urine pregnancy test kit.  
Urine samples will be analyzed at the site with results available prior to administration of study 
medication. 
12.3.4. 
Vital signs (Blood pressure/Pulse rate) 
Systolic blood pressure, diastolic blood pressure, and pulse rate will be measured at Visit 1 
(Screening), Visit 2 (Baseline, Day 1), and Visit 5 (Month 3) Exit/Early Termination.  Vital signs 
(resting blood pressure and pulse rate) will be collected anytime at Visit 1 (Screening), and 
approximately 08:00 for Visit 2 (Baseline, Day 1), and Visit 5 (Month 3) Exit/Early Termination 
before the morning dose. 
Vital signs will be collected in a sitting position after keeping quiet for more than 5 minutes. 
12.3.5. 
Best-Corrected Visual Acuity 
BCVA will be measured for each eye prior to the 08:00 IOP measurement at all visits except 
Visit 1 (Screening)/1a (Optional visit) under normal room illumination using visual acuity chart 
(Early Treatment Diabetic Retinopathy Study [ETDRS] chart) and the logMAR scoring and will 
be recorded in the subject’s source document.  For Visit 1 (Screening)/1a (Optional visit), the 
corrected visual acuity should be performed prior to IOP measurement. If ETDRS chart is used, 
the following procedure should be followed. 
12.3.5.1. ETDRS Visual Acuity Scoring 
The Examiner records each letter identified correctly by circling the corresponding letter on an 
appropriate visual acuity worksheet.  The Examiner records a letter read incorrectly, or a letter 
for which the subject made no guess, by crossing the letter out with an “x” or a line.  Each letter 
read incorrectly is scored as one point.  The last line in which a letter is read correctly will be 
taken as the Base logMAR line. 


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The total number of letters that have an “x” or a line through them (letters read incorrectly or not 
at all) down to and including the Base logMAR line and multiply the total number by 0.02.  Add 
this value to the Base logMAR value to obtain the logMAR score. 
Example: 
Subject correctly reads 4 of 5 letters on the +0.2 line, and 2 of 5 letters on the +0.1 line,  
and zero letters on the 0.0 line 
Base logMAR value = +0.1 (last line in which a letter was read correctly) 
Total number of letters missed = 4 (number of letters missed on the +0.2 line plus the number 
missed on the +0.1 line) 
LogMAR score = +0.1 + (4 x 0.02) = 0.18 
 
Table 4: 
LogMAR Scoring Grid for ETDRS Eye Chart 
 
Total Number of Letters Missed 
Snellen 
Base 
LogMAR 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
20/200 
+1.0 
1.00 
1.02 
1.04 
1.06 
1.08 
--- 
--- 
--- 
--- 
--- 
--- 
20/160 
+0.9 
0.90 
0.92 
0.94 
0.96 
0.98 
1.00 
1.02 
1.04 
1.06 
1.08 
1.10 
20/125 
+0.8 
0.80 
0.82 
0.84 
0.86 
0.88 
0.90 
0.92 
0.94 
0.96 
0.98 
1.00 
20/100 
+0.7 
0.70 
0.72 
0.74 
0.76 
0.78 
0.80 
0.82 
0.84 
0.86 
0.88 
0.90 
20/80 
+0.6 
0.60 
0.62 
0.64 
0.66 
0.68 
0.70 
0.72 
0.74 
0.76 
0.78 
0.80 
20/63 
+0.5 
0.50 
0.52 
0.54 
0.56 
0.58 
0.60 
0.62 
0.64 
0.66 
0.68 
0.70 
20/50 
+0.4 
0.40 
0.42 
0.44 
0.46 
0.48 
0.50 
0.52 
0.54 
0.56 
0.58 
0.60 
20/40 
+0.3 
0.30 
0.32 
0.34 
0.36 
0.38 
0.40 
0.42 
0.44 
0.46 
0.48 
0.50 
20/32 
+0.2 
0.20 
0.22 
0.24 
0.26 
0.28 
0.30 
0.32 
0.34 
0.36 
0.38 
0.40 
20/25 
+0.1 
0.10 
0.12 
0.14 
0.16 
0.18 
0.20 
0.22 
0.24 
0.26 
0.28 
0.30 
20/20 
0.0 
0.00 
0.02 
0.04 
0.06 
0.08 
0.10 
0.12 
0.14 
0.16 
0.18 
0.20 
20/16 
-0.1 
-0.10 
-0.08 
-0.06 
-0.04 
-0.02 
0.00 
0.02 
0.04 
0.06 
0.08 
0.10 
20/12.5 
-0.2 
-0.20 
-0.18 
-0.16 
-0.14 
-0.12 
-0.10 
-0.08 
-0.06 
-0.04 
-0.02 
0.00 
20/10 
-0.3 
-0.30 
-0.28 
-0.26 
-0.24 
-0.22 
-0.20 
-0.18 
-0.16 
-0.14 
-0.12 
-0.10 
12.3.6. 
Slit-Lamp Biomicroscopy 
As described below, slit-lamp biomicroscopy examinations will be performed and graded 
immediately prior to the 08:00 IOP measurement at all visits except Visit 1/1a (Screening or mid 
washout visit).  For Visit 1 (Screening)/1a (Optional visit), the biomicroscopy examinations 
should be performed prior to IOP measurement.  If Investigator evaluates for possible torn 
posterior lens capsule by biomicroscopy under dilation in subjects with pseudophakic eye(s) 
based on his/her decision at Visit 1 (Screening), please dilate pupil and evaluate after all other 
ocular procedures have been completed. 


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Anterior chamber cells and flare will be observed and graded using the SUN scale, before 
fluorescein instillation. 
Anterior Chamber Cells  
(0)  = No cells 
(0.5) = 1-5 cells 
(1)  = 6-15 cells 
(2)  = 16-25 cells 
(3)  = 26-50 cells 
(4)  = >50 cells 
 
Anterior Chamber Flare  
(0) = None 
(1) = Faint 
(2) = Moderate (iris/lens details clear) 
(3) = Marked (iris/lens details hazy) 
(4) = Intense (fibrin/plastic aqueous) 
The lid, conjunctiva, cornea, lens, and iris will be observed and graded on a 4-point scale  
(0-3 scale).  
Lid Hyperemia 
None 
(0) = Normal 
Mild 
(1) = Redness of most or all the lid(s) margin OR skin 
Moderate (2) = Redness of most or all the lid(s) margin AND skin 
Severe 
(3) =  Marked diffuse redness of both lid(s) margin AND skin  
Lid Edema 
None 
(0) = Normal 
Mild 
(1) = Localized to a small region of the lid(s) 
Moderate (2) = Diffuse, most or all the lid(s) but not  prominent/protruding 
Severe 
(3) = Diffuse, most or all the lid(s) AND prominent/protruding 
Conjunctival (Palpebral and Bulbar) Hyperemia 
None 
(0) = Normal 
Mild 
(1) = Slight localized injection 
Moderate (2) = Pink color, confined to palpebral OR bulbar conjunctiva 


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Severe 
(3) = Red color of the palpebral AND/OR bulbar conjunctiva 
Conjunctival Chemosis 
None 
(0) = Normal 
Mild 
(1) = Slight localized swelling 
Moderate (2) = Mild/medium localized swelling or mild diffuse swelling 
Severe 
(3) = Moderate diffuse swelling 
Corneal Edema 
None 
(0) = Normal 
Mild 
(1) = Mild, diffuse stromal haze 
Moderate (2) = Dense, diffuse stromal haze or bullae 
Severe 
(3) = Dense, diffuse bullae or stromal haze AND stromal edema 
Corneal Staining (with fluorescein) 
None 
(0) = Normal 
Mild 
(1) = Localized, occasional punctate staining 
Moderate (2) = Localized, dense OR diffuse occasional punctate staining 
Severe 
(3) = Diffuse, dense punctate staining which may be confluent staining 
Keratic Precipitate 
None 
(0) = Normal 
Mild 
(1) = Slight pigmentation or keratic precipitate 
Moderate (2) = Moderate pigmentation or keratic precipitate  
Severe 
(3) = Dense pigmentation or keratic precipitate 
Lens 
The lens will be noted as phakic, aphakic, or pseudophakic.  Phakic lens will be graded as 
described below: 
None 
(0) = No lens discoloration nor opacification 
Mild 
(1) = Yellow lens discoloration or small lens opacity (axial or peripheral) 
Moderate (2) = Amber lens discoloration or medium lens opacity (axial or peripheral) 
Severe 
(3) = Brunescent lens discoloration or complete lens opacification (no red reflex) 
 
 
 


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Anterior Synechiae of Iris 
None 
(0) = No anterior synechiae of iris is found 
Mild 
(1) = <25% anterior synechiae of iris is found 
Moderate (2) = 25% to 50% anterior synechiae of iris is found 
Severe 
(3) = >50% anterior synechiae of iris is found 
Posterior Synechiae of Iris 
None 
(0) = No posterior synechiae of iris is found 
Mild 
(1) = <25% posterior synechiae of iris is found 
Moderate (2) = 25% to 50% posterior synechiae of iris is found 
Severe 
(3) = >50% posterior synechiae of iris is found 
The presence and severity of iris color abnormalities, eyelash abnormalities, and eyelid 
abnormalities will be observed and graded on a 4-point scale (0-3 scale).   
Iris Color Abnormalities (e.g., increased pigmentation) 
The presence and severity will be assessed. If present, further specification is required. 
None 
(0) = No iris color abnormalities are found 
Mild 
(1) = Slight iris color abnormalities are found 
Moderate (2) = Moderate iris color abnormalities are found 
Severe 
(3) = Severe iris color abnormalities are found 
Eyelash Abnormalities (e.g., thickening, increased pigmentation/length/number, 
trichiasis) 
The presence and severity will be assessed. If present, further specification is required. 
None 
(0) = No eyelash abnormalities are found 
Mild 
(1) = Slight eyelash abnormalities are found 
Moderate (2) = Moderate eyelash abnormalities are found 
Severe 
(3) = Severe eyelash abnormalities are found 
Eyelid Abnormalities (e.g. increased pigmentation/hair growth) 
The presence and severity will be assessed. If present, further specification is required. 
None 
(0) = No Eyelid Abnormalities are found 
Mild 
(1) = Slight eyelid abnormalities are found 
Moderate (2) = Moderate eyelid abnormalities are found 


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Severe 
(3) = Severe eyelid abnormalities are found 
12.3.7. 
Intraocular Pressure 
IOP will be performed at each visit. At visit 1 (Screening)/1a (Optional visit), IOP can be 
measured at any time.  For Visit 2 (Baseline, Day 1) to Visit 5 (Month 3) Exit/Early Termination, 
IOP measurements will be scheduled for 08:00 (±60min), 10:00 (±60min), and 16:00 (±60min). 
IOP will be measured using calibrated manual Goldmann applanation contact tonometer with the 
subject in a sitting position.  The same Goldmann contact tonometer employing the investigator’s 
standard technique will be used throughout the study.  Measurement will be performed 
preferably by the same authorized study staff throughout the study.  Study staff who performs the 
IOP measurement must have at least 2 years of experience in IOP measurement. 
The right eye is always tested first.  At least two, and sometimes three, consecutive 
measurements are made to obtain a determination of IOP.  Each IOP measurement and the clock 
time of IOP measurement will be recorded in the subject’s source document. 
A single measurement is made as follows: 
 The study staff adjusts the force on the tonometer dial to an initial setting 
corresponding to 10 mmHg.  The slit-lamp magnification is set at 10X.  The light 
source is positioned at an angle of approximately 45°, and the aperture is maximally 
opened.  A cobalt blue filter is employed. 
 After instillation of a topical anesthetic, a fluorescein paper strip is placed near the 
lateral canthus in the lower conjunctival sac.  Once the lacrimal fluid is sufficiently 
colored, the paper strip is removed.  Alternatively, one drop of premixed fluorescein 
and anesthetic (Fluress, Barnes Hind) may be instilled.  The study staff should use the 
same technique each time, be it a paper strip or a pre-mixed eye drop. 
 The subject and slit-lamp are adjusted so that the subject’s head is firmly positioned 
on the chin rest and against the forehead rest without leaning forward or straining.  
Tight-fitting neckwear is loosened.  The subject is asked to look straight ahead at a 
distant object or fixation target.  If it is necessary to hold the eyelids open, the study 
staff holds the eyelids against the orbit rim, taking care not to apply any pressure to 
the globe.  The subject is cautioned not to hold his breath. 
 The study staff looks through the slit-lamp and gently brings the tip of the prism into 
contact with the center of the cornea.  The mires are well-focused, centered 
horizontally, and positioned vertically so that they are of equal circumference above 
and below the horizontal dividing line.  If the mires are narrower than approximately 
1/10 their diameter, additional fluorescein is instilled. 
 The study staff adjusts the measuring drum until the inner borders of the two mires 
just touch each other or, if pulsation is present, until the mires separate a given 
distance during systole and overlap the same distance during diastole. 
 The study staff removes the tip from the cornea, and records the reading on the dial, 
rounded to the next highest integer.  For example, if the measurement indicated is 


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between 16 and 17, then 17 is recorded as the measurement in the subject’s source 
document. 
 If corneal astigmatism is greater than 3.0 D, the prism is rotated so that the red line 
corresponds to the orientation of the longer axis of the elliptical applanated area. 
The above procedure is then repeated for the same eye, and that second measurement is also 
recorded in the subject’s source document. 
 If the two measurements differ by less than 3 mmHg, then the average of the two 
measurements becomes the recorded IOP. For example, if the two measurements are 
22 and 23, then 22.5 is the final recorded IOP. 
 However, if the two measurements differ by 3 mmHg or more, then a third 
measurement is made, and the median of the three measurements becomes the 
recorded IOP (the median is the middle measurement after ordering the 
measurements from low to high).  For example, if the three measurements are  
15, 19, and 16, then 16 is the final recorded IOP. 
The IOP in the left eye is then measured using the same technique. 
12.3.7.1. Goldmann Applanation Tonometer Calibration 
Every tonometer being used in the study must be calibrated for accuracy before the first subject 
undergoes screening (mandatory), and then check calibration monthly until the last subject has 
exited the study.  For checking calibration, follow the manufacturer’s instructions.  If the 
variation is within ±2 mmHg, the tonometer is considered adequately calibrated.  However, if the 
variation exceeds this amount, the tonometer should be sent for repair and a different, adequately 
calibrated instrument should be used for IOP measurement.  The date of each calibration, along 
with the name and signature (or initials) of the person who performed the calibration, will be 
documented.  The tonometer calibration record will be retained as a part of the study record. 
12.3.8. 
Gonioscopy 
Gonioscopy will be performed to examine the angle of the anterior chamber after IOP 
measurement at Visit 1 (Screening) if it has not been performed within 3 months (90 days).   
The Shaffer scale will be used to rate the degree of angle closure. 
(0) = approximately 5 degrees or less, complete or partial closure 
(1) = approximately 10 degrees 
(2) = approximately 20 degrees 
(3) = approximately 30 degrees 
(4) = approximately 40 degrees or more 
12.3.9. 
Pachymetry (Central Corneal Thickness) 
The central corneal thickness (µm) of each eye using any pachymeter including optical 
pachymeter, ultrasound pachymeter, OCT (optical coherence tomography), etc. will be measured 
and recorded after IOP measurement at Visit 1 (Screening).  Pachymetry will be performed after 
IOP measurement. 


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12.3.10. 
Visual Field 
Visual field examinations will be performed using a static or dynamic perimeter (Humphrey or 
Octopus) without pupil dilation at Visit 1 (Screening), if it has not been performed within  
3 months (90 days) or the previous visual field test(s) indicates low subject reliability (e.g., due 
to fixation losses, false positive errors, or false negative errors).  Glaucomatous visual field loss 
will be evaluated by the Investigator as presence or absence (mean deviation, pattern SD, 
glaucoma hemifield test, and type of glaucomatous visual field loss). 
Visual field tests that, in the Investigator's opinion, indicate low subject reliability (e.g., due to 
fixation losses, false positive errors, or false negative errors) can be repeated once more; if still 
low reliability then the subject should be excluded.  A copy of the computer printout from the 
visual field test(s) will be attached to the subject’s source documents. 
12.3.11. 
Ophthalmoscopy (Fundus) Examination 
The ophthalmoscopy (fundus) examination with pupil dilation will be performed for each eye at 
Visit 1 (Screening), Visit 2 (Baseline, Day 1), and Visit 5 (Month 3) Exit/Early Termination, and 
graded as described below.  The examination will be performed with pupil dilated at Visit 1 
(Screening) and Visit 5 (Month 3) Exit.  Dilate pupil and ophthalmoscopy examination will be 
performed after all other ocular procedures have been completed.  Cup to disc ratio and 
abnormality in retina, macula, choroid, and vitreous will also be evaluated. 
Glaucomatous Optic Nerve Findings 
The optic nerve will be evaluated using a 4-point scale (0-3 scale). 
None 
(0) = No damage 
Mild 
(1) = Optic nerve damage, secondary to glaucoma including any rim loss 
(sloping or thinning) 
Moderate (2) = Optic nerve damage, including cupping to disc margin at one or more 
points 
Severe 
(3) = Optic nerve damage, nearly total cupping, only nasal rim or less present 
12.3.12. 
Blood Sample for Pharmacogenomics/genomics Study 
All subjects participating in the study will have the option to participate in blood sampling for 
PGx and this will be consented to collect this optional test.  Subjects who do not wish to 
participate in the PGx sampling may still participate in the study.  For PGx, one whole blood 
sample (approximately 10 mL) will be collected on Visit 3 (Week 2) but may be collected at any 
time during the study, as shown in Schedule of Events and Procedures (Table 3).  The blood 
samples will be coded to protect the subject’s private information. DNA will be extracted from 
the blood sample and stored in the DNA repository for potential future PGx research.  The 
samples will be coded to protect the participant’s private information.  Sample handling, storage, 
and shipment will be defined in a separate procedure manual. 
If conducted, PGx research will be performed by appropriate assay platforms such as Polymerase 
Chain Reaction (PCR), hybridization, and sequencing.  Individual subjects’ results from the 
research testing of their sample will not be communicated to investigator and participants.  


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12.4. 
Appendix D- Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
1. Definition of AE 
AE Definition 
 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events Meeting the AE Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis)  
or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator (and not related to progression of underlying 
disease, unless judged by the investigator to be more severe than expected for the subject's 
condition). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.  Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent.  Such overdoses should be reported regardless of sequelae. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE.  Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will 
be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
Events NOT Meeting the AE Definition 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 


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


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3. Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 
The investigator will then record all relevant AE/SAE information in the CRF. 
 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Santen in lieu of completion of the Santen/AE/SAE CRF page. 
 
There may be instances when copies of medical records for certain cases are requested by 
Santen.  In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to Santen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Severity 
Severity of the AE should be assessed according to the following criteria: 
Mild: No interference with the subject’s daily activities; no medical intervention/therapy required. 
Moderate: Possible interference with the subject’s daily activities; no or minimal medical 
intervention/therapy required. 
Severe: Considerable interference with the subject’s daily activities; medical intervention/therapy 
required. 
 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality Note: During the double-masked period, regardless of the source of the 
reported occurrence of an AE in a subject, the masked investigator will assess the causality of the AE. 
 
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE. 
 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 
The following criterial can be used to make a causality judgment: 
 
Related (possibly or probably) 
 
There is a clinically plausible time sequence between onset of the AE and 
investigational product administration/protocol procedure; and/or  
 
There is a biologically plausible mechanism for investigational product causing or 
contributing to the AE; and 
 
The AE may or may not be attributed to concurrent/underlying illness, other drugs, or 
protocol procedures. 
 
Not Related 


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 
A clinically plausible temporal sequence is inconsistent with the onset of the AE and 
Investigational product administration/protocol procedure; and/or 
 
A causal relationship is considered biologically implausible. The investigator will use 
clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 
The investigator will also consult the Investigational Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each AE/SAE, the investigator must document in the medical records that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to Santen.  However, it is very important that 
the investigator always assess causality for every event before the initial transmission 
of the SAE data to Santen. 
 
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Procedures for Follow-up of AEs and SAEs 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Santen to 
elucidate the nature and/or causality of the AE or SAE as fully as possible.  This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
 
If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Santen with a copy of any post--mortem findings 
including histopathology.  
 
New or updated information will be recorded in the originally completed CRF. 
 
The investigator will submit any updated SAE data to Santen within 24 hours of receipt of 
the information. 
 
 
 
 
 
 


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4. Reporting of SAEs 
SAE Reporting to Santen via an Electronic Data Collection Tool 
 
The primary mechanism for reporting an SAE to Santen will be the electronic data 
collection tool. 
 
If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
 
After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken  
off-line, then the site can report this information on a paper SAE form to Santen Global 
Pharmacovigilance (Table 1). 
 
Contacts for SAE reporting can be found in Table 1. 
 
For SAE supporting information (i.e. X-ray reports, hospital summaries, etc.) that are not 
included in the EDC format, follow a procedure analogous to the manual SAE reporting 
process.  
SAE Reporting to Santen via Paper CRF (If Electronic Data Collection Tool is Unavailable) 
 
Complete both the paper AE and SAE Forms (located in your site regulatory binder). 
 
Attach a Fax Cover Sheet with your contact information and fax to Santen Global 
Pharmacovigilance (Table 1). 
 
In the rare circumstance of the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the paper AE and SAE forms sent by overnight mail or courier 
service. 
 
Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
 
Contacts for SAE reporting can be found in Table 1. 
 
 
 
 
 
 
 
 


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12.5. 
Appendix E- Adverse Event Case Report Form Items and Terms 
Concise Description of Event: 
A concise description of the signs, symptoms, complaints, or 
diagnosis of the subject’s problem (e.g., nasal congestion).  
Complete one AE form for related symptoms that can be grouped as 
one condition (e.g., If a subject complains of sneezing, nasal 
congestion, watery eyes, the AE is described as cold symptoms).  If 
two independent events occur at the same time, separate AE forms 
must be completed for each event. 
Affected Eye(s): 
Indicate if ocular event is OD, OS, or OU. Non-ocular events should 
be recorded as N/A. 
Adverse Event Serious/Event 
of Special Interest: 
If AE is serious or an Event of Special Interest, Santen must be 
notified immediately (within 24 hours).  Complete both the AE and 
the SAE eCRFs in the EDC system. In the event the EDC system is 
unavailable, and your site needs to report an SAE, please follow the 
manual process described in the body of the protocol under 
“Reporting of SAEs.” 
Date of Event Onset: 
The date the event started. 
Maximum Severity of Event: 
Record the severity of the AE according to the following definitions: 
Mild: Aware or unaware of event, but easily tolerated 
Moderate: Discomfort enough to cause interference with usual 
activity 
Severe: Incapacitating; unable to work or perform usual activity 
For intermittent events, record the maximum severity of the 
individual events.  For example, if a subject complains of 
intermittent headaches for one week and the severity of each 
headache ranges from mild to moderate, then the severity would be 
moderate.  Record that the severity of the headaches ranged from 
mild to moderate in the comment section of the form. 
If an event occurs with each administration (e.g., eyes burn mild to 
moderate for 5 minutes after every administration), record the 
maximum severity of the individual incident. In the example above, 
the severity is moderate.  Record that the severity of the event 
ranged from mild to moderate in the comment section of the form.  
Action Taken as Related to 
this AE:  
Indicate the action taken as a result of the AE.  If the frequency of 
Investigational product administration was changed or discontinued 
temporarily or if surgery was required, provide more detailed 
explanation in the comment section of the form.  If “Other” is 
indicated, specify the action taken. 


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Outcome of Event: 
Indicate the outcome of the AE and provide resolution date or date 
of death. 
For intermittent events (e.g., intermittent headache) and events that 
occur with each administration (e.g., eyes burn for 5 minutes after 
every administration), the date should reflect when the last 
occurrence resolved or stopped.  For example, if a subject has an 
intermittent headache from 12/14/2010 until 12/21/2010 and each 
individual headache lasts 3 hours a day, then the date of resolution is 
12/21/2010 (NOT 12/14/2010). 
If treatment was initiated, then include the treatment and duration in 
the comments section (e.g., subject took acetaminophen for 
headache on 12/14/2010, 12/17/2010, and 12/20/2010). 
Relationship to Study 
Drug/Investigational 
Product: 
Indicate if there is a reasonable possibility that the AE may have 
been caused by the study drug/investigational product with a Yes or 
No response.  A “reasonable possibility” means there is evidence to 
suggest a causal relationship between the study drug/investigational 
product and the AE. 
If response is No, select the possible alternative explanation of the 
event from the list provided. 
For SAE supporting information (i.e., X-ray reports, hospital summaries, etc.) that are not 
included in the EDC format, follow the same reporting process as for manual SAE reporting. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.6. 
Appendix F – The Glaucoma Quality of Life-15 Questionnaire 
 
 
 


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12.7. 
Appendix G - Protocol Amendment 1 Summary of Changes 
 
Global Changes: 
 
Herein is a summary of changes made to original protocol 
dated 16 October 2020 and reflected in Amendment 1 dated  
18 February 2021. New text is identified in bold and italicized 
and deleted text with bold/strikethrough. 
 
Updated Contact Information. 
 
Updated exploratory objective. 
 
Added Visit 1 (Screening) and Visit 2 (Eligibility/Baseline,  
D 1) may be combined into one visit for treatment-naïve 
subjects. 
 
Updated Exclusion # 6, bullet two by adding excluding join 
injections. 
 
Added Aphakia to the Exclusion # 16. 
 
Added new exclusion for the use of marijuana excluding  
28 days prior to Day 1 visit. 
 
Updated visit window for post-study follow-up phone call 
from +/- 7 days to + 7 days. 
 
Added evaluation of the presence and severity of iris color 
abnormalities, eyelash abnormalities, and eyelid abnormalities 
graded on a 4-point scale (0-3 scale). 
 
Section: 
Synopsis, Section 3.4 Exploratory objectives 
Original Text: 
To achieve the response from subjects on the Glaucoma Quality of Life 
(GQL)–15 Questionnaire. 
Revised Text: 
To achieve the response from explore Quality of Life in subjects with 
POAG or OHT when given DE-126 or Timolol for 3 months on the 
Glaucoma Quality of Life (GQL)–15 Questionnaire. 
Rationale: 
Clarified of Exploratory Objectives. 
 
 
 
 


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Section: 
Synopsis, Section 4.1 Overall Study Design 
Original Text: 
Please note: that prior to trial, subjects are allowed to have used at a 
maximum of two active ingredients for IOP reduction. 
Revised Text: 
Please note: that prior to trial, sSubjects are only allowed to be treated 
with have used at a maximum of two active ingredients for IOP reduction 
prior to screening. 
Rationale: 
Clarified that subjects are only allowed to be treated with maximum of two 
active ingredients for IOP reduction prior to Screening Visit.  
 
Section: 
Synopsis, Section 4.1 Overall Study Design 
Original Text: 
Final eligibility for randomization will be determined at Visit 2 (Baseline, 
Day 1) after all necessary washout from prior IOP-lowering medications 
have been completed.  Subjects who have not used any IOP-lowering 
medication for the last 28 days, including treatment-naive subjects, must 
have ≥ 1 day between their screening visit and Visit 2 (Baseline, Day 1). 
Revised Text: 
Final eligibility for randomization will be determined at Visit 2 (Baseline, 
Day 1) after all necessary washout from prior IOP-lowering medications 
have been completed.  Subjects who have not used any IOP-lowering 
medication for the last 28 days, including treatment-naive subjects, 
must have ≥ 1 day between their screening visit and Visit 2 (Baseline, 
Day 1). 
Rationale: 
Removed the statement and clarified in a new paragraph that both 
Screening and Day 1 may be combined for treatment-naïve subjects. 
 
Section: 
Synopsis, Section 4.1 Overall Study Design, Table 3 footnote 
Original Text: 
N/A 
Revised Text: 
Please note: Visit 1 (Screening) and Visit 2 (Eligibility/Baseline, Day 1) 
may be combined into one visit for treatment-naïve subjects as long as 
the additional requirements of Visit 2 (Eligibility/Baseline, Day 1) are 
fulfilled on the day of this combined visit; in particular, full diurnal IOP 
measurements (at 08:00, 10:00, 16:00) must be taken. 
Rationale: 
Added to allow subjects to skip unnecessary visits and reduces subject wait 
time to receive the treatment.   
 


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Section: 
Synopsis, Section 4.1 Pharmacogenomics/Genomics 
Original Text: 
Subjects who consent to the optional pharmacogenomics/genomics (PGx) 
laboratory study will provide a blood sample for future testing.  It will be 
collected at Visit 3 (Week 2) but may be collected at any time during the 
study.  The purpose of this exploratory research is to identify possible 
genetic markers associated with the study medication(s) and/or ocular 
conditions. 
Revised Text: 
Subjects who consent to the optional pharmacogenomics/genomics (PGx) 
laboratory study will provide a blood sample for future testing.  The 
earliest this sample is to It will be collected at Visit 3 (Week 2) but it may 
also be collected at any time later during the study after Visit 2 
(Eligibility/Baseline) or at a separate post-study visit, if necessary.  The 
purpose of this exploratory research is to identify possible genetic markers 
associated with the study medication(s) and/or ocular conditions. 
Rationale: 
Clarified that the PGx samples can be collected anytime after subject 
randomized or at a separate unscheduled visit.  
 
Section: 
Table 3: Schedule of Events and Procedures 
Original Text: 
Follow-up Period Visit window in days ±7 
Revised Text: 
Follow-up Period Visit window in days ± +7 
Rationale: 
Administrative change to provide additional clarity that follow-up phone 
call should be conducted at least 2 weeks of post last study drug 
administration with a visit window of +7 days.  
 
Section: 
Section 5.1. Subject Inclusion Criteria # 10 
Original Text: 
Completed the required wait/washout period. 
Revised Text: 
Completed the required wait/washout period (if required per protocol). 
Rationale: 
Added if required per protocol for clarity. 
 
 
 
 


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Version 2.0 18FEB2021 
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Section: 
Section 5.2. Subject Exclusion Criteria # 6, third bullet point and Section 
6.3.1 Prohibited Medications or Therapies 
Original Text: 
 Any ocular, periocular, inhaled, nasal, or systemic corticosteroids. 
Revised Text: 
 Any ocular, periocular, inhaled, nasal, or systemic corticosteroids 
(excluding joint injections). 
Rationale: 
Added excluding joint injections to clarify that systemic corticosteroids are 
allowed for subjects using for joint injections.  
 
Section: 
Section 5.2. Subject Exclusion Criteria # 16. 
Original Text: 
Pseudophakia with a torn posterior lens capsule, history or presence of 
macular edema or known risk factors (e.g., retinal vein occlusion, diabetic 
retinopathy, uveitis, age-related macular degeneration) for macular edema 
in either eye. 
Revised Text: 
Aphakia, pseudophakia with a torn posterior lens capsule, history or 
presence of macular edema or known risk factors (e.g., retinal vein 
occlusion, diabetic retinopathy, uveitis, age-related macular degeneration) 
for macular edema in either eye. 
Rationale: 
Added Aphakia to clarify that subjects with a history of Aphakia and 
Pseudophakia with torn posterior lens capsule will be excluded.  
 
Section: 
Section 5.2. Subject Exclusion Criteria # 23 
Original Text: 
N/A 
Revised Text: 
Use of marijuana and/or marijuana derivatives within 28 days prior to 
Visit 2 (Baseline, Day 1); including, but not limited to, cannabidiol 
topical eye drops. 
Rationale: 
Added new exclusion criteria due to marijuana can affect Intra Ocular 
Pressure, and any use of marijuana and/or marijuana derivatives are 
excluded. 
 
 
 
 
 
 


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Section: 
Section 6.2.2. Study Medication Storage 
Original Text: 
Study medications should be stored under refrigeration at 2° to 8°C (36° to 
46°F), protected from light, and stored upright.  During the refrigeration 
storage, the Investigator (or his/her designee) will verify and record that 
the temperature was maintained at 2° to 8°C (36° to 46°F) using 
temperature recorder at least once every seven days at the investigational 
site until the last subject has exited the study at the site.   
Revised Text: 
Study medications should be stored under refrigeration at 2° to 8°C (36° to 
46°F), protected from light, and stored upright.  During the refrigeration 
storage, the Investigator (or his/her designee) will verify and record that 
the temperature was maintained at 2° to 8°C (36° to 46°F) using 
temperature recorder at least once every seven days at the 
investigational site until the last subject has exited the study at the site.   
Rationale: 
Removed the statement for clarity that temperature monitoring at the site 
level will be recorded daily during normal business hours.  
 
Section: 
Section 6.3.1. Prohibited Medications or Therapies 
Original Text: 
 If artificial sodium chloride/potassium chloride ophthalmic solution, 
cataract treatment agents, Vitamin B12 formulation, over-the-counter 
dry eye artificial tears/drops are concomitantly used, there must be an 
interval of at least 5 minutes between use of these ocular medications 
and use of the study medication.  
Revised Text: 
 If artificial sodium chloride/potassium chloride ophthalmic solution, 
cataract treatment agents, Vitamin B12 formulation, over-the-counter 
dry eye artificial tears/drops are concomitantly used, there must be an 
interval of at least 5 10 minutes between use of the study medication 
and these ocular medications (the study medication to be given first) 
and use of the study medication.  
Rationale: 
Clarified that between the use of any permitted ocular medications and 
study medication there will be an interval for at least for 10 minutes and 
study medication will be given first before any allowed ocular medications.  
 
 
 
 
 


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Section: 
Section 12.3.6 Slit-Lamp Biomicroscopy 
Original Text: 
N/A 
Revised Text: 
The presence and severity of iris color abnormalities, eyelash 
abnormalities, and eyelid abnormalities will be observed and graded on a 
4-point scale (0-3 scale).   
Iris Color Abnormalities (e.g., increased pigmentation) 
The presence and severity will be assessed. If present, further 
specification is required. 
None 
(0) = No iris color abnormalities are found 
Mild 
(1) = Slight iris color abnormalities are found 
Moderate (2) = Moderate iris color abnormalities are found 
Severe 
(3) = Severe iris color abnormalities are found 
Eyelash Abnormalities (e.g., thickening, increased 
pigmentation/length/number, trichiasis) 
The presence and severity will be assessed. If present, further 
specification is required. 
None 
(0) = No eyelash abnormalities are found 
Mild 
(1) = Slight eyelash abnormalities are found 
Moderate (2) = Moderate eyelash abnormalities are found 
Severe 
(3) = Severe eyelash abnormalities are found 
Eyelid Abnormalities (e.g., increased pigmentation/hair growth) 
The presence and severity will be assessed. If present, further 
specification is required. 
None 
(0) = No Eyelid Abnormalities are found 
Mild 
(1) = Slight eyelid abnormalities are found 
Moderate (2) = Moderate eyelid abnormalities are found 
Severe 
(3) = Severe eyelid abnormalities are found 
Rationale: 
Added evaluation of the presence and severity of iris color abnormalities, 
eyelash abnormalities, and eyelid abnormalities to monitor any changes.  
4-point scale (0-3 scale) included for overall study consistency. 
 



SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:   
ANGEL-2: A Phase IIb, Randomized, Double-Masked, Active-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety of 
DE-126 Ophthalmic Solution 0.002% Compared with Timolol Maleate 
Ophthalmic Solution 0.5% in Subjects with Primary Open Angle 
Glaucoma or Ocular Hypertension. 
 
 
 
NCT Number:  
NCT04742283  
 
Date of the document: 
 15 Nov 2021 
 
 
 


 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
DE-126 ANGEL-2 Study 
 
 
 
Protocol 
Title: 
A Phase IIb, Randomized, Double-Masked, Active-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety of DE-
126 Ophthalmic Solution 0.002% Compared with Timolol Maleate 
Ophthalmic Solution 0.5% in Subjects with Primary Open Angle Glaucoma or 
Ocular Hypertension 
 
 
Product: 
DE-126 ophthalmic solution 0.002%  
 
 
Protocol 
Number:  
012604IN 
 
 
Sponsor: 
Santen Inc. 
 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608 
USA. 
 
 
Date:  
November 15th, 2021 
 
 
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. 
 
 
 


Confidential 
 
 
 


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TABLE OF CONTENTS 
ABBREVIATIONS .........................................................................................................................1 
1. 
INTRODUCTION ........................................................................................................3 
2. 
OBJECTIVES AND ENDPOINTS ..............................................................................3 
2.1. 
Objectives .....................................................................................................................3 
2.2. 
Endpoints ......................................................................................................................4 
2.2.1. 
Primary Efficacy Endpoint ...........................................................................................4 
2.2.2. 
Key Secondary Efficacy Endpoint ................................................................................4 
2.2.3. 
Other Secondary Efficacy Endpoints ............................................................................4 
2.2.4. 
Safety Endpoints ...........................................................................................................4 
2.2.5. 
Exploratory Endpoint ....................................................................................................4 
3. 
STUDY DESIGN .........................................................................................................5 
3.1. 
General Study Design ...................................................................................................5 
3.2. 
Randomization and Masking ........................................................................................6 
3.3. 
Sample Size Planning ...................................................................................................7 
3.4. 
Visits and Assessments .................................................................................................7 
4. 
DEFINTIONS .............................................................................................................10 
4.1. 
Time-Related Terms ...................................................................................................10 
4.1.1. 
Screening Visit ............................................................................................................10 
4.1.2. 
Baseline Visit ..............................................................................................................10 
4.1.3. 
Treatment Start and End Dates, Extent of Exposure (Days) ......................................10 
4.1.4. 
Study Day ...................................................................................................................10 
4.1.5. 
Days on Study .............................................................................................................11 
4.1.6. 
Analysis Visit Window and Out-of-Window Measurements .....................................11 
4.1.7. 
Analysis Timepoint Window and Out-of-Window Measurements ............................11 
4.2. 
Efficacy-Related Definitions ......................................................................................12 
4.2.1. 
Study Eye ....................................................................................................................12 
4.2.2. 
Efficacy Measure ........................................................................................................12 
4.2.3. 
Baseline Score ............................................................................................................12 
4.2.4. 
IOP Response Endpoints and Response Rate .............................................................13 
4.3. 
Safety-Related Definitions ..........................................................................................13 
4.3.1. 
Adverse Event .............................................................................................................13 


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4.3.1.1. 
Serious Adverse Event ................................................................................................13 
4.3.1.2. 
Ocular Adverse Event .................................................................................................14 
4.3.1.3. 
Suspected Adverse Reaction .......................................................................................14 
4.3.1.4. 
Events of Special Interest ...........................................................................................14 
4.3.2. 
Safety Measures ..........................................................................................................14 
4.4. 
Other Definitions ........................................................................................................15 
4.4.1. 
Prior and Concomitant Medications ...........................................................................15 
4.4.2. 
Concurrent Medical Conditions ..................................................................................15 
5. 
STUDY POPULATION .............................................................................................16 
6. 
GENERAL CONSIDERATIONS ..............................................................................17 
6.1. 
Adjustments for Covariates ........................................................................................17 
6.2. 
Handling of Missing Data ...........................................................................................17 
6.2.1. 
Efficacy Measure ........................................................................................................17 
6.2.2. 
Safety Measures ..........................................................................................................17 
6.2.3. 
Dates for Medical Events and Medications ................................................................17 
6.3. 
Multi-Center Studies ...................................................................................................18 
6.4. 
Multiple Comparisons / Multiplicity ..........................................................................18 
6.5. 
Interim Analysis ..........................................................................................................18 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................19 
7.1. 
Subject Disposition .....................................................................................................19 
7.2. 
Demographics and Baseline Characteristics ...............................................................19 
7.3. 
Medical and Surgical History .....................................................................................20 
7.4. 
Protocol Deviations ....................................................................................................20 
7.5. 
Prior and Concomitant Medications ...........................................................................20 
7.6. 
Treatment Compliance ................................................................................................21 
7.7. 
Exposure to Study Medication ....................................................................................21 
8. 
EFFICACY ANALYSES ...........................................................................................22 
8.1. 
Analyses of Primary Endpoint and Key Secondary Endpoint ....................................22 
8.1.1. 
Primary Analysis ........................................................................................................22 
8.1.1.1. 
Primary Endpoint ........................................................................................................22 
8.1.1.2. 
Key Secondary Endpoint ............................................................................................23 
8.1.2. 
Sensitivity Analyses ....................................................................................................23 
8.2. 
Analyses of Other Secondary Endpoints ....................................................................24 


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8.2.1. 
Responder Rates .........................................................................................................24 
8.3. 
Subgroup Analyses .....................................................................................................24 
9. 
SAFETY ANALYSES ...............................................................................................25 
9.1. 
Adverse Event .............................................................................................................25 
9.2. 
Best-Corrected Visual Acuity .....................................................................................25 
9.3. 
Slit-lamp Biomicroscopy ............................................................................................26 
9.4. 
Ophthalmoscopy .........................................................................................................26 
9.5. 
Central Corneal Thickness ..........................................................................................26 
9.6. 
Vital Signs ..................................................................................................................26 
10. 
ANALYSIS OF EXPLORATORY ENDPOINT .......................................................27 
11. 
REFERENCES ...........................................................................................................28 
12. 
APPENDICES ............................................................................................................29 
 
LIST OF TABLES 
Table 1: 
Schedule of Events and Procedures ..............................................................................8 
Table 2: 
Post-Baseline Analysis Visit and Analysis Window ..................................................11 
Table 3 
Response Endpoints ....................................................................................................13 
Table 4: 
Safety Assessments .....................................................................................................14 
Table 5 
GQL-15 Questionnaire Items Associated with 4 Domains ........................................27 
 
 
LIST OF FIGURES  
Figure 1: 
Study Design Diagram ..................................................................................................5 
 
 


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ABBREVIATIONS 
ACE 
Angiotensin-Converting Enzyme  
ADaM 
Analysis Data Model 
AE 
adverse event 
ATC 
Anatomical-Therapeutic-Chemical  
BCVA 
Best-Corrected Visual Acuity  
BID 
twice a day  
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CSR 
Clinical Study Report 
eCRF 
electronic Case Report Form 
ESI 
event of special interest 
ET 
early termination 
FAS 
full analysis set 
GQL-15 
Glaucoma Quality of Life –15 
IOP 
intraocular pressure 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeter of mercury 
MI 
multiple imputation 
MMRM 
Mixed-effects Model for Repeated Measures 
OHT 
ocular hypertension 
OD 
oculus dexter (right eye) 
OS 
oculus sinister (left eye) 
OU 
oculus uterque (both eyes) 
POAG 
primary open-angle glaucoma 
PMM 
pattern-mixture model 
PPS 
per-protocol set 
PT 
preferred term 
QD 
once daily  
RTSM 
Randomization and Trial Supply Management system 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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SAR 
suspected adverse reaction 
SAS 
Statistical Analysis System 
SOC 
system organ class 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 
 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the statistical methods to be implemented for the 
analysis of data collected from the 012604IN study within the scope of Santen’s Protocol 
012604IN, “A Phase IIb, Randomized, Double-Masked, Active-Controlled, Parallel-Group, 
Multicenter Study Assessing the Efficacy and Safety of DE-126 Ophthalmic Solution 0.002% 
Compared with Timolol Maleate Ophthalmic Solution 0.5% in Subjects with Primary Open 
Angle Glaucoma (POAG) or Ocular Hypertension (OHT)”.  It applies to the Study Protocol 
Amendment 1 dated 18 February 2021 and provides detailed instructions as to how each analysis 
will be performed. 
Results obtained from the analyses specified in the final approved version of the SAP will 
become the basis of the clinical study report (CSR) for this study.  Any deviations from the final 
approved version of the SAP must be substantiated by sound statistical reasoning and 
documented in the CSR. 
2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of this study is to investigate whether the IOP lowering efficacy of DE-
126 ophthalmic solution 0.002% dosed once daily (QD, in the evening at 20:00) is non-inferior 
to that of Timolol maleate ophthalmic solution 0.5% dosed twice daily (08:00 and 20:00) in 
subjects with POAG or OHT after treatment for 3 months. If non-inferiority is met, superiority 
will be tested. 
The secondary objectives of this study are:  
• to compare the mean diurnal IOP between DE-126 ophthalmic solution 0.002% and 
Timolol maleate ophthalmic solution 0.5% after 3 months of treatment. If non- inferiority 
is met, superiority will be tested.        
• to evaluate the changes and percent changes in IOP from baseline at all post-baseline 
visits.    
• to evaluate proportions of subjects achieving target pressure reductions expressed as 
either in percent reductions of ≥ 20%, ≥ 25%, or ≥ 30% or in achieving a target IOP value 
of IOP ≤ 18 mmHg. 
The safety objective of this study is to evaluate the safety of DE-126 ophthalmic solution 0.002% 
as compared to Timolol maleate ophthalmic solution 0.5% in subjects with POAG or OHT.  
The exploratory objective of this study is to explore the Quality of Life in subjects with POAG 
or OHT based on the Glaucoma Quality of Life (GQL)–15 Questionnaire when given DE-126 or 
Timolol for 3 months.   


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2.2. 
Endpoints 
2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is IOP in the study eye measured at the specified time points: 
08:00, 10:00, and 16:00 at Week 2, Week 6, and Month 3 visits.  
2.2.2. 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is mean diurnal IOP in the study eye at Month 3 (Visit 5).  
2.2.3. 
Other Secondary Efficacy Endpoints 
Other secondary endpoints include:  
• Mean diurnal IOP in the study eye at Week 2 (Visit 3) and Week 6 (Visit 4)   
• Change and percent change from baseline (Visit 2, Day 1) in IOP in the study eye at each 
timepoint of each post-baseline visit  
• Change and percent change from baseline in mean diurnal IOP in the study eye at each 
post-baseline visit, 
• Having a mean diurnal IOP reduction ≥ 20%, ≥ 25%, or ≥ 30% from Baseline (Visit 2, 
Day 1) in the study eye at each post-baseline visit  
• Having a mean diurnal IOP ≤ 18mmHg in the study eye at each post-baseline visit   
2.2.4. 
Safety Endpoints 
The safety of DE-126 will be evaluated by 
• AEs and serious AEs (SAEs), including both ocular and non-ocular AEs, 
• Visual acuity: measured by best-corrected visual acuity (BCVA), 
• Slit-lamp biomicroscopy, 
• Ophthalmoscopy examination results, 
• Vital signs, 
2.2.5. 
Exploratory Endpoint 
Exploratory endpoints to be summarized are the GQL-15 total score and 4 domain scores 
obtained from the GQL-15 Questionnaire. The 4 domains are central and near vision, outdoor 
mobility, peripheral vision, and dark adaption and glare.   
 
 
 


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3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is a Phase IIb, randomized, double-masked, active-controlled, parallel-group, and 
multicenter study assessing the efficacy and safety of DE-126 ophthalmic solution 0.002% 
compared with Timolol maleate ophthalmic solution 0.5% in subjects with POAG or OHT. 
Subjects diagnosed with POAG 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 treatment for 3 months. 
Approximately 294 adult subjects with POAG or OHT who meet all eligibility criteria will be 
randomized in a 1:1 ratio to receive either: 
• DE-126 Ophthalmic Solution 0.002% QD (20:00) and Vehicle QD (08:00), or 
• Timolol Maleate Ophthalmic Solution 0.5% BID, twice daily (20:00 and 08:00) 
In the Double-Masked Treatment Period, Timolol maleate ophthalmic solution 0.5% will be used 
as active control. 
As shown in the Study Design Diagram (Figure 1), this study consists of a Screening Period of 
up to 35 days including a washout period of up to 28 days (+ 7 days window) and a 3-month 
Double-Masked Treatment Period.    
 
Figure 1: 
Study Design Diagram 
 
At the Screening visit (Visit 1), subjects will be screened against the inclusion and exclusion 
criteria. Eligible subjects will be instructed to discontinue use of all IOP-lowering medications, if 
any, during a washout period as follows (up to +7 days as a window is allowed). 


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Final eligibility for randomization will be determined at Visit 2 (Baseline, Day 1) after all 
necessary washout from prior IOP-lowering medications have been completed. 
Approximately 294 eligible adult subjects will be randomized to receive either DE-126 
ophthalmic solution 0.002% QD in the evening and vehicle QD in the morning or Timolol 
maleate ophthalmic solution 0.5% BID in a 1:1 ratio. Randomized subjects will be treated for 
3 months with scheduled visits at Visit 2 (Baseline, Day 1), 3 (Week 2), 4 (Week 6), and 
5 (Month 3). Subjects will be contacted approximately 2 weeks post last study drug 
administration by a phone call to confirm AE. 
3.2. 
Randomization and Masking 
A stratified permuted-block randomization will be employed to randomize eligible subjects in a 
1:1 ratio to either DE-126/Vehicle arm or Timolol Maleate arm. The randomization will be 
stratified by mean diurnal IOP in the study eye at baseline visit (Visit 2): <25 mmHg vs. ≥25 
mmHg. 
The randomization schedule will be generated and implemented using central randomization via 
Interactive Response Technology (Medidata Rave RTSM). Each randomized subject will receive 
numbered study medication kits as assigned by Medidata Rave RTSM (Randomization and Trial 
Supply Management system). 
This is a double-masked study. The subjects, Investigators, Examiners, and Santen personnel 
involved in the conduct of the study will be masked to the study treatment. An authorized 
unmasked study staff member at the investigative site who is not the Investigator or Examiner 
will dispense and collect study medication(s) and will query about dosing compliance. 
Subjects will be instructed not to show the eye drop bottles or discuss the eye drops to either the 
Investigator or the Examiner or other study subjects. The active control treatment (Timolol 
Maleate) bottles will be over-labeled and packaged in the same secondary package (e.g., 
cardboard carton) as the investigational treatment (DE-126). Subjects in DE-126/Vehicle arm 
will receive a kit containing 2 bottles labeled “morning” for the morning dose and 2 bottles 
labeled “evening” for the evening dose. Subjects on Timolol arm will receive a kit containing 2 
bottles labeled morning/evening for the BID dosing. 
Each eligible subject will receive a numbered study medication kit assigned by Central 
randomization via Interactive Response Technology (Medidata Rave RTSM) at Visit 2 
(Baseline, Day 1) and at Visit 4 (Week 6). 
In case of a medical emergency, the Principal Investigator may reveal the treatment information 
by unmasking through Medidata Rave RTSM to know which treatment the subject has received. 
The Principal Investigator (or his/her designee) should contact Santen, or Santen’s designee, 
before taking this measure, if there is sufficient time. Santen, or Santen’s designee, must be 
informed of all instances where the code is broken and of the reasons for such instances. 
Additionally, the AE or SAE for which study treatment was unmasked should be reported to 
Santen Pharmacovigilance. 


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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 between-treatment difference of 0 mmHg, SD of 
4.0 mmHg and a correlation coefficient of 0.6 among repeated measures, approximately 280 
adult subjects in total (140 subjects per treatment arm) will provide 70% power to demonstrate 
non-inferiority of DE-126 Ophthalmic Solution 0.002% to Timolol maleate ophthalmic solution 
0.5%. Assuming a drop-out rate of 5%, the final needed sample size will be 294 in total, i.e. 147 
subjects/arm. 
3.4. 
Visits and Assessments 
There are 5 scheduled visits for each subject.  Assessments at each visit and the time/visit 
window for each post-baseline assessment are specified in the Assessment Schedule (Table 1).  
For subjects whose study participation is terminated prior to Month 3 (Visit 5, Day 91 ± 3), to 
the extent possible, all assessments scheduled for Visit 5 will be performed at the 
early termination (ET) visit.  Subjects who have an on-going study medication-related 
serious adverse event (SAE) at study completion or at ET from the study will be followed by 
the Clinical Investigator until the event is resolved or determined to be irreversible, chronic, or 
stable. 
 


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Table 1: 
Schedule of Events and Procedures   
 
Screening Phase 
Double-Masked Treatment Phase 
Follow-up 
Period 
Visit 1 
Screening 
* 
Optional 
Visit 1a 
Visit 2 
Eligibility
/ Baseline 
(Day 1) * 
Visit 3 
Week 2 
Visit 4 
Week 6 
Visit 5 
Month 3 
or Early 
Terminationa 
2 weeks of 
post-Last 
Study Drug 
Administrati
on  
Study day  
D-28 
D1 
D14 
D42 
D90 
Study Exit 
+ D14  
Visit window in days  
+7 
NA 
±3 
±3 
±7 
+7 
Signed and dated informed 
consent b 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria b 
X 
 
X 
 
 
 
 
Demographics and Medical 
History, including prior PGAc 
X 
 
 
 
 
 
 
Other prior or Concomitant 
Medications/Therapies/ 
Procedures 
X 
X 
X 
X 
X 
X 
 
Dosing Compliance Check 
 
 
 
X 
X 
X 
 
Adverse Events d 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test e 
X 
 
X 
 
 
 
 
Vital Signs (blood 
pressure/heart rate) f 
X 
 
X 
(08:00) 
 
 
X (08:00) 
 
Refraction g 
X 
 
 
 
 
 
 
BCVA g 
X 
X 
X 
(08:00) 
X 
(08:00) 
X 
(08:00) 
X (08:00) 
 
Slit-lamp Biomicroscopy h 
X 
 
X 
(08:00) 
X 
(08:00) 
X 
(08:00) 
X (08:00) 
 
IOP i 
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 j 
X 
 
 
 
 
 
 
Instill study medication after 
IOP measurement at site by 
unmasked site staff and 
record dosing 
 
 
 
X 
(08:00) 
X 
(08:00) 
X (08:00) 
 
Gonioscopy k 
X 
 
 
 
 
 
 
Visual Field l 
X 
 
 
 
 
 
 
Ophthalmoscopy m 
X 
 
X 
(16:00) 
 
 
X (16:00) 
 
Blood Sampling for PGx n 
 
 
X 
Dispense Study Medication & 
Diary 
 
 
X 
 
X 
 
 
Collect Study Medication & 
Diary 
 
 
 
 
X 
X 
 
Phone call o 
 
 
 
X 
X 
X 
X 
GQL-15 questionnaire p 
 
 
X 
 
 
X 
 
*  Visit 1 (Screening) and Visit 2 (Eligibility/Baseline, Day 1) may be combined into one visit for treatment-naïve subjects as 
long as the additional requirements of Visit 2 (Eligibility/Baseline, Day 1) are fulfilled, and assessment started at 8:00 (±60 
min) on the day of the combined visit. 


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a  Optional at unscheduled visit, required for early terminated subjects. 
b  Informed Consent Form must be signed and dated before study procedures are performed. Informed consent for the optional 
PGx laboratory research study may be obtained at any visit prior to the study exit. 
c  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. 
d  AE will be recorded starting after the signing of the informed consent form until 2 weeks post Last Study Drug Administration. 
Regardless of the source of the reported occurrence of an AE in a subject, the masked investigator will assess the causality of 
the AE. 
e  A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
f  Vital signs (resting blood pressure and pulse rate) will be collected in sitting position anytime at Visit 1 (Screening), and 
approximately at 08:00 for Visit 2 (Baseline, Day 1), and Visit 5 (Month 3)/exit or early termination before the morning dose. 
g  Refraction will be performed at the screening visit anytime. 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. 
h  Slit-lamp Biomicroscopy examination must be completed before IOP is measured at 08:00. Aqueous flare and cell evaluation 
will be performed before fluorescein instillation. 
I   IOP measurements using Goldmann applanation tonometer will be performed at 08:00 (±60 min), 10:00 (±60 min), and 16:00 
(±60 min) at all visits except for Visit 1 (Screening), and Optional Visit 1a (mid-washout). 
j   Pachymetry will be performed after IOP measurement at Visit 1 (Screening). 
k   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. If needed, Gonioscopy will be performed after IOP measurement at 
Visit 1 (Screening). 
l  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. 
m Ophthalmoscopy with pupil dilation will be performed at Visit 1 (Screening) anytime, Visit 2 (Baseline), and Visit 5 (Month 
3)/exit or early termination at the 16:00 (±60 min) after IOP measurements.   
n Blood sampling for the PGx laboratory research study may be performed at any visit after PGx informed consent obtained, 
subject randomized, and study drug dosing has begun. 
o At Visit 3, 4, and 5, subject will be reminded to take evening dose on the day before each visit. At follow-up Period, subject will 
be contacted by a phone call to confirm AE after 2 weeks post last study drug administration.  
p GQL-15 questionnaire will be administered by subject. 
 
 
 
 
 


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4. 
DEFINTIONS 
4.1. 
Time-Related Terms  
4.1.1. 
Screening Visit 
The Screening visit is Visit 1 when subjects will be screened against the inclusion and exclusion 
criteria. Eligible subjects will be instructed to discontinue use of all IOP-lowering medications, 
if any, during a washout period.  
4.1.2. 
Baseline Visit 
The Baseline visit is Visit 2 (Day 1) when the subjects are randomized.   
4.1.3. 
Treatment Start and End Dates, Extent of Exposure (Days) 
Treatment start date is the date at which a randomized subject takes the first dose of the study 
medication.  Treatment end date is the date at which a randomized subject takes the last dose of 
the same study medication.  For all treatment arms except the placebo arm, if the date of the last 
dose is missing, then 
• The date prior to Month 3 (Visit 5) will be considered the treatment end date for subjects 
who completed the study, and 
• the date prior to ET visit will be used for subjects who prematurely discontinued the 
study.  If the ET visit date of a non-completer is not available, then the date prior to last 
available visit date will be considered the treatment end date. 
The treatment end date will be set to missing if the treatment start date is missing.  
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. 
4.1.4. 
Study Day  
The study day describes the relative day of an observation starting with the reference date 
designated as Study Day 1.   
In this study, for efficacy analyses, the randomization date is the reference day and the study day 
will be calculated as: 
• For days prior to the randomization date, Study Day = Date – Randomization Date. 
• For days on/after the randomization date, Study Day = Date – Randomization Date + 1. 
For safety analyses, the treatment start date is the reference day and 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. 
Note that there is no Study Day 0. 


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4.1.5. 
Days on Study 
The days on study measures the duration of stay since randomization in the study.  For each 
randomized subject, the days on study will be derived as: 
Days on Study = (Study Exit date – Baseline Visit Date) + 1. 
4.1.6. 
Analysis Visit Window and Out-of-Window Measurements 
For this study, a measurement collected at a visit is an out-of-window measurement if the study 
day of the visit falls outside of a visit window specified in Assessment Schedule (Table 1Table 
1), or a within-window measurement otherwise.   
Analysis visit is a timing variable to be used for analyses involving visits.  For each analysis visit, 
an analysis window is set up to determine the analysis visit a measurement should be mapped to.  
The analysis visit of a measurement will be determined based on the study day of the 
measurement and specified analysis windows and is not necessarily the same with the study visit 
where the measurement was collected.  For example, an out-of-window measurement collected 
at the Week 2 study visit will be mapped to the Week 6 analysis visit, if the study day of the 
measurement falls into the analysis window of Week 6.  
The following analysis windows for post-baseline visits will be applied to minimize the amount 
of missing data for analysis purposes: 
Table 2: 
Post-Baseline Analysis Visit and Analysis Window 
Post-Baseline Analysis Visit 
(Target Assessment Date) 
Protocol Visit Window 
Analysis Window 
Week 2 (Day 14) 
[11, 17] 
 [2-25] 
 
Week 6 (Day 42) 
[39, 45] 
 [26-61] 
 
Month 3 (Day 90) 
[83, 97] 
 [62- 
 
For analyses involving post-baseline visits, if there are two or more measurements that fall into 
the same analysis window of a post-baseline visit, then a visit in which IOP are measured at all 
the scheduled timepoints (8:00, 10:00 and 16:00) will be selected for that analysis visit.  In case 
that there are two or more such visits within the same analysis window, the measurement closest 
to the target assessment day will be selected for that analysis visit.  In the case that two 
measurements are closest and equidistant to the target assessment day, i.e., one is before, and one 
is after the target assessment day, the later one will be selected for that visit. 
4.1.7. 
Analysis Timepoint Window and Out-of-Window Measurements 
 


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Analysis timepoint is a timing variable to be used for analyses involving timepoints. The IOP will 
be measured two or three times for each timepoint, and the last recorded time will be used for 
determining its timepoint. For each analysis timepoint, an analysis timepoint window is set up to 
determine the allowance range (Table 3).  
  
Table 3. Analysis Timepoint and Analysis Timepoint Window  
Analysis Timepoint  
Timepoint Window  
Analysis Timepoint Window  
8:00  
[7:00, 9:00]  
- 8:59]  
10:00  
[9:00, 11:00]  
[9:00, 12:59]  
16:00  
[15:00, 17:00]  
[13:00 -  
  
If there are two or more measurements that fall into the same analysis timepoint window, the 
measurement closest to the target assessment time will be selected for that timepoint.  In the case 
that two measurements are closest and equidistant to the target assessment time, i.e., one is 
before and one is after the target assessment time, the later one will be selected for that 
timepoint.  
 
4.2. 
Efficacy-Related Definitions 
4.2.1. 
Study Eye  
The study eye will be the eye that qualifies per eligibility criteria at Visit 2 (Baseline, Day 1).  If 
both eyes meet the eligibility criteria, the eye with the higher mean diurnal IOP at Visit 2 
(Baseline, Day 1) will be designated as the study eye. For example, IOP must be ≥ 22 mmHg at 
all IOP measurement time-points (08:00, 10:00 and 16:00).   If both eyes meet the eligibility 
criteria and have the same mean diurnal IOP, the right eye will be designated as the study eye.   
4.2.2. 
Efficacy Measure 
IOP (in mmHg) is the efficacy measure for this study.  For the IOP at each timepoint of 
measurement, a mean of two consecutive measurements using the Goldmann applanation 
tonometer will be used.  If the two measurements differ by 3 mmHg or more, then a third 
measurement will be made, and the median of the three consecutive measurements will be used. 
The mean diurnal IOP at each visit is defined as the mean of the three scheduled timepoints 8:00, 
10:00, and 16:00 at the visit.  If there are one or more missing IOP measurement at timepoints, 
the mean diurnal IOP will not be calculated.  
To assess the efficacy of DE-126, the mean/median IOP at each scheduled timepoint (8:00, 
10:00, 16:00) and the mean diurnal IOP in the study eye will be analyzed.  In addition, changes 
and percent changes from baseline in IOP at each timepoint and the mean diurnal IOP in the 
study eye will also be analyzed. 
4.2.3. 
Baseline Score 
For any measure, the baseline score is the last observed measurement or derived score prior to 
the first dose of study medication. 


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4.2.4. 
IOP Response Endpoints and Response Rate 
Four IOP response endpoints shown in Table 3 will be evaluated at each post-Baseline visit of 
Week 2 (Visit 3), Week 6 (Visit 4), or Month 3 (Visit 5).   
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 visit. 
 
Table 3 
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 
  
4.3. 
Safety-Related Definitions 
4.3.1. 
Adverse Event 
Events reported on the AE electronic Case Report Form (eCRF) will be assessed according to the 
recently amended Food and Drug Administration regulations 21 CFR Parts 312 and 320.   
Under Protocol 012601IN, an AE is defined as any untoward medical occurrence  that occurs in 
a study subject, regardless of the suspected cause and regardless of timing of study medication 
administration.  An on-study AE can occur any time after the date of informed consent through 
the last study visit.  An AE will be considered as treatment-emergent if the AE occurred on or 
after the treatment start date up to the 2 days (twice the scheduled dosing interval) after treatment 
end date.  Treatment-emergent AEs are a subset of on-study AEs.  Both on-study and treatment-
emergent AEs will be recorded, but only treatment-emergent AEs will be tabulated. 
The severity of each AE will be graded by the Clinical Investigator as Mild, Moderate, or 
Severe.  
Each AE will be classified into a system organ class (SOC) and coded to a preferred term (PT) 
using Medical Dictionary for Regulatory Activities (MedDRA), version 23.1 published in 2020.   
4.3.1.1. 
Serious Adverse Event 
An AE will be counted as a serious adverse event (SAE) if the Clinical Investigator selected 
“Yes” under Item 5 (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) 
• Inpatient hospitalization and/or prolonged hospitalization 


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• A persistent or significant disability/incapacity (i.e., the AE resulted in a substantial 
disruption of the subject’s ability to carry out normal life functions) 
• A congenital anomaly/birth defect in the offspring of a study subject who was exposed to 
study therapy prior to conception or during pregnancy 
• Sight threatening event 
• Other medically important event (e.g. requires medical or surgical intervention to prevent 
one or more of the listed above) 
4.3.1.2. 
Ocular Adverse Event 
An AE will be counted as an ocular AE if the Clinical Investigator selected “OD”, “OS”, or 
“OU” under ‘Item 2 (Eye(s) affected)’ on the AE eCRF.  
4.3.1.3. 
Suspected Adverse Reaction 
An AE will be counted as a suspected adverse reaction (SAR) if the Clinical Investigator 
selected answered ‘Related’ to the AE eCRF Item 10 (Relationship to Study Drug). 
4.3.1.4. 
Events of Special Interest 
Events of special interest (ESI), such as pregnancy, study medication administration error, and 
AEs leading to study discontinuation or unmasking, will be identified throughout the study. 
4.3.2. 
Safety Measures  
Table 4: 
Safety AssessmentsTable 4 lists the safety measures to be evaluated for this study. 
Table 4: 
Safety Assessments 
Safety Measures 
Note 
BCVA 
BCVA will be measured prior to the 08:00 IOP 
measurement at all visits except Visit 1 (Screening)/ 
1a (Optional visit) using visual acuity chart (Early 
Treatment Diabetic Retinopathy Study [ETDRS] chart) 
and the logMAR scoring.  For Visit 1/1a, the corrected 
visual acuity is performed prior to IOP measurement.  
Slit-lamp biomicroscopy: 
anterior chamber cells 
anterior chamber flare 
lid hyperemia 
lid edema  
conjunctival (palpebral and bulbar) 
hyperemia  
conjunctival chemosis 
corneal edema 
Anterior Chamber Cells will be graded as 0 = No cells, 0.5 = 
1-5cells, 1 = 6-15 cells, 2 = 16-25 cells, 3 = 26-50 cells, or 4 
= > 50 cells. 
 
Anterior Chamber Flare will be graded as 0 = None, 
1 = Faint, 2 = Moderate, 3 = Marked, or 4 = Intense. 
 
The other biomicroscopy parameters will be graded as   0 = 
None, 1 = Mild, 2 = Moderate, or 3 = Severe. 


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corneal staining (with fluorescein) 
keratic precipitate  
lens 
anterior synechiae of iris  
posterior synechiae of iris  
iris color abnormalities  
eyelash abnormalities 
eyelid abnormalities 
Ophthalmoscopy 
glaucomatous optic nerve 
Damage to optic nerve will be graded as 0 = None 
1 = Mild, 2 = Moderate, 3 = Severe. 
Vital signs: 
systolic blood pressure 
diastolic blood pressure 
pulse rate 
Systolic blood pressure and diastolic blood pressure will be 
measured in mmHg.  
 
Pulse rate will be measured by beats/minute. 
 
4.4. 
Other Definitions  
4.4.1. 
Prior and Concomitant Medications 
Non-study medications will be categorized into prior medications and concomitant medications.  
Specifically, the prior medication is defined as any non-study medication taken and ended prior 
to the treatment start date.  The concomitant medication is defined as any non-study medication 
taken concurrently while on the study medication, i.e., the treatment period of a concomitant 
medication taken by a subject’s needs to overlap with his/her treatment period of the study 
medication. 
4.4.2. 
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  
Analysis populations utilized for this study are defined below.   
The Full Analysis Set (FAS) includes all randomized subjects who received at least one dose of 
the study medication (test or control medication) and had at least one post-baseline efficacy 
assessment of the study eye during the study.  This will be the population used for efficacy 
analyses.  Unless specified otherwise, subjects in efficacy analyses are classified by planned 
treatment, irrespective of the actual treatment received. 
The Per-Protocol Set (PPS) will be a subset of the FAS population, restricted to the subjects who 
fulfill the protocol in the terms of the eligibility, interventions, and outcome assessment.  It will 
be the analysis population for some sensitivity analyses. 
Before the unmasking of treatment assignment, Santen’s study team will review all protocol 
deviations, identify subjects with any protocol deviation that could impact the efficacy outcome, 
and determine whether or not to exclude the subject or certain data point from the PPS. 
The Safety population will include all randomized subjects who received at least one dose of the 
study medication.  It will be the analysis population for safety analyses to be performed with 
subjects as treated. 
 
 
 
 
 


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6. 
GENERAL CONSIDERATIONS 
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 summarized using frequency (n) and percent (%).   
The statistical testing will be conducted at a significance level of 0.05 (2-sided) unless specified 
otherwise.  No statistical testing will be conducted for safety measures. 
6.1. 
Adjustments for Covariates 
In general, baseline IOP score will be adjusted in the inferential analysis of each IOP endpoint.  
Detailed information on covariate adjustment is provided in Section 8.1. 
6.2. 
Handling of Missing Data 
6.2.1. 
Efficacy Measure 
For each IOP endpoint, no imputation is needed for the MMRM analyses. For sensitivity analysis 
purpose multiple imputation will be adopted in some analyses.   
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 events, i.e., medical 
history events and AEs will be imputed in a conservative fashion as follows. 
Missing onset dates 
• Completely missing: No imputation will be applied. 
• Only year is available: Use the first day of the year to impute the missing month and date 
parts of the onset date 
• Year and month are available, but day is missing: Use the first day of the month to 
impute the missing date part of the onset date. 
Missing resolution dates 
• Completely missing: No imputation will be applied. The event will be considered 
ongoing (i.e., not resolved) at the last visit date. 
• Only year is available: Use the last day of the year to impute the missing month and date 
parts of the resolution date 
• Year and month are available, but day is missing: Use the last day of the month to impute 
the missing date part of the resolution date 
Same rules will be followed to impute the completely or partially missing start and end dates of 
non-study medications.   


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6.3. 
Multi-Center Studies 
This is a multi-center study. The number of subjects enrolled from each site will not be pooled in 
this study. 
6.4. 
Multiple Comparisons / Multiplicity 
Fixed sequence procedure will be applied to control the overall Type I error rate across the four 
hypotheses in the primary and key secondary endpoints at the 0.05 level.  Fixed sequence 
procedure tests hierarchically ordered hypotheses at level 0.05 until the first non-rejection. 
The fixed sequence for the four hypotheses in this study is as follows: 
1. Hypothesis of non-inferiority of DE-126 ophthalmic solution 0.002% to Timolol maleate 
ophthalmic solution 0.5% for the primary endpoint, IOP at each scheduled timepoint 
(08:00, 10:00, and 16:00) at Week 2, Week 6, and Month 3. 
2. Hypothesis of non-inferiority of DE-126 ophthalmic solution 0.002% to Timolol maleate 
ophthalmic solution 0.5% for the key secondary endpoint, mean diurnal IOP at Month 3. 
3. Hypothesis of superiority of DE-126 ophthalmic solution 0.002% to Timolol maleate 
ophthalmic solution 0.5% for the key secondary endpoint, mean diurnal IOP at Month 3. 
4. Hypothesis of superiority of DE-126 ophthalmic solution 0.002% to Timolol maleate 
ophthalmic solution 0.5% for the primary endpoint, IOP at each scheduled timepoint 
(08:00, 10:00, and 16:00) at Week 2, Week 6, and Month 3. 
6.5. 
Interim Analysis 
No formal interim analysis is planned for this study.  
 
 


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7. 
SUMMARY OF STUDY POPULATION DATA 
7.1. 
Subject Disposition 
The disposition of all randomized subjects will be summarized by treatment and overall.  The 
summary will include the number of subjects in the FAS population the Safety population, and 
the PP population.  The disposition summary will also include the number and percentage of 
completers and non-completers at Month 3 (Visit 5), by the primary discontinuation reason. 
7.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be descriptively summarized for the FAS 
population by planned treatment, Safety population by actual treatment, and overall.  
Specifically, for subject demographics, the following variables will be summarized:  
• Age at randomization (continuous and categorical: < 65 years or ≥ 65 years) 
• Sex (categorical: Male or Female) 
• Race (categorical: Asian, Black or Africa American, or White) 
For baseline characteristics, the following variables will be summarized for study eye and fellow 
eye separately: 
• Baseline mean diurnal IOP in the study eye: <25 mmHg vs. ≥25 mmHg. 
• Primary ocular diagnosis (categorical: POAG or OHT) 
• Prior use of IOP-lowering medication(s) (categorical: ß-adrenergic antagonist, 
prostamide or prostaglandin analogue, α-adrenergic agonist, carbonic anhydrase 
inhibitors, miotic agent, ROCK inhibitor, other, or none) 
• Prostaglandin naive (Yes or No) 
• 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) 
• Baseline central corneal thickness 
• Glaucomatous optic nerve findings (categorical: none, mild, moderate, or severe) 
• Baseline glaucoma hemifield test result by device (categorical: within normal limits, 
borderline, or outside normal limits) 
• Baseline visual field global indices by device  
o mean deviation 
o pattern standard deviation 


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7.3. 
Medical and Surgical History 
For this study, medical and surgical history (i.e., medical events) will be coded using MedDRA 
23.1, 2020.  Each medical event will be classified into a SOC and mapped to a PT.   
The medical and surgical history will be summarized for the FAS population.  Subjects reporting 
any medical and surgical history at baseline will be tabulated by SOC and PT for each planned 
treatment and overall. 
Baseline lens status (categorical: phakic or pseudophakic/aphakic) 
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 issues  
• Time Window 
• Protocol implementation issues 
• Other deviations 
A protocol deviation is considered major if it may affect the subject’s rights, safety, or well-
being and/or the completeness, accuracy, and reliability of the study data.  Santen’s study team 
will review all protocol deviations and determine the list of major protocol deviations prior to 
database lock.  All randomized subjects with any major protocol deviation(s) will be tabulated by 
deviation category for each planned treatment and overall.   
7.5. 
Prior and Concomitant Medications 
For this study, non-study medications, including prior and concomitant medications, will be 
coded using World Health Organization Drug Dictionary Enhanced (WHO-DDE) (March 2017).  
Each non-study medication will be classified using the Anatomical-Therapeutic-Chemical (ATC) 
classification system and mapped to a WHO-DDE preferred drug name.   
Non-study medications will be summarized for the Safety population.  Subjects taking any prior 
medications will be tabulated by ATC level 3, level 4 and preferred drug name for each actual 
treatment received and overall.  A subject will be counted at most once for each prior 
medication, even if the subject took the same prior medication on multiple occasions.  Subjects 
taking any concomitant medications will be tabulated similarly.  In addition, prior medications 
and concomitant medications will also be listed, separately.  


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7.6. 
Treatment Compliance 
A subject will be considered fully compliant to treatment if he/she responded “0” at all post-
baseline visits to the eCRF question “How many doses were missed since the previous visit?”   
The treatment compliance rate for a subject at a visit will be as following.  
Treatment Compliance Rate (%) 
     =  
(Duration – Total Number of Missed Dose) 
Duration
 ×100 
if the subject did not withdraw the 
study medication before this visit 
= 
Duration – Total Number of Missed Dose − (Current Visit Date – Treatment End Date) 
Duration
×100 
       if the subject withdrew the study medication before this visit,  
where 
• duration is the number of days subjects should have administered study medication, 
calculated as current visit date – baseline date, and 
• total number of missed dose is the total number of days that subject did not follow the 
proper dosing procedures or dosing schedule since baseline. 
For FAS subjects, treatment compliance will be summarized by post-baseline analysis visit for 
each planned treatment and overall. 
7.7. 
Exposure to Study Medication 
The duration of exposure to a study medication is measured by days on treatment as derived in 
Section 4.1.3.  For Safety subjects, the duration of exposure will be summarized using 
descriptive statistics for actual treatment received and overall.  Frequency and percentage of 
subjects will also be tabulated by analysis visit. 
 
 


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8. 
EFFICACY ANALYSES 
Unless specified otherwise, the efficacy analyses will be performed on the FAS, where subjects 
are classified by planned treatment, irrespective of the actual treatment received. 
Unless specified otherwise, all efficacy analyses will be performed on the study eye, and the data 
on fellow eye will not be used.  
8.1. 
Analyses of Primary Endpoint and Key Secondary Endpoint 
8.1.1. 
Primary Analysis 
8.1.1.1. 
Primary Endpoint 
The primary efficacy endpoint is the IOP in the study eye at each scheduled timepoint (08:00, 
10:00, and 16:00) at each of three follow-up visits, Week 2, Week 6, and Month 3.  The nine 
combinations of three scheduled timepoints at each of three visits are referred to subsequently as 
nine timepoints.  For the primary endpoint, the following hypotheses will be tested: 
𝐻0:  𝜇𝑇− 𝜇𝐶 > ∆   for at least one timepoint 
versus 
𝐻𝐴:  𝜇𝑇− 𝜇𝐶 ≤ ∆   at all nine timepoints 
where  𝜇𝑇 and 𝜇𝐶 denote the mean values of the primary endpoint in the DE-126 arm and the 
Timolol arm, respectively, and Δ denotes the noninferiority margin of 1.5 mmHg.  
The primary analysis of the primary efficacy endpoint will be performed using a MMRM 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 kth timepoint, the model will include treatment (𝑇𝑖), analysis visit 
(𝑉𝑗), and treatment-by-visit interaction (𝑇𝑉𝑖𝑗) as fixed effects, and the baseline IOP (𝐵𝑘) as 
covariates:   
IOP𝑖𝑗𝑘𝑛= 𝜇+ 𝑇𝑖+ 𝑉𝑗+ 𝑇𝑉𝑖𝑗+ 𝐵𝑘+ 𝜀𝑖𝑗𝑘𝑛  
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. 
Correlations of IOP measurements within-subject will be modeled using an unstructured 
covariance matrix.  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. 
For the 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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Noninferiority criteria for primary endpoint: With respect to the primary study objective, 
noninferiority of DE-126 to Timolol is established if the upper limit of the two-sided  
95% confidence interval for the difference in the mean IOP (DE-126 minus Timolol) is  
≤ 1.5 mmHg at all nine timepoints and ≤ 1.0 mmHg in majority (five or more) of the nine 
timepoints.  
Superiority of DE-126 to Timolol for the primary efficacy endpoint will be claimed if the upper 
limit of the two-sided 95% confidence interval for the difference in the mean IOP (DE-126 
minus Timolol) is < 0 mmHg at all nine timepoints. 
 
8.1.1.2. 
Key Secondary Endpoint 
The key secondary efficacy endpoint is the mean diurnal IOP in the study eye at Month 3.      
The following null (versus alternative) hypothesis will be tested: 
𝐻0𝑆:  𝜇𝑇𝑀− 𝜇𝐶𝑀 > ∆     vs.   𝐻𝐴𝑆:  𝜇𝑇𝑀− 𝜇𝐶𝑀 ≤ ∆ 
where 𝜇𝑇𝑀 and 𝜇𝐶𝑀 denote the mean diurnal IOP at Month 3 of the DE-126 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 2, Week 6, or Month 3), and treatment-by-
visit interaction as fixed effects, and baseline mean diurnal IOP 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-126 to Timolol is achieved for this endpoint if the upper limit of the 95% 
confidence interval for the difference between DE-126 and Timolol (DE 126 minus Timolol) in 
the mean diurnal IOP at Month 3 is ≤ 1.5 mmHg.  Superiority of DE-126 to Timolol is achieved 
for this endpoint if the upper limit of the 95% confidence interval is < 0 mmHg. 
8.1.2. 
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 following sensitivity 
analyses will be performed: 
• Using the analysis population of the PPS  
• Using a pattern-mixture model (PMM) with delta-adjustment approach where missing 
values are imputed by multiple imputation.   


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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 censoring after having received 
IOP-lowering rescue therapy, or early study discontinuation due to lack of efficacy or 
AE, these values will adjust 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. 
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-126 and Timolol arms is greater than 5 percentage 
points, a trimmed mean analysis (Permutt et al., 2017) will be conducted as a sensitivity analysis. 
8.2. 
Analyses of Other Secondary Endpoints 
For continuous secondary endpoints (IOP, mean diurnal IOP, change and percent change from 
baseline in IOP/mean diurnal IOP) at Week 2, Week 6 and Month 3, both MMRM and 
descriptive summaries will be performed.  The MMRM will be the same as the one for key 
secondary endpoint but without multiplicity adjustment.   
8.2.1. 
Responder Rates 
For binary secondary endpoints, the responder rates will be summarized at each post-baseline 
visit.  Subjects discontinued study by any reason without response will be treated as non-
responder. A sensitivity analysis will be conducted by multiple imputing for discontinued 
subjects with reasons other than AE or lack of efficacy.  DE-126/Vehicle arm will be compared 
with Timolol Maleate arm using Fisher’s exact test, and the differences between the two 
treatment arms will be reported along with 95% CIs.  
8.3. 
Subgroup Analyses 
To assess the homogeneity of treatment effects among subgroups, descriptive summaries for all 
IOP endpoints will be conducted by the following categories: 
• age group (< 65, or ≥ 65 years)  
• sex (males or females)  


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• race (White or non-White)   
• mean diurnal IOP in the study eye at baseline visit (<25 mmHg vs. ≥25 mmHg) 
• primary ocular diagnosis (primary open-angle glaucoma or ocular hypertension.   
If there are a sufficient number of subjects in each subgroup, the test of interaction will be 
conducted using an MMRM with treatment, visit, treatment-by-visit, subgroup, and treatment-
by-subgroup as fixed effects, baseline IOP score (score at the corresponding timepoint or mean 
diurnal score) as a covariate, and subject as a random effect.   
 
9. 
SAFETY ANALYSES 
The safety-related measures collected in this study include AEs, slit-lamp biomicroscopy, 
ophthalmoscopy, corrected visual acuity, ocular symptoms, central corneal thickness, iris color, 
eyelash, and eyelid by photographs, vital signs, and clinical laboratory tests.  The Safety 
population will be used for all safety summaries, where subjects will be classified by actual 
treatment received.  If a subject was administered a different treatment than that which was 
assigned in the study, this subject will be included in the higher dose of DE-126 arm or Timolol 
arm if the subject didn’t receive any DE-126 in the study. 
All the safety-related measures will be summarized descriptively by actual treatment received.  
Except AEs, the descriptive summary of each safety-related measure and the change from 
baseline in that measure will be performed.  
9.1. 
Adverse Event 
Subjects with any AEs will be tabulated AEs by treatment arm using actual treatment received.   
Subjects with any AEs will be tabulated by SOC and PT where a subject who experienced 
multiple AEs within a SOC or PT will be counted only once for that SOC or PT.  SAEs, SARs, 
and Serious SARs will be tabulated similarly.   
Subjects with any ocular and non-ocular AEs will be tabulated separately.  AEs, ocular, and non-
ocular will also be summarized by relationship to treatment and maximum severity.  Any ocular 
AE that occurred simultaneously to both eyes will be counted once.   
AE, SARs, ocular and non-ocular AEs will also be summarized by country.  
AEs, AEs leading to death, AEs leading to discontinuation, SAEs, and ESIs, if any, will be listed 
separately. 
9.2. 
Best-Corrected Visual Acuity 
BCVA measures the acuteness or clearness of the best-corrected vision, with a range of [0, 97] in 
ETDRS letters.  An increase in BCVA indicates an improvement in the best-corrected vision.  
BCVA will be measured for each eye prior to the 08:00 IOP measurement at each visit at 
Baeline, Week 2, Week 6, and Month 3 using a Snellen chart using visual acuity chart (Early 
Treatment Diabetic Retinopathy Study [ETDRS] chart) and the logMAR scoring. 


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BCVA in Snellen scale will be converted to logMAR scale using the following equation and be 
used in all the BCVA analyses: 
LogMAR VA = − log10 ( Snellen numerator
Snellen denominator) 
BCVA (logMAR scores) and changes from baseline will be summarized by treatment and 
analysis visit 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 severity rating score will be 
summarized by actual treatment received and analysis visit for study eyes and fellow eyes, 
separately.  In addition, subjects with improvement (decrease) or worsening (increase) or 
maintaining from baseline in severity rating score will be tabulated by analysis visit and 
biomicroscopy parameter.  Subjects with worsening of 2 units or more from baseline will be 
listed. 
9.4. 
Ophthalmoscopy  
For cup to disc ratio, scores and changes from baseline will be summarized by actual treatment 
received and analysis visit for study eyes and fellow eyes, separately. 
For glaucomatous optic nerve, frequency and percentage of severity rating score will be 
summarized by actual treatment received and analysis visit for study eyes and fellow eyes, 
separately.   
9.5. 
Central Corneal Thickness 
Central corneal thickness scores at screening will be summarized by actual treatment received 
for study eyes and fellow eyes, separately.   
9.6. 
Vital Signs 
Blood pressures and pulse rate, and changes from baseline may be summarized by actual 
treatment received and analysis visit. 
 
 


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10. 
ANALYSIS OF EXPLORATORY ENDPOINT 
Glaucoma Quality of Life-15 (GQL-15) questionnaire (protocol Appendix F) is a 15-item 
questionnaire measuring the severity of visual disability in glaucoma patients.  The GQL-15 will 
be administered at Baseline (Visit 2, Day 1) and Month 3 (Visit 5).   
The GQL-15 total score and 4 domain scores will be summarized descriptively by actual 
treatment received.  In addition, change from baseline will be presented. The 4 domains are 
central and near vision, outdoor mobility, peripheral vision, and dark adaption and glare. 
Table 5 
GQL-15 Questionnaire Items Associated with 4 Domains  
Domain 
Questionnaire Item 
Central and near vision 
  1.  Reading newspapers  
15. Recognizing faces 
Peripheral vision 
  4. Walking on uneven ground 
  8. Tripping over objects 
  9. Seeing objects coming from the side 
11. Walking on steps/stairs 
12. Bumping into objects 
13. Judging distance of foot to step/curb 
Glare and dark adaption  
  2. Walking after dark 
  3. Seeing at night 
  5. Adjusting to bright lights 
  6. Adjusting to dim lights 
  7. Going from light to dark or vice versa 
14. Finding dropped objects 
Outdoor mobility 
10. Crossing the road 
Total score is derived by summing all item-level response scores. Subscale scores are derived by 
coding the item-level responses on a numerical interval scale ranging from 0 (no difficulty) to 
100 (severe difficulty). Subscale scores are average of the sum of scores generated for the item-
level subscale responses. Higher subscale scores indicate lower QOL and greater difficulty with 
subscale specific tasks (Nelson et al, 2003; Sencanic et al, 2018). 
 
 
 


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11. 
REFERENCES 
Nelson, P., Aspinall, P., Papasouliotis, O., Worton, B., & O'Brien, C. (2003). Quality of life in 
glaucoma and its relationship with visual function. Journal of glaucoma, 12(2), 139-150. 
Permutt, T., & Li, F. (2017). Trimmed means for symptom trials with dropouts. Pharmaceutical 
statistics, 16(1), 20-28. 
Sencanic, I., Gazibara, T., Dotlic, J., Stamenkovic, M., Jaksic, V., Bozic, M., & Grgurevic, A. 
(2018). Validation of the glaucoma quality of life-15 questionnaire in serbian language. 
International journal of ophthalmology, 11(10), 1674. 
 
 
 
 


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12. 
APPENDICES 


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