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
Phase: PHASE2
Conditions: Open-angle Glaucoma, Ocular Hypertension
Sponsor: Santen Inc.

 
 
Study Protocol Cover Page 
 
Official Study Title:   
A Phase IIb Safety and Efficacy Study of DE-126 Ophthalmic 
Solution in Primary Open-Angle Glaucoma or Ocular 
Hypertension- Angel Study 
 
 
 
NCT Number:  
NCT03216902 
 
 
 
Date of the document: 
16 June 2017 
 
 
 

Protocol 0 1260 1 IN 
DE-126 Ophthalmic Solution 
DE-126 
Protocol 012601IN 
Amendment 1 
TITLE: A Phase lib, Randomized, Observer-Masked, Placebo- and Active-Controlled, 
Parallel-Group, Multinational and Multicenter Study Assessing the Safety and Efficacy 
ofDE-126 Ophthalmic Solution in Subjects with Primary Open-Angle Glaucoma or 
Ocular Hypertension- Angel Study 
SPONSOR: 
Santen Inc. 
6401 Hollis Street, Suite 125, 
Emeryville, CA 94608, USA 
STUDY DRUG: 
Vehicle ofDE-126 ophthalmic solution 
0.0005% DE-126 Ophthalmic Solution 
0.001% DE-126 Ophthalmic Solution 
0.002% DE-126 Ophthalmic Solution 
0.003% DE-126 Ophthalmic Solution 
0.005% Latanoprost Ophthalmic Solution 
I have read the 012601 IN 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 indicates that the data therein has been reviewed and accepted by me 
as the Investigator. I agree to maintain the confidentiality of all information received or 
developed in connection with this protocol. 
INVESTIGATOR: 
Date: 
Signature: 
Name: 
(PRINT OR TYPE) 
Address: 
Phone: 
This study will be conducted in accordance with applicable Good Clinical Practices (GCP), 
International Conference on Harmonization (ICH) guidelines, the Declaration of Helsinki and 
applicable regulatory requirements. 
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Protocol 012601IN 
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DE-126 Ophthalmic Solution 
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Protocol012601TIN 
DE-126 Ophthalmic Solution 
1. 
PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
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Protocol 012601IN 
2. 
SYNOPSIS 
Name of Sponsor/Company: 
Santen Inc. 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608 
Name of Investigational Product: DE-126 Ophthalmic Solution 
DE-126 Ophthalmic Solution 
N arne of Active Ingredient: Propan-2-yl 4-{ (3S,5aR,6R, 7 R,SaS)-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: A Phase Ilb, Randomized, Observer-Masked, Placebo- and Active-Controlled, 
Parallel-Group, Multinational and Multicenter Study Assessing the Safety and Efficacy ofDE-
126 Ophthalmic Solution in Subjects with Primary Open-Angle Glaucoma or Ocular 
Hypertension- ANGEL Study 
Study centers: Approximately 40 sites in the U.S. and Japan 
Study period: 
Phase of development: lib 
Estimated date of first subject screened: July 2017 
Estimated date last subject completed: February 2018 
Primary objective: 
To determine the optimal dose ofDE-126 by investigating the safety and efficacy of four (4) 
concentrations ofDE-126 ophthalmic solution (0.0005%, 0.001%, 0.002%, and 0.003%) when 
compared to latanoprost (0.005% latanoprost) at Month 3 in subjects with primary open-angle 
glaucoma or ocular hypertension. 
Secondary objective: 
To determine if any one of four (4) concentrations ofDE-126 (0.0005%, 0.001%, 0.002% and 
0.003%) is superior to the placebo (vehicle ofDE-126) in mean lOP reduction at each specified 
time point (09:00, 13:00 and 17:00) at Week 6 compared to baseline. 
To investigate the dose response of four (4) concentrations ofDE-126 ophthalmic solution 
(0.0005%, 0.001%, 0.002% and 0.003%). 
Safety objective: 
To determine the safety ofDE-126 ophthalmic solutions (0.0005%, 0.001%, 0.002% and 
0.003%) given once daily as compared to 0.005% latanoprost given once daily in this population. 
Methodology: 
This is a phase lib, randomized, observer-masked, placebo-and active-controlled, parallel-group, 
multinational, multi-center study. Approximately 220 subjects diagnosed with POAG or OHT 
who meet eligibility criteria at Visit 1 (Screening) will washout of their current topical lOP-
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 
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Protocol012601TIN 
DE-126 Ophthalmic Solution 
randomized to receive treatment for up to 3 months. Subjects in the placebo arm will receive 
placebo eye drops for 6 weeks and then switch to DE-126 0.003% ophthalmic solution for the 
remaining 6 weeks till study exit. 
Approximately 220 subjects with POAG or OHTwill be randomized to one of the six (6) 
treatment arms in a 1:2:2:2:2:2 ratio, as follows: 
• 
Placebo (Vehicle ofDE-126 ophthalmic solution)~0.003% DE-126 at Week 6 
• 
0.0005% DE-126 Ophthalmic Solution 
• 
0.001% DE-126 Ophthalmic Solution 
• 
0.002% DE-126 Ophthalmic Solution 
• 
0.003% DE-126 Ophthalmic Solution 
• 
0.005% Latanoprost Ophthalmic Solution 
Study Design 
VIsit 1 
(Day-35to-1) 
Visit 2 
Visit 3 
VIsit 4 
(Day 1) (Week 1) (Week 2) 
VisitS 
(Week ·6) 
Vlsit6 
(Month3) 
Screening 
Baseline/Randomization 
Screening Phase 
Treatment Phase 
"""" 
... """' 
I 
.... 
., 
-... 
-
Placebo {N=20) 
I 0.003% DE-126 I 
I 
I 
,. 
Walt/Washout 
0 .. 000596 DE-126 
Period (~1-35 Days) 
0.00196 DE-126 
N=220 (40 /arm 
0.00296 DE·126 
for DE-126 and 
W; 20/arm for 
0.00396 DE-126 
Placebo) 
0.00596 latanoprost 
one drop, once dally at 21.00 
The study will consist of a screening phase of up to 35 days including a washout period of up to 
28 days and a 3-month 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 lOP-lowering medications 
during a washout period as follows (up to +7 days as a window is allowed): 
• 
Miotics: 7 days 
• 
OraVtopical Carbonic Anhydrase Inhibitors (CAis): 7 days 
• 
Alpha agonists: 14 days 
• 
Alpha/beta agonists: 14 days 
• 
Beta antagonists(~ blocker, including a~ blockers): 28 days 
• 
Alpha antagonists (a1 blocker): 28 days 
• 
Prosta landins Analo s (PGA): 28 da s 
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Protocol 012601IN 
DE-126 Ophthalmic Solution 
• 
Rho kinase inhibitor: 28 days 
For combination drugs, the longest washout period of the individual component will be used. 
During the required washout period, subjects who discontinue their current treatment may, if the 
investigator deems it necessary for safety, be treated with a topical CAl, e.g., brinzolamide or 
dorzolamide eye drops, one drop twice daily. Topical CAl treatment must stop 1 week before the 
randomization at Visit 2 (Baseline, Day 1). An interim safety visit, mid washout visit (Visit 1a), 
may be performed during the washout period if, in the investigator's opinion, a subject's lOP 
may be of concern during the washout period. If subjects are treated with a topical CAl by 
1 week before the randomization at Visit 2 (Baseline, Day 1), mid washout visit (Visit la) is 
recommended to be performed. 
Final eligibility will be determined at Visit 2 (Baseline) after all necessary washout from prior 
lOP-lowering medications has been completed. Subjects who have not used an lOP-lowering 
medication for the last 28 days prior to the screening visit, including treatment-naive subjects, 
must have at least one day between their screening visit and Visit 2 (Baseline). 
At Visit 2, baseline lOP will be measured for both eyes at 09:00, 13:00 and 17:00 (±60 minutes). 
The study eye will be the eye that qualifies per eligibility criteria at Visit 2. If both eyes meet 
eligibility criteria, the eye with the higher diurnal lOP at Visit 2 will be designated as the study 
eye. If both eyes meet eligibility criteria and have the same mean diurnal lOP, the right eye will 
be designated as the study eye. In cases where only one eye is fully qualified for the study, both 
eyes can be treated for the duration of the study. Approximately 220 eligible subjects will be 
randomized to one of the six (6) treatment arms. Forty (40) subjects per treatment arm will be 
randomized to each DE-126 and Latanoprost arms, and 20 subjects will be randomized to the 
Placebo arm. Central randomization via Interactive Response Technology (Medidata 
BALANCE) will be used to allocate the subjects to each of the six treatment arms in the U.S. and 
Japan separately. Each eligible subject will be assigned to receive a study medication kit 
numbered as allocated by the randomization schedule and assigned by BALANCE. 
The study eye drops will be given once daily at 21 :00 ( ±60 minutes), starting on the evening of 
Visit 2 and continuing through the evening prior to Visit 6 (Month 3). During the 3-month 
treatment period Subjects will return for Visits 3,4, 5, and 6 (Weeks 1, 2, 6 and Month 3) and 
lOP will be measured at 09:00, 13:00 and 17:00 (±60 minutes). At these scheduled visits 
corrected visual acuity and slit lamp biomicroscopy will be performed at 09:00 immediately 
prior to lOP measurement, and corneal thickness measurement (pachymetry) and 
ophthalmoscopy (fundus examination) will be performed at 17:00 immediately after lOP 
measurement. 
Subjects will be invited to separately consent to provide a saliva sample for a future 
pharmacogenomics/genomics laboratory research study, however providing such consent is not a 
prerequisite to participating in the main study. The purpose of this exploratory research is to 
identify possible genetic markers associated with the study drug(s) and/or ocular conditions. 
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Protocol 012601IN 
DE-126 Ophthalmic Solution 
Number of subjects (planned): 
Approximately 220 subjects in the U.S. and Japan in a 1:1 ratio. 
Masking: 
The appearance of the bottles used for the 4 active DE-126 groups and the placebo group will be 
identical. However, due to differences in appearance between the containers used for the test 
treatments (DE-126 and placebo) and the commercially available active control treatment 
(0.005% latanoprost) this study is classified as observer-masked. In order to maintain masking of 
investigators, examiners and sponsor personnel involved in the conduct of the study, only an 
authorized study staff member who is not the investigator or examiner at the investigative site 
will be permitted to dispense and collect study medication. Subjects will be instructed not to 
show the bottles to either the investigator or the examiner or other study subjects. The active 
control treatment containers will be overlabeled and packaged in the same secondary package 
(e.g., cardboard carton) as the test treatments. 
Masking of treatment for subjects assigned to the placebo group, will be maintained when they 
are switched to 0.003% DE-126 at the Week 6 visit, since the appearance of the 0.003% DE-126 
bottles will be identical to the placebo bottles. 
Diagnosis and main criteria for inclusion: 
At Visit 1 (Screening), the subject must meet all of the following inclusion criteria: 
1. Provide signed written informed consent on the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) approved Informed Consent Form (ICF) and 
provide authorization as appropriate for local privacy regulations. 
2. Be 20 years or older in Japan and 18 years of age or older in the U.S. (or meets specific 
state requirement for legal age if that is greater than 18 years of age) on the date of 
signing the ICF and able and willing to comply with all treatment and follow-up study 
procedures. 
3. If a subject is a female of childbearing potential (i.e. not post-menopausal [within 12 
months since the last menses] or surgically sterile [less than 6 months]), she must have a 
negative urine pregnancy test and must use at least one of the following acceptable 
contraceptive methods during, and for 28 days following the· study. 
• 
Abstinence 
• 
Hormonal contraceptive method- oral and 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 
The male partner of the female subject of childbearing potential should use/practice an 
acceptable contraceptive method, such as abstinence, condom or vasectomy (surgery at 
least 6 months prior) or other contraception deemed adequate by the investigator 
throughout the course of the study. 
Male subjects, with a female partner of childbearing potential, should use/ practice an 
acceptable contraceptive method, such as abstinence, condom or vasectomy (surgery at 
least 6 months prior) or other contraception deemed adequate by the investigator 
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Protocol 012601IN 
DE-126 Ophthalmic Solution 
throughout the course of the study. 
4. Subjects must have a diagnosis ofPOAG or OHT in both eyes (excluding 
pseudoexfo liation syndrome). 
5. Corrected visual acuity of +0.60 logMAR (Snellen equivalent 20/80, Decimal visual 
acuity 0.3) or better in each eye. 
6. Central corneal thickness ~ 480 J.tm and ~ 620 J.tm in each eye. 
7. Anterior chamber angle grade ~ 2 (Shaffer scale) in each eye. 
In addition, the subject must meet the inclusion criterion #3 again if applicable and the following 
criteria at Visit 2 (Baseline, Day 1 ): 
8. Completed the required wait/washout period if applicable. 
9. At all lOP measurement time-points (09:00, 13:00 and 17:00), lOP must be~ 22 mmHg 
in at least one eye and~ 34 mmHg in both eyes. 
Exclusion Criteria: 
A subject with any of the following ocular conditions in any eye or non-ocular conditions or 
characteristics are not eligible to participate in the study: 
General-
1. Females who are pregnant, nursing or planning a pregnancy. 
2. Subjects with known or suspected drug or alcohol abuse. 
3. Current or planned participation in any other clinical trial involving an investigational 
product or device within 30 days prior to Visit 1 (Screening) or at any time during this 
trial. 
4. Subjects who have been exposed to DE-126 prior to Visit 1 (Screening). 
Medications I Therapies-
5. Subjects who cannot safely discontinue use of ocular hypotensive medications during the 
wait/washout period. 
6. Subjects who will be required to initiate or modify any systemic or topical medication 
known to affect lOP (e.g., ~-adrenergic antagonists, a-adrenergic agonists, calcium 
channel blockers, angiotensin-converting enzyme [ACE] inhibitors, and angiotensin II 
receptor blockers [ARB] ) within the first 30 days prior to Visit 1 (Screening), or 
anticipated change in such therapy during the study. 
7. Intended or current use of the fo Bowing prohibited medications during the study: 
• 
All ocular medications other than artificial tear, cataract treatment agents, and 
Vitamin B12 formulation, and study medications during the study. 
• 
All systemically administered ocular hypotensive medication (e.g., oral or 
intravenous CAl, oral glycerol). 
• 
Any ocular, periocular, inhaled, nasal or systemic corticosteroids. 
8. Known allergy, hypersensitivity or contraindications to prostaglandins, benzalkonium 
chloride (BAK) or any other components of the study medications or other study related 
procedures/medications. 
9. History of ocular surgery specifically intended to lower lOP (e.g., laser trabeculoplasty, 
filtering surgery, Minimally Invasive Glaucoma Surgery [MIGS], or trabeculotomy) in 
either eye. 
10. History ofkeratorefractive surgery in either eye. 
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Protocol 01260 1 IN 
DE-126 Ophthalmic Solution 
11. Use of contact lenses within one week prior to Visit 2 (Baseline, Day 1) until end of 
treatment. 
12. Any ocular surgery or ocular laser treatment within 90 days prior to Visit 1 (Screening) 
and throughout the study in either eye. 
Diseases-
13. Advanced glaucoma (e.g., visual field mean deviation worse than -12 dB) in either eye. 
14. Any corneal abnormality or other condition interfering with or preventing reliable 
Goldmann applanation tonometry (e.g., Fuch's dystrophy, band-shaped keratopathy, 
Avellino corneal dystrophy or significant corneal surface abnormality) in either eye. 
15. Presence of any active severe external ocular disease, inflammation, or infection of the 
eye and/or eyelids in either eye. 
16. History of iritis and/or uveitis, corneal inflammatory conditions, and/or viral infections 
such as herpes virus in either eye; history of adenovirus is not an exclusion provided no 
associated inflammation was observed within 6 months prior to screening. 
17. Pseudophakic with a tom 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 or within 90 days after ocular surgery) for macular edema in either 
eye 
18. 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. 
19. Subjects with a history of severe ocular trauma in either eye. 
20. Subjects with any condition that prevents clear visualization of the fundus in either eye. 
21. Presence or history of any ocular or systemic disease, clinical laboratory test abnormality 
that in the opinion of the study investigator may put the subject at significant risk, may 
confound study results, or may interfere significantly with the subject's participation in 
the study (e.g., recurrent corneal erosion syndrome, uncontrolled cardiovascular disease 
etc.). 
22. Any decision by the Principal Investigator or Medical Monitor to terminate a subject in 
screening or declare any subject ineligible for any reason. 
Investigational product/reference therapy, dosage and mode of administration: 
Subjects will be randomly assigned in a 1:2:2:2:2:2 ratio to receive one of the following 
treatments: 
• 
Placebo (Vehicle ofDE-126 ophthalmic solution)~ 0.003% DE-126 at Week 6. 
• 
0.0005% DE-126 Ophthalmic Solution 
• 
0.001% DE-126 Ophthalmic Solution 
• 
0.002% DE-126 Ophthalmic Solution 
• 
0.003% DE-126 Ophthalmic Solution 
• 
0.005% Latanoprost Ophthalmic Solution 
Each subject will be instructed to instill one drop of study medication in each eye at 21:00 daily during 
the Treatment Phase of the study. 
Route of administration: Topical ocular 
Duration of treatment: 3 months 
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Protocol012601~ 
DE-126 Ophthalmic Solution 
Criteria for evaluation: 
Safety: 
Safety assessments will be composed of adverse events, vital signs, clinical laboratory tests, 
corrected visual acuity, ocular symptoms, slit lamp biomicroscopy, ophthalmoscopy findings, 
central corneal thickness measurement (pachymetry), iris color, eyelash and eyelid examination. 
Efficacy: 
Efficacy will be assessed by evaluating lOP at each scheduled time point as follows: 09:00, 
13:00 and 17:00 (plus or minus 60 minutes). 
Other: 
Subject demographics and baseline characteristics, exposure to study medication and 
concomitant medications will be summarized. 
Efficacy Endpoints: 
Primary Efficacy Endpoint: 
• 
lOP in the study eye at each specified time point (09:00, 13:00 and 17:00) at Visit 6 
(Month 3). 
Key Secondary Efficacy Endpoint: 
• 
lOP in the study eye at each specified time point (09:00, 13:00 and 17:00) at Visit 5 
(week 6). 
Other Secondary Efficacy Endpoints: 
• 
lOP in the study eye at each specified time point (09:00, 13:00 and 17:00) at Visit 3 and 4 
(Week 1 and Week 2). 
• 
Mean diurnal lOP in the study eye at Visits 3, 4, 5, and 6 (Week 1, Week 2, Week 6, and 
Month 3). 
• 
Change and percent change from baseline (CFB) in mean diurnal lOP in the study eye at 
each post-baseline visit (Visits 3, 4, 5, and 6 [Week 1, Week 2, Week 6 and Month 3, 
respectively]). 
• 
Change and percent change from baseline (CFB) in lOP in the study eye at the specified 
time points: 09:00, 13:00, and 17:00 at each post-baseline visit. 
• 
Proportion of subjects with mean diurnal lOP reduction from baseline~ 20%, 25% and 
30% in the study eye at Visit 3 (Week 1), Visit 4 (Week 2), Visit 5 (Week 6) and Visit 6 
(Month 3). 
• 
Proportion of subjects with mean diurnal lOP~ 18 mmHg in the study eye at Visit 3 
(Week1), Visit 4 (Week 2), Visit 5 (Week 6) and Visit 6 (Month 3). 
Safety Endpoints: 
• 
Incidence of ocular and systemic adverse events (AEs). 
• 
Corrected visual acuity. 
• 
Ocular symptoms. 
• 
Slit-lamp biomicroscopy: conjunctival hyperemia, corneal staining, aqueous flare and cell 
etc. 
• 
Ophthalmoscopy. 
• 
Central corneal thickness. 
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Protocol 012601IN 
DE-126 Ophthalmic Solution 
• 
Iris color/eyelash/eyelid by photographs. 
• 
Vital signs. 
• 
Clinical laboratory tests. 
Statistical methods: 
The sample size is not planned on the primary efficacy endpoint. For the key secondary 
endpoint, assuming that the minimal expected treatment difference across all timepoints is 
-5.1 mmHg between an optimal DE-126 dose and placebo (based on ON0-9054IOU002 and 
ON0-9054IOU003 studies) and the standard deviation of such a difference is 3.9 mmHg, with a 
2:1 ratio, a sample size of36 for each DE-126 arm and 18 for placebo will provide 92% power to 
detect the difference at all timepoints using at-test (2-sided, a=0.0125 adjusted by Bonferroni 
correction). With 10% dropout rate, the sample size is 40 for each DE-126 arm and 20 for 
placebo arm. 
Moreover, this sample size will provide less than 20% power to claim non-inferiority ofDE-126 
optimal dose to Latanoprost, assuming no treatment difference and 1.5 mmHg non-inferiority 
margin. 
A mixed-effects model for repeated measures (MMRM) will be fitted and 95% confidence 
interval for each least-squares mean difference (DE-126 of each dose vs. placebo) will be 
estimated. To control an overall type I error rate of the study, Hochberg procedure will be used 
for multiple comparisons between DE-126 and control for the key secondary efficacy endpoint. 
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Protocol 012601IN 
DE-126 Ophthalmic Solution 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
PROCEDURES IN CASE OF EMERGENCY ...... 0000000000000000000000000000000000000000000000000003 
20 
SYNOPSISooooooooo•••ooooo•••oo·····•ooooooooooooooooooo••o•o••o···•oo•····o••ooo•···o···•oo••oo••o••ooo••oooooo•o••oooo4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .. o .. o.•o•••oo12 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ooo•••o••o••o•o••oooooooo .. o.17 
5. 
INTRODUCTION ooooooooooooooooooooo••o••oooooooo•o••oo•o••o···•oo•···················o··············o•oo•···o•o•19 
6. 
TRIAL OBJECTIVES AND PURPOSEooooooooooooooooooooo·····o·····ooo••ooo••oooooooooooooooooooooo.21 
6.1. 
Primary Objective ... o.ooooooooooo••o••o••o•ooooooooooo••ooooooo••o•ooo•o•o•••oo••••oo•••oo•o•oo•o••o•ooooo•o•o•ooooo21 
6.2. 
Secondary Objective ... o .. ooooooooooooooo••oooooooooo••o••o••o····•oo•·······o·····o····o····o•o••o••oooooo•o••o•oo21 
6.3. 
Safety Objective o••••oo••o•••oo••o•••ooooooooo•o••ooooo••oo•o•oo·o····oo•······o·····o····o···•oooooooooooooooooooooo21 
7. 
INVESTIGATIONAL PLAN ooooooooooo•••ooo•···o••o••o•o•••o•o·o·····o·····o····o···oo•o••oooo•o••ooooooooo22 
7 .1. 
Overall Study Design. •o ...... •o. 0.0. 0. 0 o .. o. o. 00 o o o o .. o o 00.00. o .. 0000 ...... •o .... 00 .... o ... 00. o .. o. 00. o o o o. 00 •o. o o 22 
7.2. 
Number of Subjects ooooooooooooo••oo••••o••o••••o••••o•o••o••••o··············o··············o·······o·····o•o•o•o•24 
7.30 
Treatment Assignmentooooooooooooooooooooo•o••ooo••o····o····o·····o····o········o·····o•••o••o•·o•o·····o•o•ooo.24 
7 .4. 
SCHEDULE OF EVENTS AND PROCEDURES o ... o.oooo•••o•o••o•oooooo••ooooooooooooooooooooo.25 
7 .4.1. 
Visit 1 (Screening) .. 000000 .. •o .. 00. •o 0 •o 0 00.00 00 0 0 0 0 0 •o. 0 .. 0 .. 00 0. 0 .. 0 0. 0 o• 0 .. 00.0. 000.0. 00.0. 0 0 00 0 •o 0 0 0 00 0 00.0 0 0 0 0 0 28 
7.4.2. 
Visit 1a (Optional, Washout Period) o••oo•o••ooo••o••ooo•····o········o···•oo•••oo•••o••ooooooooooooooooooo30 
7o4.3o 
Visit 2 (Baseline, Day 1) .. o.oooooooooooooooooooooooooo••oooooooo••oo••o•ooooo•o••oooooooooooooooooooooooooooooooo30 
704.4. 
Visit 3 (Week 1, Day 8 ±2) •oo••oo•o•oooooooooooooooo••o••ooooooooo•o•••o•oo•o•oo••o•o•••ooooooooooooooo•o•o····32 
7.4.50 
Visit 4 (Week 2, Day 15 ±2) o••oooooooo•o•o•o•o•oo••••o•••o······o·······o·····o····o····o·········o••o······o·32 
7.4.6. 
Visit 5 (Week 6, Day 43 ±3) ooooooooooooo•o•oooooo•o••o•••ooo••••o·······o·····o····o······o••o••••o••o•••o····33 
7.4.7. 
Visit 6 (Month 3, Day 91±3) Study Exit/Early Termination ... o .... oo···o·•o••o•o••oooooooo .. o.34 
7.5. 
Study Termination .....•........................................................................... o ..... o.oo···oo .. 35 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..... o·····o····o···o··········o·········o··36 
8.1. 
Subject Inclusion Criteria ..... oooooooo••o•o•·oooooooo••o••o·o···•oo•······o····o····o•••oo••o••ooo••o••ooo•o•o••36 
8.2. 
Subject Exclusion Criteria •o························o·······o···················································37 
8.3. 
Subject Withdrawal Criteriao···························································o···················o···39 
9. 
TREATMENT OF SUBJECTS o••••oo•o•o••o•o••o•o•••o•o•••oo••••o•oo····o···•ooo•····o··o····o•oo········o40 
9 .1. 
Description of Study Medication ......... o .......................................... o ....................... 40 
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9.2. 
9.2.1. 
9.3. 
9.4. 
10. 
10.1. 
10.1.1. 
10.1.2. 
10.1.3. 
10.2. 
10.3. 
10.4. 
10.5. 
10.6. 
10.7. 
10.8. 
11. 
11.1. 
12. 
12.1. 
12.1.1. 
12.1.1.1. 
12.1.1.2. 
12.1.2. 
12.1.2.1. 
12.1.2.2. 
12.1.2.3. 
12.1.3. 
12.1.4. 
12.1.5. 
12.2. 
12.2.1. 
13. 
Concomitant Medications or Therapies ................................................................... 40 
Prohibited Medications or Therapies ... oo••••oo··· .............................................. oo ......... 41 
Treatment Compliance ............................................................................................ 41 
Randomization and Masking ................................................................................... 42 
STUDY MEDICATION MATERIALS AND MANAGEMENT ............................ 44 
Study Medication .................................................................................................... 44 
Investigational Product ........................... 00 .. 00 ....................................... . .................. 44 
Active Control ................................................................................................. oo ..... 44 
Placebo ................................................................................................................... 44 
Study Medication Packaging and Labeling ............................................................. 44 
Study Medication Storage ... 00 ....... 00 ............ 0000 00 ....................................................... 45 
Study Medication Preparation ................................................................................. 45 
Study Medication Administration .................................... 00 ..................................... 45 
Study Medication Accountability 00 .......................................................................... 45 
Study Medication Handling and Disposal ............................................................... 46 
Study Supplies ........................ oooo ............. oo ............................................................. 46 
ASSESSMENT OF EFFICACY ............................................................................. 47 
Efficacy Parameter ................................................................................................. 4 7 
ASSESSMENT OF SAFETY oooo .. oo ...... oo.oo••oooooooo•······ .... oo ........ oo .. oo .. oo ......... oo .. oo ...... 48 
Adverse Events and Serious Adverse Events ....... 00 ........................ oo• ... oo• ........ 00 ••• oo .. 48 
Definition of Adverse Eventsoo.ooooooo•oo•oooo••oooooo ........................................ oo ..... oo ....... 48 
Assessment of Adverse Events ............................................................................... 48 
Reporting Adverse Events .. oo ... oo ............................................................................. 49 
Serious Adverse Events .......................................................................................... 51 
Assessment of Serious Adverse Events ................................................................... 51 
Reporting Serious Adverse Events .......................................................................... 51 
Expedited Reporting of Serious Adverse Events ..................................................... 52 
Reporting Pregnancy .............................................................................................. 52 
Follow-up of Adverse Events .................................................................................. 52 
Manual Back-Up Reporting Procedures .................................................................. 52 
Safety Parameters ................................................................................................... 53 
Ocular Assessments ................................................................................................ 53 
OTiffiR ASSESSMENTS ....................................................................................... 54 
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13.1. 
14. 
14.1. 
14.1.1. 
14.1.2. 
14.2. 
14.2.1. 
14.2.2. 
14.3. 
14.3.1. 
14.3.2. 
14.3.3. 
14.4. 
14.5. 
14.6. 
14.6.1. 
14.6.2. 
14.6.2.1. 
14.6.2.2. 
14.7. 
15. 
15.1. 
15.2. 
15.3. 
16. 
16.1. 
16.2. 
17. 
17.1. 
17.2. 
17.3. 
18. 
18.1. 
Demographic, Baseline Characteristics and Other Assessments .............................. 54 
STATISTICAL METHODS .............................................. , .................................... 55 
Analysis Time Points .............................................................................................. 55 
Interim Analysis ..................................................................................................... 55 
Final Analysis ......................................................................................................... 55 
General Considerations ........................................................................................... 55 
Sample Size ............................................................................................................ 55 
Statistical Hypotheses and Level of Significance .................................................... 56 
Study Populations ................................................................................................... 56 
Safety Population ............................................................................. 0. 0 ... 0. 0 ........... 0. 0 56 
Full Analysis Set ..................................................................................................... 56 
Per-Protocol Population .................. 0 ......................... 0 .......................................... 0 .. 56 
Handling of Missing Values .................................................................................... 57 
Demographic and Baseline Characteristics .............................................................. 57 
Efficacy Analyses ........... o•••oo ... oooo••••o····· ................ o o•··· ......... o ....... o ••••• o .. •••o····· o .... o•• 57 
Analysis of Primary Efficacy Endpoint ............. o····· ...................... o•···· .................... 57 
Analysis of Secondary Efficacy Endpoints .. 0. 0 ••••••••• 0 ••••••••••••••••••••••••• 0. 0 ••••• 0 ••••••••••••• 57 
Key Secondary Efficacy Endpoint ................................ •o ........................................ 57 
Other Secondary Efficacy Endpoints ....................................................................... 57 
Safety Analyses ................................ 
0 ....................................................... 
0 ............. 58 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ....................................... 59 
Study Monitoring .................................................................................................... 59 
Audits and Inspections ............................................................................................ 60 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ................. 60 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 61 
Quality Control ........................................................................................ 0 .............. 61 
Quality Assurance ............... 0 0 ... 0 0 •••••••••••••••••••••• 0 ................... 0 ••• 0 ......... 0 0 •••••••••• 0 .... 0 •• 61 
ETHICS ............................... o .................. o ••• o •• o •• o ........ o ... •o•o····o·······o·····o .................. 62 
Ethics Review ......................................................................................................... 62 
Ethical Conduct of the Study .................................................................................. 62 
Written Informed Consent ...................................................................................... 62 
DATA HANDLING AND RECORDKEEPING ..................................................... 63 
Inspection of Records ............................................................................................. 63 
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18.2. 
18.2.1. 
18.2.2. 
18.2.3. 
19. 
20. 
20.1. 
20.2. 
21. 
21.1. 
21.2. 
21.3. 
21.3.1. 
21.3.2. 
21.3.3. 
21.3.4. 
21.3.5. 
21.3.6. 
21.3.6.1. 
21.3.6.2. 
21.3.6.3. 
21.3.7. 
21.3.8. 
21.3.8.1. 
Retention of Records ................................................................ oooo•··········· .. ·······oo···63 
Source Documents ... oo• ............................................................................................ 63 
Source Data ........................................................................................... oo•·· .••.••.•..•• 64 
Data Collection ... 00 ................................ 00 ................................................................ 64 
PUBLICATION POLICY ....................................................................................... 65 
REFERENCES ....................................................................................................... 66 
Literature ................................................................................................................ 66 
Study Data .............................................................................................................. 67 
APPENDICES ........................................................................................................ 68 
Appendix A - Obligations of Investigators ................... 00 ......................................... 68 
Appendix B - Elements of Informed Consent ............... 00 ......................................... 70 
Appendix C - Procedures for Assessments .............................................................. 72 
Demographics, Medication/Therapy and Medical History ....................................... 72 
Pregnancy Test ....................................................................................................... 72 
Urinalysis, Hematology, and Serum Biochemistry ............................................. 00 ... 72 
Vital signs (Blood pressure/heart rate) .................................................................... 73 
Ocular Symptoms .................................. 00 .. oo ..... 00 ............... oo• ........ oo• 00 ............ 0000 •• 00.73 
Iris, Eyelash, Eyelid ...... oo.•oo•oo••oooo .. oo .............. oo ......... oo ....... oo ................................ oo. 75 
Iris Color ................................. 00 ...... oooo ................................................................... 75 
Eyelash .................................................................................................... oo ............. 75 
Eyelid .............. oo ....................................... oo ............................................................ 76 
Refraction ............................................................................................................... 76 
Corrected Visual Acuity ............................................................................... 00 ........ 76 
ETDRS Visual Acuity Scoring ............................................................................... 76 
21.3.9. 
Slit-lamp Biomicroscopy ........................................................................................ 77 
21.3.10. 
Intraocular Pressure ................................................................................................ 80 
21.3 .1 0.1. Tonometer Calibration ....................................................................................... oo ... 81 
21.3.11. 
21.3.12. 
21.3.13. 
21.3.14. 
21.3.15. 
21.4. 
Central Corneal Thickness ................................... 00 ................................................. 82 
Gonioscopy ............................................................................................................ 82 
Visual Field .................................................................................. •oo ... 00 .................. 82 
Ophthalmoscopy (Fundus) Examination ................................................................. 83 
Saliva Sample for Pharmacogenomics/genomics Study ........................................... 83 
Appendix D - Latanoprost Ophthalmic Solution, 0.005% Package Insert ................ 84 
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22. 
PROTOCOL AMENDMENT 1 SUMMARY OF CHANGES ................................ 93 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ............................................................................... 3 
Table 2: 
Abbreviations and Specialist Terms ........................................................................ 17 
Table 3: 
LogMAR Scoring Grid for ETDRS Eye Chart ........................................................ 77 
Table 4: 
Protocol Amendment 1 Summary of Changes ......................................................... 93 
LIST OF FIGURES 
Figure 1: 
Study Design .......................................................................................................... 22 
Figure 2: 
DE-126 Structure .................................................................................................... 40 
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4. 
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 
AE 
Adverse event 
AGIS 
Advanced Glaucoma Intervention Study 
Al-P 
Alkaline phospha~ase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BAK 
Benzalkonium chloride 
BUN 
Blood urea nitrogen 
CAis 
Carbonic Anhydrase inhibitors 
Cl 
Chlorine 
dB 
Decibel 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EP3 
Prostaglandin E receptor 3 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full analysis set 
FP 
Prostaglandin F receptor 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
lOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
K 
Potassium 
LDH 
Lactate dehydrogenase 
LOCF 
Last Observation Carried Forward 
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Table 2: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Definition 
LogMAR 
Logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeters of mercury 
Jlg 
Microgram 
Jlm 
Micrometer 
MIGS 
Minimally Invasive Glaucoma Surgery 
MMRM 
Mixed-effects Model for Repeated Measures 
Na 
Sodium 
OAG 
Open Angle Glaucoma 
OCT 
Optical Coherence Tomography 
OHT 
Ocular Hypertension 
PACG 
Primary Angle Closure Glaucoma 
PG 
Prostaglandin 
PGA 
Prostaglandin Analogue 
POAG 
Primary Open Angle Glaucoma 
pp 
Per-Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SUN 
Standardization of Uveitis Nomenclature 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
y-GT 
Gamma-glutamy I transferase 
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5. 
INTRODUCTION 
Glaucoma represents a group of related diseases associated frequently with elevated lOP. When 
left untreated, glaucoma leads to retinal ganglion cell death and optic nerve damage, resulting in 
progressive and irreversible loss of vision. Glaucoma is the second leading cause of blindness 
worldwide, with an estimated prevalence of 60.5 million people in 2010 increasing to an 
estimated 79.6 million by 2020 (Quigley et al., 2006). It affects one in two hundred people aged 
fifty or younger and one in ten over the age of eighty (Resnikoff et al., 2004). Similarly in Japan, 
glaucoma is the first leading cause of blindness and it's prevalence is 5.0% (POAG 3.9%, PACG 
0.6%, secondary glaucoma 0.5%) and OHT 0.8% in population over the age of forty (lwase et 
al., 2004; Yamamoto et al., 2005). 
Although currently there is no cure for open-angle glaucoma, results from multiple studies, 
including the Advanced Glaucoma Intervention Study (A GIS) (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 lOP with 
topical ocular hypotensive agents is effective in delaying or preventing disease progression. The 
lowering of lOP is currently the only method for reducing the risk of glaucomatous visual field 
loss and remains the primary goal of therapy. 
Several classes of ocular hypotensive medications exist today and are differentiated by their 
mechanism of action at the cellular/molecular level. These include miotics, ~-adrenergic receptor 
antagonists (~-blockers), carbonic anhydrase inhibitors (CAis ), a-adrenergic receptor agonists 
( a-agonists ), and prostaglandin analogues (PGAs ). The pharmacodynamic effect of these 
medications can differ substantially, as some affect aqueous humor production (~-blockers, 
a-agonists, and CAis) while others affect the outflow pathway (miotics, PGs, and a-agonists). In 
general, PGAs are recommended as the first choice agent for most eyes with ocular hypertension 
and open-angle glaucoma. The main reasons for this choice include their effective lOP reduction, 
lack of relevant systemic side effects, convenient once-daily dosing, and good tolerability profile 
(Aim, 2014). 
With first line treatment with PGAs or ~-blockers' lOP reduction is very effective; however, 
mono-therapy is often insufficient to achieve target lOP. 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 lOP reduction than existing PGAs or ~-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 lOP in patients with ocular hypertension or 
open angle glaucoma. 
The ocular hypotensive effects of PGAs have been fully investigated in many animal models. 
Although current PGAs, such as latanoprost, are thought to lower lOP mainly via the prostanoid 
FP receptor, a novel mechanism of action via EP3 receptor has been reported recently 
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(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 lOP (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 lOP 
reduction than PGAs, and indeed it was proven such compounds exhibit more potent lOP 
reduction than latanoprost. Among the 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 lOP than approved PGAs or the fixed combination ofPGA 
and P-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. 
Three clinical studies (ON0-9054IOU001, ON0-9054IOU002, ON0-9054IOU003) were 
conducted in the U.S. with DE-126 in healthy adult subjects, or subjects with POAG or OHT to 
evaluate the safety and efficacy ofDE-126. As a result, DE-126 ophthalmic solution in 
concentrations of up to 0.003% appeared to be tolerated and effective. 
DE-126 with a novel mechanism of action could be a new hypotensive agent for patients with 
OHTorOAG. 
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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To determine the optimal dose ofDE-126 by investigating the safety and efficacy of four (4) 
concentrations ofDE-126 ophthalmic solution (0.0005%, 0.001%, 0.002%, and 0.003%) when 
compared to latanoprost (0.005% latanoprost) at Month 3 in subjects with primary open-angle 
glaucoma or ocular hypertension. 
6.2. 
Secondary Objective 
To determine if anyone offour (4) concentrations ofDE-126 (0.0005%, 0.001%,0.002% and 
0.003%) is superior to the placebo (vehicle ofDE-126) in mean lOP reduction at each specified 
time point (09:00, 13:00 and 17:00) at Week 6 compared to baseline. 
To investigate the dose response of four (4) concentrations ofDE-126 ophthalmic solution 
(0.0005%, 0.001%, 0.002% and 0.003%). 
6.3. 
Safety Objective 
To determine the safety ofDE-126 ophthalmic solutions (0.0005%, 0.001%, 0.002% and 
0.003%) given once daily as compared to 0.005% latanoprost given once daily in this population. 
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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a randomized, observer-masked, placebo- and active-controlled, parallel-group, 
multinational and multicenter study assessing the safety and efficacy of four ( 4) concentration of 
DE-126 ophthalmic solution (0.0005%, 0.001%, 0.002%, and 0.003%) in subjects with POAG or 
OHT. Latanoprost ophthalmic solution 0.005% will be used as active control. This study will 
consist of a screening phase of up to 35 days, including a washout period of up to 28 days (up to 
7 additional days allowed prior to baseline visit) and a 3-month treatment period (Figure 1). If 
subject does not require washout of any medication, a minimum of 1 day is required between 
screening and baseline visits (or minimum of 7 days if subject uses contact lenses). 
Figure 1: Study Design 
Visit 1 
(Day -35 to -1) 
Visit 2 
Visit 3 
VIsit 4 
(Day 1) (Week 1.) (Week 2) 
VisitS 
(Week 6) 
Screening 
Baseline/Randomization 
""""' 
Screening Phase .. 
""""' 
Treatment Phase 
~ 
,. ~ 
Placebo (N=20) 
I 0.003% DE-126 
I 
Wait/Washout 
0.000596 DE-126 
Period (~1-35 Days) 
0.00196 DE-126 
N=220 (40 /arm 
0.00296 DE-126 
for DE-126 and 
La.t· 20/arm for 
0.00396 DE-126 
Placebo) 
0.00596 Latanoprost 
I 
I 
Vislt6 
(Month3) 
... ,. 
... 
... 
, 
.. 
... , 
.. 
. 
One drop, once dally at 21.00 
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 lOP-lowering medications 
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 
• 
Beta antagonists (B blocker, including aB blockers): 28 days 
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Protocol 012601IN 
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• 
Alpha antagonists (a1 blocker): 28 days 
• 
Prostaglandins Analogs (PGA): 28 days 
• 
Rho kinase inhibitor: 28 days 
For combination drugs, the longest washout period of the individual component will be used. 
During the required washout period, subjects who discontinue their current treatment may, if the 
investigator deems it necessary for safety, be treated with a topical CAl, e.g., brinzolamide or 
dorzolamide eye drops, one drop twice daily. Topical CAl treatment must stop 1 week before the 
randomization at Visit 2 (Baseline, Day 1 ). 
An interim safety visit, mid washout visit (Visit 1a), may be performed during the washout 
period if, in the investigator's opinion, a subject's lOP may be of concern during the washout 
period. If subjects are treated with a topical CAl by 1 week before the randomization at Visit 2 
(Baseline, Day 1), mid washout visit (Visit 1a) is recommended to be performed. 
Final eligibility will be determined at Visit 2 (Baseline) after all necessary washout from prior 
lOP-lowering medications has been completed. Subjects who have not used an lOP-lowering 
medication for the last 28 days prior to the screening visit, including treatment-naive subjects, 
must have at least one day between their screening visit and Visit 2 (Baseline). 
At Visit 2, baseline lOP will be measured for both eyes at 09:00, 13:00 and 17:00 (±60 minutes). 
The study eye will be the eye that qualifies per eligibility criteria at Visit 2. If both eyes meet 
eligibility criteria, the eye with the higher diurnal lOP at Visit 2 will be designated as the study 
eye. Ifboth eyes meet eligibility criteria and have the same mean diurnal lOP, the right eye will 
be designated as the study eye. 
In cases where only one eye is fully qualified for the study, both eyes can be treated for the 
duration of the study. Approximately 220 eligible subjects will be randomized to one of the six 
(6) treatment arms. Forty (40) subjects per treatment arm will be randomized to each DE-126 and 
Latanoprost arm, and 20 subjects will be randomized to the Placebo arm. Central randomization 
via Interactive Response Technology (Medidata BALANCE) will be used to allocate the subjects 
to each of the six treatment arms in the U.S. and Japan separately. Each eligible subject will be 
assigned to receive a study medication kit number as allocated by the randomization schedule 
and assigned by BALANCE. 
The study eye drops will be given once daily at 21 :00 ( ±60 minutes), starting on the evening of 
Visit 2 and continuing through the evening prior to Visit 6 (Month 3). During the 3-month 
treatment period, subjects will return for Visits 3, 4, 5, and 6 (Weeks 1, 2, 6 and Month 3) and 
lOP will be measured at 09:00, 13:00 and 17:00 (±60 minutes). At these scheduled visits, 
corrected VA and slit lamp biomicroscopy will be performed at 09:00 immediately prior to lOP 
measurement. Corneal thickness measurement (pachymetry) and ophthalmoscopy (fundus 
examination) will be performed at 17:00 immediately after lOP measurement. 
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Subjects will be invited to separately consent to provide a saliva sample for a future 
pharmacogenomics/genomics laboratory research study, however providing such consent is not a 
prerequisite to participating in the main study. The purpose of this exploratory research is to identify 
possible genetic markers associated with the study drug(s) and/or ocular conditions. 
7.2. 
Number of Subjects 
Approximately 220 subjects in the U.S. and Japan in a 1:1 ratio. 
7 .3. 
Treatment Assignment 
Subjects will be randomly assigned in a 1:2:2:2:2:2 ratio to receive one of the following 
treatments: 
• 
Placebo (Vehicle ofDE-126 ophthalmic solution)~ 0.003% DE-126 at Week 6. 
• 
0.0005% DE-126 Ophthalmic Solution 
• 
0.001% DE-126 Ophthalmic Solution 
• 
0.002% DE-126 Ophthalmic Solution 
• 
0.003% DE-126 Ophthalmic Solution 
• 
0.005% Latanoprost Ophthalmic Solution 
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7.4. 
SCHEDULE OF EVENTS AND PROCEDURES 
Screening Phase 
Treatment Phase 
Washout 
Visit 6 
Visit 1 
Period 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Month3 
Screening 
(optional 
Baseline 
Week1 
Week2 
Week6 
(Day91±3, 
Visit 1a) 
(Day 1) 
(Day 8±2) 
(Day 15±2) 
(Day43±3) 
Exit) or 
Early Term 
Informed Consent(s t 
X 
Inclusion/Exclusion Criteria 
X 
X 
Demographics and Medical Histo~ 
X 
(incl. Prostaglandin Analogs naive ) 
Concomitant Medications/Therapies 
X 
X 
X 
X 
X 
X 
X 
Dosing Compliance 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Teste 
X 
X 
X 
Urinalysis 
X 
X 
Hematology and Serum Biochemistry 
X 
X 
Vital signs (Blood pressure/heart rate )d 
X 
X 
X 
Refractione 
X 
X 
X 
X 
X 
X 
Corrected V Ar 
X 
X 
X (09:00) 
X (09:00) 
X (09:00) 
X (09:00) 
X (09:00) 
Ocular Symptoms questionnair~ 
X 
X 
X 
X 
X 
X 
Biomicroscopy (including conjunctival 
hyperemia, aqueous flare, cells l 
X 
X 
X.(09:00) 
X (09:00) 
X (09:00) 
X (09:00) 
X (09:00) 
X 
X 
09:00 
09:00 
09:00 
09:00 
09:00 
Intraocular Pressure (IOpf)h 
13:00 
13:00 
13:00 
13:00 
13:00 
17:00 
17:00 
17:00 
17:00 
17:00 
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Screening Phase 
Treatment Phase 
Washout 
Visit 6 
Visit 1 
Period 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Month 3 
Screening 
(optional 
Baseline 
Week1 
Week2 
Week6 
(Day 91±3, 
Visit 1a) 
(Day 1) 
(Day8±2) 
(Day 15±2) 
(Day 43±3) 
Exit) or 
Early Term 
Pachymetry (Central Corneal 
X 
X (17:00) 
X (17:00) 
X (17:00) 
ThicknessY 
Iris, Eyelas~, Eyelid assessment and 
X 
X 
X 
photograpl:l 
Gonioscopyc 
X 
Visual Fieldk 
X 
Ophthalmoscopy1 
X 
X (17:00) 
X (17:00) 
X (17:00) 
Pharmacogenomics/genomicsm 
X 
Dispense Study Medication 
X 
X 
Collect Study Medication 
X 
X 
a Informed Consent and authorization as appropriate for local privacy regulations must be signed and dated before study procedures are performed. Informed consent for the 
optional pharmacogenomics/genomics laboratory research study may be obtained at any visit prior to study exit. 
b Prostaglandin naive subjects are defmed 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 medical records or subject history. 
c A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
d Vital signs should be recorded at same timepoint at each visit, where possible. 
eRefraction will be required if the prescription is not up to date within 12 months at the screening visit. If more than 10 letters in corrected visual acuity were lost compared to the 
screening visit, then refraction must be performed. 
r Corrected VA and biomicroscopy examination will be completed before lOP is measured at 09:00. Aqueous flare and cell evaluation will be performed before fluorescein 
instillation. If investigator evaluates for possible tom 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. 
g Ocular symptoms questionnaire should be performed at the screening visit, and at the beginning of each post-screening visit (Visits 2 to 6). 
h lOP Measurements will be taken at 09:00 ±60min, 13:00 ±60min and 17:00 ±60min at all visits except for Visit 1 (Screening). 
i Pachymetry will be performed after lOP measurement at Visit 1 (if pachymetry is contact type), and after the 17:00 lOP measurement at Visits 2, 5, and 6. 
j Iris, eyelash and eyelid photograph will be maintained as source documentation. 
k Gonioscopy and visual field measurement will be performed if not done within 3 months prior to Visit 1. Gonioscopy will be performed after lOP measurement. 
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1 Ophthalmoscopy will be performed after lOP measurement at Visit 1 and after the 17:00 lOP measurement at Visits 2, 5, and 6.1finvestigator performs ophthalmoscopy under 
dilation based on his/her decision, please dilate pupil and perform after all other ocular procedures have been completed 
m Saliva collection for the pharmacogenomics/genomics laboratory research study may be collected at any visit after informed consent obtained and subject randomized 
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7.4.1. 
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 pharmacogenetic 
laboratory research study may be obtained at any visit prior to study exit. Ensure 
that the subject understands that if they do not wish to provide a saliva sample for 
the pharmacogenomics/genomics laboratory research study that it will not affect the 
subject's enrollment in main study. 
• 
Prepare the list of screening/registration of subjects. 
• 
Obtain demographics. 
• 
Obtain medications, ocular procedures/therapies and medical history including all 
ocular medical history, any other medical history within 5 years, POAG or OHT 
diagnosis, ocular surgical history, current ocular and systemic conditions. 
• 
Obtain urine and perform urine pregnancy test, if the subject is a women of child-
bearing potential. 
• 
Perform the following procedures or assessments (all ophthalmic procedures to be 
performed in both eyes): 
o Vital signs (at same timepoint at each visit, where possible) 
o Refraction (if it has not been performed in the previous twelve months) 
o Corrected visual acuity (before lOP measurement) 
o Ocular symptoms questionnaire 
o Biomicroscopy (before lOP measurement. If investigator evaluates for 
possible tom posterior lens capsule by biomicroscopy under dilation in 
subjects with pseudophakic eye(s) based on his/her decision, please dilate 
pupil and evaluate after all other ocular procedures have been completed) 
o lOP 
o Pachymetry (if pachymetry is contact type, central corneal thickness is 
measured after lOP measurement) 
o Gonioscopy (if it has not been performed in the previous three months, after 
lOP measurement) 
o Visual field (if it has not been performed in the previous three months) 
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o Ophthalmoscopy (after lOP measurement. If investigator performs 
ophthalmoscopy under dilation based on his/her decision, please dilate pupil 
and perform after all other ocular procedures have been completed) 
o Urinalysis 
o Hematology and serum biochemistry 
• 
Determine if the subject meets eligibility criteria. 
• 
If the subject meets eligibility criteria and will continue in the study, discontinue 
any current lOP medication according to the following schedule (up to +7 days as a 
window is allowed): 
o Miotics: 7 days 
o Oral/topical Carbonic Anhydrase Inhibitors (CAis): 7 days 
o Alpha agonists: 14 days 
o Alpha/beta agonists: 14 days 
o Beta antagonists(~ blocker, including a~ blockers): 28 days 
o Alpha antagonists (a1 blocker): 28 days 
o Prostaglandins Analogs (PGA): 28 days 
o Rho kinase inhibitor: 28 days 
• For combination drugs, the longest washout period of the individual component will 
be used. During the required washout period, subjects who discontinue their current 
treatment may, if the investigator deems it necessary for safety, be treated with a 
topical CAl, e.g., brinzolamide or dorzolamide eye drops, one drop twice daily. 
Topical CAl treatment must stop 1 week before the randomization at Visit 2 
(Baseline, Day 1 ). 
• 
An interim safety visit, mid washout visit (Visit 1a}, may be performed during the 
washout period if, in the investigator's opinion, a subject's lOP causes any safety 
concern during the washout period. If subjects are treated with a topical CAl by 
1 week before the randomization at Visit 2 (Baseline, Day 1 }, mid washout visit 
(Visit 1a) is recommended to be performed. 
• 
The eligibility visit (Visit 2) will be scheduled at the end of the washout period for 
those subjects on prior lOP-lowering medications. 
• 
Subjects who have not used an lOP-lowering medication for the last 28 days, 
including treatment-naive subjects, will need a wait period of~ 1 day before their 
Visit 2 (Baseline, Day 1). 
o If a subject does not require washout from an lOP-lowering medication, but 
they use contact lenses in either eye, they will need a wait period of~ 7 days 
with no contact use before their Visit 2 (Baseline, Day 1 ). 
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• 
Schedule the eligible subject to return for Visit 2 (Baseline, Day 1) after the 
required wait/washout period. 
• 
A subject who does not meet eligibility criteria or will not otherwise continue in the 
study is considered a screen failure. 
7.4.2. 
Visit la (Optional, Washout Period) 
• 
Visit 1a is an interim safety visit, mid washout visit that may be performed during 
the washout period if, the investigator's opinion, a subject's lOP causes any safety 
concern during washout period. 
• 
Update concomitant medications and ocular procedures/therapies. 
• 
Query the subject regarding AEs. 
• 
Perform the following procedures or assessments (all ophthalmic procedures to be 
performed in both eyes): 
o Corrected visual acuity (before lOP measurement) 
o Biomicroscopy (before lOP measurement) 
o lOP measurement 
7 .4.3. 
Visit 2 (Baseline, Day 1) 
• 
Update concomitant medications and ocular procedures/therapies. 
• 
Query the subject regarding AEs. 
• 
Confirm the subject has complied with the required wait/washout period for ocular 
hypotensive medication(s), or contact lenses use. 
• 
Complete ocular symptoms questionnaire prior to performing procedures listed below. 
• 
Obtain urine and perform urine pregnancy test, if the subject is a women of child-
bearing potential. 
• 
Perform all ophthalmic procedures in both eyes. 
• 
Perform corrected visual acuity and biomicroscopy immediately prior to the 09:00 
lOP measurement. 
• 
If more than 1 0 letters in corrected visual acuity were lost compared to the screening 
visit, then refraction should be performed. 
• 
Perform lOP measurement at 09:00 (±60 minutes). 
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• 
If subject meets the 09:00 lOP eligibility requirements, schedule additional lOP 
measurements at 13:00 and perform within ±60 minutes of the scheduled time. 
• 
If subject meets the 09:00 and 13:00 lOP eligibility requirements, schedule additional 
lOP measurements at 17:00 and perform within ±60 minutes of the scheduled time. 
• 
Perform pachymetry and ophthalmoscopy immediately after the 17:00 lOP 
measurement. 
• 
Perform vital signs measurement at same timepoint at each visit, where possible. 
• 
Collect Iris, Eyelash, Eyelid photographs at any time during this visit. 
• 
Perform final review of eligibility criteria after the 17:00 lOP measurement. If the 
subject meets all eligibility criteria, upon completion of the above procedures and 
assessments, the Investigator will determine the study eye. The subject will then be 
randomized, via Interactive Response Technology (Medidata BALANCE). 
o The study eye will be the eye that qualifies per inclusion/exclusion criteria at 
Visit 2. If both eyes meet eligibility criteria, the eye with the higher mean 
diurnal lOP at Visit 2 will be the study eye. If both eyes meet eligibility 
criteria and have the same mean diurnal lOP, the right eye will be the study 
eye. 
• 
After the subject has been randomized to a treatment arm, and assigned a treatment 
kit by BALANCE, an authorized study staff, other than the Investigator or examiner, 
must: 
o Dispense three bottles of study medication from the assigned subject kit. 
o Give the subject verbal and written instructions for proper instillation of the 
study medication, the dosing regimen, and study medication storage. Instruct 
the subject not to show or discuss their study medication with other study staff 
or other study subjects. 
• 
If the subject provided written consent to provide a saliva sample for a future 
pharmacogenomics/genomics laboratory research study, collect the sample at this 
visit or subsequent visit prior to exit from the study. 
o Note: If a saliva sample cannot be collected at this visit, it may be collected at 
any one of the following Visits, for example, Visits 3, 4, 5, 6, or unscheduled 
or early termination visit, the subject has provided written consent prior to 
collection of the sample. 
• 
Schedule the subject to return on Day 8 ±2 for Visit 3 (Week 1 ). 
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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. 
• 
Remind the subject to bring all used and unused study medication at Visit 3. 
7.4.4. 
Visit 3 (Week 1, Day 8 ±2) 
• 
Update concomitant medications and ocular procedures/therapies. 
• 
Query the subject regarding dosing compliance. An authorized study staff, other than 
the Investigator or examiner should ensure subject has sufficient study medication to 
complete dosing through Visit 4. 
• 
Query the subject regarding AEs. 
• 
Complete ocular symptoms questionnaire prior to performing procedures listed below. 
• 
Perform all ophthalmic procedures in both eyes. 
• 
Perform corrected visual acuity and biomicroscopy immediately prior to the 09:00 
lOP measurement. 
• 
If more than 10 letters in corrected visual acuity were lost compared to the screening 
visit, then refraction should be performed. 
• 
Perform lOP measurement at 09:00, 13:00, and 17:00 within ±60 minutes of the 
scheduled time. 
• 
If the subject provided written consent to provide a saliva sample for a future 
pharmacogenomics/genomics 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 15 ±2 for Visit 4 (Week2). 
• 
Remind the subject to continue dosing according to the written instructions. 
• 
Remind the subject to bring all used and unused study medication at Visit 4. 
7.4.5. 
Visit 4 (Week 2, Day 15 ±2) 
• 
Update concomitant medications and ocular procedures/therapies. 
• 
Query the subject regarding dosing compliance. An authorized study staff, other than 
the Investigator or examiner should ensure subject has sufficient study medication to 
complete dosing through Visit 5. 
• 
Query the subject regarding AEs. 
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• 
Complete ocular symptoms questionnaire prior to performing procedures listed below. 
• 
Perform all ophthalmic procedures in both eyes. 
• 
Perform corrected visual acuity and biomicroscopy immediately prior to the 09:00 
lOP measurement. 
• 
If more than 10 letters in corrected visual acuity were lost compared to the screening 
visit, then refraction should be performed. 
• 
Perform lOP measurement at 09:00, 13:00, and 17:00 and perform within ±60 
minutes of the scheduled time. 
• 
If the subject provided written consent to provide a saliva sample for a future 
pharmacogenomics/genomics 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 43 ±3 for Visit 5 (Week6). 
• 
Remind the subject to continue dosing according to the written instructions. 
• 
Remind the subject to bring all used and unused study medication at Visit 5. 
7 .4.6. 
Visit 5 (Week 6, Day 43 ±3) 
• 
Update concomitant medications and ocular procedures/therapies. 
• 
Query the subject regarding dosing compliance. An authorized study staff, other than 
the Investigator or examiner should ensure subject has sufficient study medication to 
complete dosing through Visit 6. 
• 
Query the subject regarding AEs. 
• 
Complete ocular symptoms questionnaire prior to performing procedures listed below. 
• 
Perform all ophthalmic procedures in both eyes. 
• 
Perform corrected visual acuity and biomicroscopy immediately prior to the 09:00 
lOP measurement. 
• 
If more than 10 letters in corrected visual acuity were lost compared to the screening 
visit, then refraction should be performed. 
• 
Perform lOP measurement at 09:00, 13:00, and 17:00 and perform within ±60 
minutes of the scheduled time. 
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• 
Perform pachymetry and ophthalmoscopy immediately after the 17:00 lOP 
measurement. 
• 
Collect Iris, Eyelash, Eyelid photographs at any time during this visit. 
• 
Assess any changes from baseline in Iris, Eyelash, Eyelid at any time during this visit. 
• 
An authorized study staff member, other than the Investigator or examiner, must: 
o Collect all used and unused bottles of study medication. 
o Dispense three bottles of study medication. Instruct the subject not to show or 
discuss their study medication with other study staff or other study subjects. 
• 
If the subject provided written consent to provide a saliva sample for a future 
pharmacogenomics/genetics 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 91 ±3 for Visit 6 (Month 3) Study Exit. 
• 
Remind the subject to continue dosing according to the written instructions. 
• 
Remind the subject to bring all used and unused study medication at Visit 6. 
7.4.7. 
Visit 6 (Month 3, Day 91±3) Study Exit/Early Termination 
• 
An authorized study staff member, other than the Investigator or examiner, must 
collect all used and unused bottles of study medication. 
• 
Update concomitant medications and ocular procedures/therapies. 
• 
Query the subject regarding dosing compliance. 
• 
Query the subject regarding AEs. 
• 
Complete ocular symptoms questionnaire prior to performing laboratory tests and 
procedures listed below. 
• 
Obtain urine and perform urine pregnancy test, if the subject is a women of child-
bearing potential. 
• 
Perform urinalysis, hematology, and serum biochemistry. 
• 
Perform all ophthalmic procedures in both eyes. 
• 
Perform corrected visual acuity and biomicroscopy immediately prior to the 09:00 
I 0 P measurement. 
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• 
If more than 1 0 letters in corrected visual acuity were lost compared to the screening 
visit, then refraction should be performed. 
• 
Perform lOP measurement at 09:00, 13:00, and 17:00 and within ±60 minutes of 
scheduled time. 
• 
Perform pachymetry and ophthalmoscopy immediately after the 17:00 lOP 
measurement. 
• 
Perform vital signs measurement at same timepoint at each visit, where possible. 
• 
Collect Iris, Eyelash, Eyelid photographs at any time during this visit. 
• 
Assess any changes from baseline in Iris, Eyelash, Eyelid at any time during this visit. 
• 
If the subject provided written consent to provide a saliva sample for a future 
pharmacogenomics/genomics laboratory research study, and the sample was not 
collected a previous visit, it must be collected at this visit. 
• 
Exit the subject from the study. 
Note: If a subject's study participation is terminated prior to Visit 6, then, to the extent 
possible, all scheduled Visit 6 procedures will be performed on the day of early 
termination. 
Note: If subject requires an unscheduled visit, procedures and assessments will be 
performed as needed. 
7 .5. 
Study Termination 
• 
Santen may stop this study at any time by appropriate notification. 
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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
Subjects must meet all eligibility (inclusion and exclusion) criteria described in Sections 8.1 and 
8.2. 
8.1. 
Subject Inclusion Criteria 
At Visit 1 (Screening), the subject must meet all of the following inclusion criteria: 
1. Provide signed written informed consent on the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) approved Informed Consent Form (ICF) and 
provide authorization as appropriate for local privacy regulations. 
2. Be 20 years or older in Japan and 18 years of age or older in the U.S. (or meets specific 
state requirement for legal age if that is greater than 18 years of age) on the date of 
signing the ICF and able and willing to comply with all treatment and follow-up study 
procedures. 
3. If a subject is a female of childbearing potential (i.e. not post-menopausal [within 12 
months since the last menses] or surgically sterile [less than 6 months]), she must have a 
negative urine pregnancy test and must use at least one of the following acceptable 
contraceptive methods during, and for 28 days following the study. 
• 
Abstinence 
• 
Hormonal contraceptive method- oral and 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 
The male partner of the female subject of childbearing potential should use/practice an 
acceptable contraceptive method, such as abstinence, condom or vasectomy (surgery at 
least 6 months prior) or other contraception deemed adequate by the investigator 
throughout the course of the study. 
Male subjects, with a female partner of childbearing potential, should use/ practice an 
acceptable contraceptive method, such as abstinence, condom or vasectomy (surgery at 
least 6 months prior) or other contraception deemed adequate by the investigator 
throughout the course of the study. 
4. Subjects must have a diagnosis ofPOAG or OHT in both eyes (excluding 
pseudoexfoliation syndrome). 
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5. Corrected visual acuity of +0.60 logMAR (Snellen equivalent 20/80, Decimal visual 
acuity 0.3) or better in each eye. 
6. Central corneal thickness~ 480 J.Lm and~ 620 J.Lm in each eye. 
7. Anterior chamber angle grade ~ 2 (Shaffer scale) in each eye. 
In addition, the subject must meet the inclusion criterion #3 again if applicable and the following 
criteria at Visit 2 (Baseline, Day 1 ): 
8. Completed the required wait/washout period if applicable. 
9. At all lOP measurement time-points (09:00, 13:00 and 17:00), lOP must be~ 22 mmHg 
in at least one eye and ~ 34 mmHg in both eyes. 
8.2. 
Subject Exclusion Criteria 
A subject with any of the following ocular conditions in any eye or non-ocular conditions or 
characteristics are not eligible to participate in the study: 
General-
1. Females who are pregnant, nursing or planning a pregnancy. 
2. Subjects with known or suspected drug or alcohol abuse. 
3. Current or planned participation in any other clinical trial involving an investigational 
product or device within 30 days prior to Visit 1 (Screening) or at any time during this 
trial. 
4. Subjects who have been exposed to DE-126 prior to Visit 1 (Screening). 
Medications I Therapies-
5. Subjects who cannot safely discontinue use of ocular hypotensive medications during the 
wait/washout period. 
6. Subjects who will be required to initiate or modify any systemic or topical medication 
known to affect lOP (e.g., ~-adrenergic antagonists, a-adrenergic agonists, calcium 
channel blockers, angiotensin-converting enzyme [ACE] inhibitors, and angiotensin II 
receptor blockers [ARB]) within the first 30 days prior to Visit 1 (Screening), or 
anticipated change in such therapy during the study. 
7. Intended or current use of the following prohibited medications during the study: 
• 
All ocular medications other than artificial tear, cataract treatment agents, and 
Vitamin B12 formulation, and study medications during the study. 
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• 
All systemically administered ocular hypotensive medication (e.g., oral or 
intravenous CAl, oral glycerol). 
• 
Any ocular, periocular, inhaled, nasal or systemic corticosteroids. 
8. Known allergy, hypersensitivity or contraindications to prostaglandins, benzalkonium 
chloride (BAK) or any other components of the study medications or other study related 
procedures/medications. 
9. History of ocular surgery specifically intended to lower lOP (e.g., laser trabeculoplasty, 
filtering surgery, Minimally Invasive Glaucoma Surgery [MIGS], or trabeculotomy) in 
either eye. 
10. History ofkeratorefractive surgery in either eye. 
11. Use of contact lenses within one week prior to Visit 2 (Baseline, Day 1) until end of 
treatment. 
12. Any ocular surgery or ocular laser treatment within 90 days prior to Visit 1 (Screening) 
and throughout the study in either eye. 
Diseases-
13. Advanced glaucoma (e.g., visual field mean deviation worse than -12 dB) in either eye. 
14. Any corneal abnormality or other condition interfering with or preventing reliable 
Goldmann applanation tonometry (e.g., Fuch's dystrophy, band-shaped keratopathy, 
Avellino corneal dystrophy or significant corneal surface abnormality) in either eye. 
15. Presence of any active severe external ocular disease, inflammation, or infection of the 
eye and/or eyelids in either eye. 
16. History of iritis and/or uveitis, corneal inflammatory conditions, and/or viral infections 
such as herpes virus in either eye; history of adenovirus is not an exclusion provided no 
associated inflammation was observed within 6 months prior to screening. 
17. Pseudophakic with a tom 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 or within 90 days after ocular surgery) for macular edema in either 
eye. 
18. 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. 
19. Subjects with a history of severe ocular trauma in either eye. 
20. Subjects with any condition that prevents clear visualization of the fundus in either eye. 
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21. Presence or history of any ocular or systemic disease, clinical laboratory test abnormality 
that in the opinion of the study investigator may put the subject at significant risk, may 
confound study results, or may interfere significantly with the subject's participation in 
the study (e.g., recurrent corneal erosion syndrome, uncontrolled cardiovascular disease 
etc.). 
22. Any decision by the Principal Investigator or Medical Monitor to terminate a subject in 
screening or declare any subject ineligible for any sound medical reason. 
8.3. 
Subject Withdrawal Criteria 
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 may 
terminate a subject's study participation due to any of the following reasons: 
• 
Adverse Event (e.g., not compatible with study continuation) 
• 
Non-compliance with study drug 
• 
Lack of efficacy (e.g., lOP 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., any contact is not possible) 
• 
Death 
• 
Other 
• 
If a subject is voluntarily discontinued from study drug administration, he or she will 
be discontinued from the study. 
• 
If a subject's study participation is terminated prior to Visit 6, then to the extent 
possible, all scheduled Visit 6 procedures will be performed on the day of early 
termination. Subjects who are discontinued from the study early will not be replaced. 
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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Medication 
DE-126 ophthalmic solution is an aqueous solution containing DE-126. Benzalkonium chloride 
0.005% is added as a preservative. 
Figure 2: DE-126 Structure 
Investigational Product: 
• 
DE-126 ophthalmic solution 0.0005% contains 0.005 mg/mL DE-126. 
• 
DE-126 ophthalmic solution 0.001% contains 0.01 mg/mL DE-126. 
• 
DE-126 ophthalmic solution 0.002% contains 0.02 mg/mL DE-126. 
• 
DE-126 ophthalmic solution 0.003% contains 0.03 mg/mL DE-126. 
Active Control: 
• 
Latanoprost ophthalmic solution 0.005% contains 0.05 mg/mL latanoprost. 
Placebo: 
• 
DE-126 vehicle ophthalmic solution. 
9.2. 
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 taken in addition to the study medication during the study duration will be 
considered as a concomitant treatment. The following information of concomitant treatment must 
be recorded in the subject's source documents. 
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9.2.1. 
• 
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. 
Prohibited Medications or Therapies 
• 
All ocular medications other than artificial tear, cataract treatment agents, and 
Vitamin B12 formulation, and study medications, must be discontinued after Visit 1 
(Screening). 
-
If artificial tear, cataract treatment agents, and Vitamin B12 formulation are 
concomitantly used, there must be an interval of at least 5 minutes between use of 
these ocular medications and use of the study medication. 
• 
All systemically administered ocular hypotensive medications (e.g., oral or 
intravenous CAl, oral glycero 1) during the study duration. 
• 
Any ocular, periocular, inhaled, nasal or systemic corticosteroids during the study 
duration. 
• 
Initiate or modify any systemic or topical medication known to affect lOP 
(e.g., ~-adrenergic antagonists, a-adrenergic agonists, calcium channel blockers, 
angiotensin-converting enzyme [ACE] inhibitors, and angiotensin II receptor blockers 
[ARB]) within the frrst 30 days prior to Visit 1 (screening) and during the study 
duration. 
• 
Contact lens wear must be dis_continued at least one week prior to Visit 2 (Baseline, 
Day 1) and is prohibited during the remainder of the study. 
• 
Any ocular surgery or ocular laser treatment will not be allowed within 90 days prior 
to Visit 1 (Screening) and throughout the study in either eye. 
• 
Participation in any other clinical trial involving an investigational product within 
30 days prior to Visit 1 (Screening) and during the study is not allowed. 
The decision to administer a prohibited medication or therapy should be made with the safety of 
the subject as the primary consideration. Whenev~r possible, Medical monitor should be notified 
before any prohibited medication or therapy is administered. There may be additional prohibited 
therapies not mentioned above. Medical monitor should be contacted if the permissibility of a 
specific medication or therapy is in question. 
9.3. 
Treatment Compliance 
To obtain reliable safety and efficacy data, the following precautions will be taken to ensure 
compliance with the treatment regimen during the study: 
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• 
Subjects will receive verbal and written instructions for proper instillation of the study 
medication, the dosing regimen, and study medication storage. Subjects will be reminded 
at Visit 2 (Baseline, Day 1 ), Visit 3 (Day 8 ±2), Visit 4 (Day 15 ±2), and Visit 5 
(Day 43 ±3) to consistently dose at the same time of the day (once daily at 21:00 
[±60min]). Since subjects must have a diagnosis ofPOAG or OHT in both eyes, both 
eyes will be treated for the duration of the study, even if only one eye is eligible per lOP 
inclusion criteria. 
• 
Subjects will be queried regarding compliance with the protocol's dosing regimen at Visit 
3 (Day 8 ±2),Visit 4 (Day 15 ±2), Visit 5 (Day 43 ±3), and Visit 6 (Day 91 ±3) Study 
Exit/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 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 (Day 8 ±2), 
Visit 4 (Day 15 ±2), Visit 5 (Day 43 ±3), and Visit 6 (Day 91 ±3) Study Exit/Early 
Termination. Subjects may be discontinued from the study at the discretion of the 
Investigator if the subject cannot be brought into compliance. 
9.4. 
Randomization and Masking 
Subjects will be randomized to one of the six (6) treatment arms. Forty (40) subjects per 
treatment arm will be randomized to each DE-126 and Latanoprost arms, and 20 subjects will be 
randomized to the Placebo arm. Central randomization via Interactive Response Technology 
(Medidata BALANCE) will be used to allocate the subjects to each of the six treatment arms in 
the U.S. and Japan separately. Each eligible subject will be assigned to receive a study 
medication kit numbered as allocated by the randomization schedule. 
The appearance ofthe bottles used for the 4 active DE-126 groups and the placebo group will be 
identical. However, due to differences in appearance between the containers used for the test 
treatments (DE-126 and placebo) and the commercially available active control treatment 
(0.005% latanoprost), this study is classified as observer-masked. In order to maintain masking 
of investigators, examiners and sponsor personnel involved in the conduct of the study, only an 
authorized study staff member who is not the investigator or examiner at the investigative site 
will be permitted to dispense and collect study medication. Subjects will be instructed not to 
show the bottles to either the investigator or the examiner or other study subjects. The active 
control treatment containers will be overlabeled and packaged in the same secondary package 
(e.g., cardboard carton) as the test treatments. 
Masking of treatment for subjects assigned to the placebo group, will be maintained when they 
are switched to 0.003% DE-126 at the week 6 visit, since the appearance of the 0.003% DE-126 
bottles will be identical to the placebo bottles. 
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In case of a medical emergency, the Principal Investigator may reveal the treatment information 
by unmasking through Interactive Response Technology (Medidata BALANCE) 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 adverse event or serious adverse event for which study treatment was 
unmasked should be reported to Santen Pharmacovigilance. 
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10. 
STUDY MEDICATION MATERIALS AND MANAGEMENT 
10.1. 
Study Medication 
10.1.1. 
Investigational Product 
Each 2.5 mL ofDE-126 ophthalmic solution 0.0005%,0.001%, 0.002% and 0.003% contains 
12.5, 25, 50 and 75 Jlg ofDE-126, respectively. In addition, the formulation contains excipients 
required to produce a stable ophthalmic solution dosage form. The solution is preserved with 
benzalkonium chloride (BAK) at 0.005%. Other inactive ingredients are polysorbate 80, sodium 
citrate, mannitol, edetate disodium, sodium hydroxide, hydrochloric acid and purified water. 
10.1.2. 
Active Control 
The active control used in this clinical study, Latanoprost ophthalmic solution 0.005% is 
supplied as a sterile, isotonic, buffered aqueous solution. 
Latanoprost ophthalmic solution 0.005% 
Each 2.5 mL ofLatanoprost ophthalmic solution 0.005% contains 125 Jlg oflatanoprost. 
Benzalkonium chloride 0.02% is added as a preservative. The inactive ingredients are: sodium 
chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, 
and water for injection. See Section 21.4, Appendix D. 
10.1.3. 
Placebo 
The formulation contains excipients required to produce a stable ophthalmic solution dosage 
form. The solution is preserved with benzalkonium chloride (BAK) at 0.005%. Other inactive 
ingredients are polysorbate 80, sodium citrate, mannitol, edetate disodium, sodium hydroxide, 
hydrochloric acid and purified water. 
10.2. 
Study Medication Packaging and Labeling 
DE-126 ophthalmic solution 0.0005%, 0.001%, 0.002%, 0.003% and DE-126 vehicle ophthalmic 
solution will be supplied as a 2.5 mL solution in a 5 mL clear polypropylen bottle. 
Latanoprost ophthalmic solution 0.005% will be supplied as a 2.5 mL solution in a 5 mL clear 
low density polyethylene bottle. 
Four eye drop bottles of study medication will be placed in one kit. The eye drop bottles and the 
kit will be labeled with the protocol number, kit number, storage conditions, and dosing 
instructions. 
Three eye drop bottles of study medication in one kit will be dispensed at Visit 2 (Day 1, 
Baseline) and Visit 5 (Day 43 ±3), respectively. An authorized study staff, other than the 
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Investigator or examiner, will dispense and collect study medications. When collecting the study 
medications, the kit containing the all used and unused eye drop bottles will be sealed. 
10.3. 
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 S°C (36° to 46°F), protected from 
light and stored upright. Undispensed kits should be stored under refrigeration at 2° to soc 
(36° to 46°F) until dispensed. After the refrigeration storage, the Investigator (or his/her 
designee) will verify and record that the temperature was maintained at 2° to S°C (36° to 46°F) 
using temperature recorder at least once every seven days of the investigational site thereafter, 
until the last subject has exited the study. 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, protection 
from light and upright. Study medications should not be frozen. 
10.4. 
Study Medication Preparation 
The study medications will arrive at the site prepared for instillation. 
10.5. 
Study Medication Administration 
Subjects will instill one drop of study medication in each eye at approximately 21:00 (::1::60min) 
daily for 3 months. 
10.6. 
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 soc (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. 
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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. 
10.7. 
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 
reconciliation by Santen (or designee), all used and unused study medication will be returned to 
the assigned central drug depot. 
10.8. 
Study Supplies 
Commercial urine pregnancy test kits, laboratory test kits and customized saliva sample 
collection kits for the pharmacogenomics/genomics will be provided by Santen (or designee). 
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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Efficacy Parameter 
The lOP (mmHg) measured in the study eye (identified at the baseline visit) is the efficacy 
measure for this study. The lOP at each scheduled time point (09:00, 13:00 and 17:00) will be 
evaluated at each post-baseline visit. Besides observed lOP measurements, change from baseline 
in lOP, and percent changes from baseline in lOP at each scheduled time point as well as the 
change from baseline in mean diurnal lOP will also be calculated and evaluated. 
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12. 
ASSESSMENT OF SAFETY 
12.1. 
Adverse Events and Serious Adverse Events 
12.1.1. 
Definition of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical trial subject. An AE 
does not necessarily have a causal relationship with the study treatment. For this study, the 
investigational products are DE-126 vehicle, DE-126 and latanoprost. Regardless of relationship 
to the study treatment, 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 written informed consent, 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 an 
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 anSAE. 
The lack of efficacy of the study treatment for the condition being investigated is not considered 
an AE unless a clinically significant change is assessed by the Investigator. 
12.1.1.1. 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 12.1.2. 
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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 t) 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 if: 
-
There is a plausible temporal relationship between the onset of the AE and 
administration of the study medication 
-
The AE abates or resolves upon discontinuation of the study medication or dose 
reduction and, if applicable, reappears upon rechallenge 
-
The AE cannot be readily explained by the subject's clinical state, intercurrent 
illness, or concomitant therapies 
-
The AE follows a known pattern of response to the investigational product 
• 
Reporting the event as Not Related to study medication may be considered if: 
-
There is good evidence that the AE has an etiology other than the investigational 
product (e.g., pre-existing medical condition, underlying disease, intercurrent 
illness, or concomitant medication) 
-
The AE has no plausible temporal relationship to administration of the 
investigational product (e.g., cancer diagnosed 2 days after first dose of study 
medication) 
12.1.1.2. 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 electronic case report 
form ( 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 the last study procedure is performed, must be recorded. 
To improve the quality and precision of acquired AE data, Investigators should observe the 
following guidelines: 
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• 
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 
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 14SEP20 15 lasting for three hours, then subsequently experienced intermittent 
episodes of headache every day for approximately 3 hours until21SEP2015, then the 
AE date of onset is 14SEP20 15 and the resolution date is 21 SEP20 15. 
• 
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. 
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12.1.2. 
• 
If treatment was initiated, include the treatment and duration of the medication(s) in 
the eCRF. 
Serious Adverse Events 
12.1.2.1. Assessment of Serious Adverse Events 
An AE is considered serious if it fulfills one or more of the following criteria: 
• 
It resulted in death (i.e., the AE caused or led to death). 
• 
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. 
12.1.2.2. 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. 
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12.1.2.3. 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. 
12.1.3. 
Reporting Pregnancy 
There are no controlled data with the investigational product in human pregnancy. It is required 
that women of childbearing potential use effective contraception during, and for 28 days 
following the study. Any pregnancy in a subject occurring during study treatment should be 
reported on the appropriate eCRF with as much information as available within 24 hours of 
knowledge of the event and the subject removed from the study. The subject should be followed 
until the end of pregnancy. 
12.1.4. 
Follow-up of Adverse Events 
All reported AEs should be followed until resolution or until the subject's participation in the 
study ends. Subjects who have an on-going study medication-related SAE at study completion or 
at early termination from the study will be followed by the Investigator until the event is resolved 
or determined to be irreversible, chronic, or stable. 
In addition, on a case by case basis, Santen (or designee) may request follow up beyond the end 
ofthe study. 
If Santen Pharmacovigilance requests follow-up on an individual SAE or AE, the response will 
be entered into the eCRF, as appropriate. If the information requested from Santen 
Pharmacovigilance is not part of the SAE or AE eCRF, the information will be sent to Santen 
Pharmacovigilance. 
12.1.5. 
Manual Back-Up Reporting Procedures 
This study is utilizing an electronic data capture (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 and an SAE Form and/or pregnancy form. 
• 
Attach a cover sheet with your contact information and address to Santen (or its 
designee). 
• 
Email (preferred) or Fax the cover sheet and the completed form(s) to Santen (or its 
designee) at santensafety@santen.com or fax number +81-6-6359-3843 (in JP) and 
+ 1-415-276-5882 (in US). 
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When the EDC system becomes available, the EDC system should be updated with all 
previously reported information. 
12.2. 
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. 
12.2.1. 
Ocular Assessments 
Ocular assessments include: 
• 
Ocular symptoms: burning/stinging, foreign body sensation, tearing, itching, 
photophobia, and pain 
• 
Corrected visual acuity 
• 
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 
• 
Central corneal thickness 
• 
Ophthalmoscopy variables: glaucomatous optic nerve 
• 
Iris color/eyelash/eyelid 
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13. 
OTHER ASSESSMENTS 
13.1. 
Demographic, Baseline Characteristics and Other Assessments 
Subject demographics and baseline characteristics will be recorded. Subject demographics 
include age, sex, race, and ethnicity. Baseline characteristics include iris color, concurrent 
disease, prior medications especially lOP-lowering medications, and baseline lOP. 
Other assessments include exposure (number of days on study medication) and concomitant 
medications/therapies. 
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14. 
STATISTICAL METHODS 
This section outlines topics related to the statistical methods used in the design and analysis of 
the study. A more detailed description of all the analyses and methods is provided in the 
Statistical Analysis Plan (SAP). 
14.1. 
Analysis Time Points 
A single analysis at the end of the study will be performed. 
14.1.1. 
Interim Analysis 
There are no interim analyses planned during this study. 
14.1.2. 
Final Analysis 
An unmasked final analysis will be performed to evaluate the safety and efficacy ofDE-126 
ophthalmic solution in each dose (0.0005%, 0.001%, 0.002% and 0.003%) compared with 
placebo and latanoprost ophthalmic solution 0.005%. 
14.2. 
General Considerations 
Descriptive statistics, unless otherwise noted, will include the number of subjects {N), mean, 
standard deviation (SD), median, minimum, and maximum for continuous variables and Nand 
percent for categorical variables. 
The study eye will be defined as the eye that qualifies per inclusion criteria at Visit 2. If both 
eyes qualify, the eye with the higher mean diurnal lOP at baseline (Visit 2) will be the study eye, 
although both eyes may receive study drug. If both eyes have the same mean diurnal lOP at 
baseline, then the right eye will be designated as the study eye. 
The SAP with more details on the statistical methods will be finalized prior to unmasking the 
data. Unless otherwise stated, all analyses will be implemented using SAS® v9. 
14.2.1. 
Sample Size 
The sample size is not planned on the primary efficacy endpoint. For the key secondary 
endpoint, assuming that the minimal expected treatment difference across all timepo ints is 
-5.1 mmHg between an optimal DE-126 dose and placebo (based on ON0-9054IOU002 and 
ON0-9054IOU003 studies) and the standard deviation of such a difference is 3.9 mmHg, with a 
2:1 ratio, a sample size of36 for each DE-126 arm and 18 for placebo will provide 92% power to 
detect the difference at all timepoints using at-test (2-sided, a=0.0125 adjusted by Bonferroni 
correction). With 10% dropout rate, the sample size is 40 for each DE-126 arm and 20 for 
placebo arm. 
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Moreover, this sample size will provide less than 20% power to claim non-inferiority ofDE-126 
optimal dose to Latanoprost, assuming no treatment difference and 1.5 mmHg non-inferiority 
margin. 
14.2.2. 
Statistical Hypotheses and Level of Significance 
The primary efficacy endpoint is the lOP at each scheduled time point (09:00, 13:00 and 17:00) 
in the study eye at Visit 6 (Month 3). No formal statistical hypothesis testing will be 
implemented for the primary endpoint. Descriptive summaries will be provided by groups. 
For the key secondary endpoint, the comparison between DE-126 of each dose group and 
placebo group will be performed with the following pair of testing hypotheses: 
Ho: f.JP = f.Jr versus H1: f.JP i- f.Jr 
where flT and flpdenote the mean values of the primary endpoint in DE-126 treatment group and 
placebo group, respectively. 
Treatment differences between the DE-126 of each dose group and the placebo group will be 
reported for each time point along with 95% confidence intervals. Superiority ofDE-126 to 
placebo is established if the upper limit of the 95% confidence interval for the difference is less 
than 0 mmHg for lOP at all timepoints at Visit 5 (week 6). To control the overall Type I error 
rate associated with the four comparisons at the 0.05 level (two-sided), the Hochberg procedure 
will be used, and the statistical significance will be evaluated with the adjusted P-values. 
14.3. 
Study Populations 
14.3.1. 
Safety Population 
The Safety Population will include all randomized subjects who received at least one dose of the 
study medication. The safety analysis will be performed on the Safety Population. 
14.3.2. 
Full Analysis Set 
The Full Analysis Set (F AS) will include all randomized subjects who received at least one dose 
of study medication and provided at least one post-baseline lOP measurement. The efficacy 
analysis will be performed on the F AS or a subset of the F AS. 
14.3.3. 
Per-Protocol Population 
The Per-Protocol (PP) Population is a subset ofthe FAS. It includes all FAS subjects without 
protocol deviations that could affect the primary efficacy endpoint. Subjects excluded from the 
PP Population will be identified before unmasking the data. 
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14.4. 
Handling of Missing Values 
Efficacy endpoints will be analyzed using available data at the end of the study. Sensitivity 
analyses using last observation carried forward (LOCF) may be performed. Details on sensitivity 
analyses, if any, will be included in the SAP. 
14.5. 
Demographic and Baseline Characteristics 
Age, sex, race, ethnicity, iris color, and baseline lOP will be summarized with descriptive 
statistics by treatment. 
Concurrent diseases will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA). Subjects with any concurrent diseases will be tabulated by primary 
system organ class and preferred term specified in the MedORA. 
Subjects using any prior medications that has been used for POAG or OHTwithin 28 days 
before the date of Visit 1 will be tabulated by treatment, Anatomical Therapeutic Chemical 
(ATC) levels, and preferred term specified in the latest version of World Health Organization 
Drug Dictionary Enhanced (WHO-DDE, 2011). 
14.6. 
Efficacy Analyses 
14.6.1. 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoirit is the lOP at each scheduled time point (09:00, 13:00 and 17:00) 
in the study eye at Visit 6 (Month 3). 
An optimal dose ofDE-126 will be specified based on the descriptive summary and no statistical 
hypothesis testing will be implemented. 
14.6.2. 
Analysis of Secondary Efficacy Endpoints 
14.6.2.1. Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is the mean lOP in the study eye at each specified time 
point (09:00, 13:00 and 17:00) at Visit 5 (week 6). 
A mixed-effect model for repeated measures (MMRM) will be carried out and 95% confidence 
interval for the difference in means (DE-126 of each dose; 0.0005%, 0.001%, 0.002% and 
0.003%, vs. placebo) will be estimated. Superiority ofDE-126 to placebo is established if the 
upper limit of the 95% confidence interval for the difference is less than 0 mmHg for lOP at all 
timepoints at Week 6. 
14.6.2.2. Other Secondary Efficacy Endpoints 
• 
lOP in the study eye at each specified time point (09:00, 13:00 and 17:00) at Visit 3 
and Visit 4 (Week 1 and Week 2). 
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• 
Mean diurnal lOP in the study eye at Visits 3, 4, 5, and 6 (Week 1, Week 2, Week 6, 
and Month 3). 
• 
Change and percent change from baseline (CFB) in mean diurnal lOP in the study eye 
at each post-baseline visit (Visit 3, 4, 5, and 6 [Week 1, Week 2, Week 6 and Month 3, 
respectively]). 
• 
Change and percent change from baseline (CFB) in lOP in the study eye at the 
specified time points: 09:00, 13:00, and 17:00 at each post-baseline visit. 
• 
Proportion of subjects with mean diurnal lOP reduction from baseline 2:: 20%, 25 % 
and 30% in the study eye at Visit 3 (Week 1 ), Visit 4 (Week 2), Visit 5 (Week 6) and 
Visit 6 (Month 3). 
• 
Proportion of subjects with mean diurnal lOP :::; 18 mmHg in the study eye at Visit 3 
(Week 1), Visit 4 (Week 2), Visit 5 (Week 6) and Visit 6 (Month 3). 
14.7. 
Safety Analyses 
All safety outcome measures will be summarized descriptively for the Safety Population. The 
safety outcome measures include AEs, corrected visual acuity, ocular symptoms, slit-lamp 
biomicroscopy findings, central corneal thickness, ophthalmoscopy variables, iris color, eyelash, 
and eyelid by photographs, vital sign and clinical laboratory tests. 
AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). Subjects with any AEs will be tabulated by primary system organ class and 
preferred term 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. 
Ocular safety parameters listed in Section 12.2.1 will be summarized using descriptive statistics 
by treatment. Changes from baseline in these ocular safety parameters will also be summarized 
by treatment. 
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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Principal Investigator will allow representatives of Santen' s monitoring team (or designee}, 
the governing institutional review board (IRB) or independent ethics committee (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 ICH-GCP or other 
regulatory agency regulations. 
15.1. 
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 Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC). 
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• 
Confirm sites have a complete record of all study 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. 
15.2. 
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 San ten (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. 
15.3. 
Institutional Review Board (IRB)IIndependent Ethics Committee 
(IEC) 
The Principal Investigator must obtain IRB/IEC approval for the study. Initial IRBIIEC 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. 
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16. 
QUALITY CONTROL AND QUALITY ASSURANCE 
16.1. 
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 completion of eCRFs, 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. 
16.2. 
Quality Assurance 
Santen (or designee) may conduct a quality assurance audit at any time. See Section 15.2. 
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17. 
ETHICS 
17.1. 
Ethics Review 
The final study protocol and the final version of the informed consent form (ICF), for the main 
study and the ICF for the pharmacogenetics study, 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 saliva samples for optional future pharmacogenetic research, this 
will not affect the approvals for conducting the main study. The Principal Investigator must 
submit written IRB or IEC approval to Santen (or designee) before study initiation. Refer to 
Section 21.1, 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. 
17.2. 
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 
Conference on Harmonization (ICH) guidelines, and the Declaration of Helsinki. 
17.3. 
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 saliva samples for future pharmacogenetic research 
studies. If the subject does not wish to provide a saliva sample for the biomarker research study 
that it 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 21.2, Appendix B. 
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18. 
DATA HANDLING AND RECORDKEEPING 
18.1. 
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. 
18.2. 
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. 
18.2.1. 
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 
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• 
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 
18.2.2. 
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. 
18.2.3. 
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. Review of the 
eCRFs will be completed remotely by Santen (or designee). At designated intervals, a study 
monitor will perform Source Data Verification on site. During those visits, Santen (or designee) 
will monitor the subject data recorded in the eCRF against source documents at the study site. 
Santen (or designee) will review and evaluate eCRF data and use standard system edits, and may 
use centralized monitoring evaluations, to detect errors in data collection. At the end of the study, 
a copy of the completed eCRFs will be sent to the site to be maintained as study records. 
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19. 
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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20. 
REFERENCES 
20.1. 
Literature 
1. 
AGIS _Investigators. (2000). The Advanced Glaucoma Intervention Study (AGIS): 7. 
The Relationship Between Control of Intraocular Pressure and Visual Field Deterioration. 
American Journal of Ophthalmology. 130(4):429-40. 
2. 
Alm, A. (2014). Latanoprost in the treatment of glaucoma. Clin Ophthalmol. 8:1967-85. 
doi: 10.2147/0PTH.S59162. PubMed PMID: 25328381; PubMed Central PMCID: 
PMCPMC4196887. 
3. 
Iwase, A., Suzuki, Y., Araie, M., Yamamoto, T., Abe, H., Shirato, S., Kuwayama, Y., 
Mishima, H. K., Shimizu, H., Tomita, G., Inoue, Y., Kitazawa, Y., Tajimi Study Group, 
J. G. S. (2004). The prevalence of primary open-angle glaucoma in Japanese: the Tajimi 
Study. Ophthalmology. 111(9):1641-8. doi: 10.1016/j.ophtha.2004.03.029. PubMed 
PMID: 15350316. 
4. 
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. 
5. 
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. 
6. 
MedDRA. Medical Dictionary for Regulatory Activities. 14.1. 
7. 
Ota, T., Aihara, M., Saeki, T., Narumiya, S., Araie, M. (2006). The effects of 
prostaglandin analogues on prostanoid EP 1, EP2, and EP3 receptor-deficient mice. Invest 
Ophthalmol Vis Sci. 47(8):3395-9. doi: 10.1167/iovs.06-0100. PubMed PMID: 
16877408. 
8. 
Quigley, H., Broman, A. (2006). The number of people with glaucoma worldwide in 
2010 and 2020. Br J Ophthalmol. 90(3):262-7. 
9. 
Resnikoff, S., Pascolini, D., Etya ale, D., Kocur, 1., Pararajasegaram, R., Pokharel, G., 
Mariotti, S. (2004). Global data on visual impairment in the year 2002. Bulletin of the 
World Health Organization. 82(11):844-52. 
10. 
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. 
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11. 
WHO-DDE, W. H. 0. (20 11 ). World Health Organization Drug Dictionary Enhanced. 
12. 
Yamamoto, T., Iwase, A., Araie, M., Suzuki, Y., Abe, H., Shirato~ S., Kuwayama, Y., 
Mishima, H. K., Shimizu, H., Tomita, G., Inoue, Y., Kitazawa, Y., Tajimi Study Group, 
J. G. S. (2005). The Tajimi Study report 2: prevalence of primary angle closure and 
secondary glaucoma in a Japanese population. Ophthalmology. 112(10):1661-9. doi: 
10.1016/j.ophtha.2005.05.012. PubMed PMID: 16111758. 
20.2. 
Study Data 
1. Data on File: ON0-9054IOU001. A Double-masked, Placebo-controlled, Single-dose 
Escalation Study To Evaluate The Safety, Tolerability, And Pharmacokinetics Of 
ON0-9054 In Healthy Adult Subjects 
2. Data on File: ON0-9054IOU002. A Double-Masked, Placebo-Controlled, Dose-
Escalation Stusy And Double-Masked, Two-sequence, Crossover Study To Evaluate The 
Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics ofON0-9054 In 
Patients With Ocular Hypertension Or Mild Openangle Glaucoma 
3. Data on File: ON0-9054IOU003. A 28-Day, Double-masked, Randomized, Parallel-
group, Active-controlled Study of ON0-9054 Ophthalmic Solution in Subjects With 
Ocular Hypertension or Open-angle Glaucoma 
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21. 
APPENDICES 
21.1. 
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: 
o A signed Form FDA 1572, Statement of Investigator, if applicable. 
o A signed Financial Disclosure Form. 
o A current Curriculum Vitae (CV) if not submitted to Santen previously or if 
updated. 
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o CVs for all Sub-Investigators. 
o A letter from the IRB or IEC indicating that the protocol was approved, including 
the name and address of the IRB or IEC. 
o A copy of the consent form approved by the IRB or IEC. 
o A list of current members ofthe IRB or IEC. 
o A copy of the source data location list. 
o A copy of delegation list/log. 
o A copy of training log. 
II. While the Study is in Progress 
o Acknowledgment of receipt of the test and control articles; documentation of 
disposition of all test and control articles. 
o eCRFs for each subject enrolled in the study. 
o Information regarding all deviations from the protocol. 
o Information regarding all AEs occurring to a subject while enrolled in the study. 
o 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 
o Disposition of all used and/or unused test and control articles, as well as 
documentation of all drug accountability. 
o Providing Santen a final study report. 
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21.2. 
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. 
0. 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 
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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. 
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 pharmacogenomics/genomics 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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21.3. 
Appendix C - Procedures for Assessments 
21.3.1. 
Demographics, Medicationffherapy and Medical History 
Demographics including age, sex, race, prostaglandin analogs naive status, and ethnicity will be 
obtained through subject interviews at Visit 1 (Screening). 
Medications and ocular procedures/therapies will be confirmed through subject interviews during 
the study. 
Following details of prior medication that has been used for POAG or OHT within 28 days 
before the date of Visit 1, or any concomitant medication, must be recorded in the subject's 
source documents. 
• 
Name of medication, route of administration, treated eye(s) (if applicable), dose, 
frequency, indication, start date and stop date 
Following details of prior ocular procedure/therapy that has been received for POAG or OHT 
within 28 days before the date of Visit 1, or any concomitant ocular procedure/therapy, must be 
recorded in the subject's source documents. 
• 
Name of ocular procedure/therapy, treated eye(s) (if applicable), indication, start date 
and stop date 
Medical history including all ocular medical history, any other medical history within 5 years, 
POAG or OHT diagnosis, ocular surgical history, current ocular and systemic conditions will be 
confirmed through subject interviews at Visit 1 (Screening) to determine if the subject meets 
eligibility criteria. Primary diagnosis, POAG or OHT, and the affected eye must be recorded in 
the subject's source documents. 
Name of concurrent disease, and affected eye(s) (if applicable) will be confirmed at Visit 1 
(Screening) and Visit 2 (Baseline, Day 1 ), and recorded in the subject's source documents. 
21.3.2. 
Pregnancy Test 
A urine pregnancy test will be conducted using a commercially available test kit at Visit 1 
(Screening), Visit 2 (Baseline, Day 1) and Visit 6 (Day 91 ±3) Study Exit/Early Termination for 
all women 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. 
21.3.3. 
Urinalysis, Hematology, and Serum Biochemistry 
Blood and urine samples will be collected at the Visit 1 and 6 for urinalysis, hematology, and 
serum biochemistry. The amount of one blood sample is 5.5 mL and the amount of one urine 
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sample is 6 mL. Urine to be used is midstream urine. Detailed procedures are listed in the 
Central Laboratory Services Manual. 
Urinalysis 
Urine glucose (qualitative), urine protein (qualitative), and urobilinogen (qualitative) 
Hematology 
Erythrocytes, leukocytes, hemoglobin, hematocrit, platelet count, leukocyte differentiation 
(neutrophil, eosinophil, basophil, monocyte, and lymp~ocyte) 
Serum Biochemistry 
AST, AL T, y-GT, Al-P, LDH, total bilirubin, total protein, albumin, cholesterol (total, HDL, 
LDL and triglycerides), BUN, creatinine, uric acid, Na, K, and Cl 
21.3.4. 
Vital signs (Blood pressure/heart rate) 
Systolic blood pressure, diastolic blood pressure, and heart rate will be measured at same 
timepoint at each visit, where possible, after keeping quiet in a sitting position for more than 5 
minutes. 
21.3.5. 
Ocular Symptoms 
Ocular Symptoms will be graded on 4-point scales prior to performing any other procedures at 
each visit except Visit 1, as described below: 
Burning/Stinging 
Burning or stinging sensation involving ocular structures. 
None 
(0) = 
Absent. 
Mild 
(1) = Subject aware of ocular discomfort. 
Moderate (2) = Subject experiencing intermittent burning sensation causing a desire to 
rub, and tearing over the lid margin. 
Severe 
(3) = Constant burning for extended period of time causing tearing, hyperemia, 
swelling, etc. 
Foreign Body Sensation 
Sensation of grittiness or having something under the eyelid or on the ocular surface. 
None 
(0) = 
Absent. 
Mild 
(1) = Similar to the sensation of fine dust or powder in the eye. 
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Moderate (2) = 
Similar to the sensation of sand or dust in the eye, resulting in moderate 
tearing and blinking. 
Severe 
Tearing 
(3) = Similar to the sensation of a hot cinder in the eye, associated with constant 
tearing and blepharospasm. 
None 
(0) = 
Absent. 
Mild 
(1) = 
Positive sensation of fullness of the conjunctival sac without tears spilling 
over the lid margin. 
Moderate (2) = 
Infrequent or intermittent spilling of tears over the lid margin. 
Severe 
Itching 
(3) = Constant or nearly constant spilling of tears over the lid margin, associated 
with blowing nose. 
Sensation of the need to scratch or rub the eyelids or the periorbital area. 
None 
(0) = 
Absent. 
Mild 
(1) = Subject aware of intermittent sensation. Not severe enough to rub. 
Moderate (2) = 
Intermittent sensation with desire to rub. 
Severe 
(3) = 
Constant awareness of sensation with tearing and rubbing, resulting in 
disruption of normal schedule. 
Photophobia 
None 
(0) = Absent. 
Mild 
(1) = 
Very minimal light intolerance which may require some degree of 
sunglass protection to eliminate the symptom, noticed primarily in 
sunlight. 
Moderate (2) = 
Infrequent or intermittent discomfort in the globe associated with exposure 
to room light or sunlight which is only partially relieved by dark glasses or 
subdued light. The symptoms still persist to some degree even with 
sunglasses. 
Severe 
(3) = Constant or nearly constant exquisite pain in the eye that is not relieved by 
sunglasses and is only relieved by total occlusion of the eye with an eye 
patch or by closing the eyes. This sensation is so significant that 
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Pain 
frequently bed rest and occasionally, systemic sedation is required to 
relieve this severe grade of symptoms. 
Sensation in the periocular region of the external eye including burning, itching around the 
eye, headache, orbital aching etc. 
None 
(0) = 
Absent. 
Mild 
(1) = 
Awareness of one's eyes, difficulty in describing specific type of 
discomfort, e.g., fullness or heaviness, diffuse foreign body sensation, 
mild aching. 
Moderate (2) = 
Ability to describe the pain modality in specific terms, e.g., burning, 
itching, focal foreign body sensation, moderate aching. 
Severe 
(3) = 
Exquisite ocular, periocular, or radiating pain, e.g., throbbing headache, 
which may be accompanied by nausea and vomiting requiring analgesia 
and/ or sedation. 
21.3.6. 
Iris, Eyelash, Eyelid 
The investigator (or his/her designee) will take frontview and sideview photograph of each eye at 
Visit 2, Visit 5, and Visit 6. The photographs must include iris, eye lids and eyelashes of each 
eye. The photographs taken at Visit 2 (Baseline) will be used to help the Investigator assess iris 
color (e.g., brown, yellow-brown, green-brown, green with slightly brown, green, blue/gray-
brown, blue/gray with slightly brown, blue/gray) and any changes from baseline (decreased/no 
change/increased) in iris color, eyelash and eyelid at Visit 5 and Visit 6 Study Exit/Early 
Termination. 
Each photograph will be labeled with subject number, OD or OS, and Visit number, and kept 
with the subject's source document. 
21.3.6.1. Iris Color 
The investigator will assess the iris color and any change (e.g., pigmentation) at Visit 5 and Visit 
6 Study Exit/Early Termination using the photographs obtained at Visit 2 (Baseline). 
21.3.6.2. Eyelash 
The investigator will assess eyelash change at Visit 5 and Visit 6 Study Exit/Early Termination 
(e.g., length, thickness, pigmentation and number) using the photographs obtained at Visit 2 
(Baseline). 
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21.3.6.3. 
Eyelid 
The investigator will assess eyelid change at Visit 5 and Visit 6 Study Exit/Early Termination 
(e.g., pigmentation and hair growth) using the photographs obtained at Visit 2 (Baseline). 
21.3.7. 
Refraction 
Refraction will be performed for each eye at Visit 1, if it has not been performed in the previous 
12 months. At Visits 2 to 6, if more than 10 letters in corrected visual acuity were lost compared 
to the screening visit, then refraction should be performed. 
21.3.8. 
Corrected Visual Acuity 
Corrected visual acuity will be measured for each eye immediately prior to the 09:00 lOP 
measurement at all visits except Visit 1/1 a (Screening or mid washout visit) under normal room 
illumination using visual acuity chart (e.g., ETDRS chart, Snellen chart) and the logMAR 
scoring will be recorded in the subject's source document (ETDRS only- if Snellen chart is used 
the logMAR score will be converted by the sponsor). For Visit 1/1a, the corrected visual acuity 
should be performed prior to lOP measurement. IfETDRS chart is used, the following procedure 
should be followed. 
21.3.8.1. 
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. 
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 +0.1line) 
LogMAR score= +0.1 + (4 x 0.02) = 0.18 
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Table 3: 
LogMAR Scoring Grid for ETDRS Eye Chart 
Total Number of Letters Missed 
Snellen 
Base 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
LogMAR 
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 
20132 
+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 
21.3.9. 
Slit-lamp Biomicroscopy 
As described below, slit-lamp biomicroscopy examinations will be performed and graded 
immediately prior to the 09:00 lOP measurement at all visits except Visit 111 a (Screening or mid 
washout visit). For Visit lila, the biomicroscopy examinations should be performed prior to lOP 
measurement. If investigator evaluates for possible tom 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. 
Anterior chamber cells and flare will be observed and graded using the Standardization of 
Uveitis Nomenclature (SUN) scale, before fluorescein instillation. 
Anterior Chamber Cells 
(0) =No cells 
(0.5) = 1-5 cells 
(1) = 6-15 cells 
(2) = 16-25 cells 
(3) = 26-50 cells 
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(4) =>50 cells 
Anterior Chamber Flare 
(O)=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 ofthe lid(s) 
Moderate (2) = Diffuse, most or all the lid(s) but not prominent/protruding 
Severe 
(3) = Diffuse, most or all the lid(s) AND prominent/protruding 
Conjunctival (Palpebral and Bulbar) Hyperemia 
None 
(0) = Normal 
Mild 
(1) = Slight localized injection 
Moderate (2) = Pink color, confined to palpebral OR bulbar conjunctiva 
Severe 
(3) = Red color of the palpebral AND/OR bulbar conjunctiva 
Conjunctival Chemosis 
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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 punctuate 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) = Yell ow lens disco !oration or small lens opacity (axial or peripheral) 
Moderate (2) =Amber lens discoloration or medium lens opacity (axial or peripheral) 
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Severe 
(3) = Brunescent lens discoloration or complete lens opacification (no red reflex) 
Anterior Synechiae of Iris 
None 
(0) = No anterior synechiae of iris is found 
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 
21.3.10. 
Intraocular Pressure 
lOP will be performed at each visit. At visit lila, lOP can be measured at any time. For Visit 2, 
Visit 3, Visit 4, Visit 5, and Visit 6 Study Exit/Early Termination, lOP measurements will be 
scheduled for 09:00 (±60min), 13:00 (±60min) and 17:00 (±60min). 
lOP will be measured using calibrated Goldmann applanation tonometer. Measurement will be 
performed preferably by the same Investigator (operator) and the same authorized study staff 
(recorder) throughout the study. 
The right eye is always tested first. At least two, and sometimes three, consecutive measurements 
are made to obtain a determination of intraocular pressure. Each lOP measurement and the clock 
time of lOP measurement will be recorded in the subject's source document. 
A single measurement is made as follows: 
• 
The Investigator adjusts the force on the tonometer dial to an initial setting 
corresponding to 10 mmHg. The slit lamp magnification is set at 1 OX. 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 Investigator should use 
the same technique each time, be it a paper strip or a pre-mixed eye drop. 
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• 
The subject and slit lamp are adjusted so that the subject's head is firmly positioned 
on the chin rest and against the forehead rest without leaning forward or straining. 
Tight-fitting neckwear is loosened. The subject is asked to look straight ahead at a 
distant object or fixation target. If it is necessary to hold the eyelids open, the 
Investigator holds the eyelids against the orbit rim, taking care not to apply any 
pressure to the globe. The subject is cautioned not to hold his breath. 
• 
The investigator looks through the slit lamp and gently brings the tip of the prism into 
contact with the center of the cornea. The mires are well-focused, centered 
horizontally, and positioned vertically so that they are of equal circumference above 
and below the horizontal dividing line. If the mires are narrower than approximately 
1/10 their diameter, additional fluorescein is instilled. 
• 
The Investigator adjusts the measuring drum until the inner borders of the two mires 
just touch each other or, if pulsation is present, until the mires separate a given 
distance during systole and overlap the same distance during diastole. 
• 
The Investigator removes the tip from the cornea, and the authorized study staff 
(recorder) records the reading on the dial, rounded to the next highest integer. For 
example, if the measurement indicated is between 16 and 17, then 17 is recorded as 
the measurement in the subject's source document. 
-
The Investigator may be recorder instead of the authorized study staff, if he/she is 
not assigned. 
• 
If corneal astigmatism is greater than 3.0 D, the prism is rotated so that the red line 
corresponds to the orientation of the longer axis of the elliptical applanated area. 
The above procedure is then repeated for the same eye, and that second measurement is also 
recorded in the subject's source document. 
• 
If the two measurements differ by less than 3 mmHg, then the average of the two 
measurements becomes the recorded lOP. For example, if the two measurements are 
22 and 23, then 22.5 is the final recorded lOP. 
• 
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 lOP (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 lOP._ 
The lOP in the left eye is then measured using the same technique. 
21.3.10.1. Tonometer Calibration 
The tonometer must be calibrated for accuracy before the first subject undergoes screening 
(mandatory), and then in accordance with the site's established procedure and frequency for 
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calibration maintenance, until the last subject has exited the study (as much as possible). 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 lOP 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. 
21.3.11. 
Central Corneal Thickness 
The central corneal thickness (J!m) of each eye using any pachymeter including optical 
pachymeter, ultrasound pachymeter, OCT (optical coherence tomography) etc. will be measured 
and recorded immediately after the 17:00 lOP measurement at Visit 2, Visit 5 and Visit 6 Study 
Exit/Early Termination. For Visit 1 (Screening), pachymetry should be performed after lOP 
measurement (if pachymetry is contact type). 
21.3.12. 
Gonioscopy 
Gonioscopy will be performed to examine the angle of the anterior chamber after lOP 
measurement at Visit 1 (Screening), if it has not been performed within 3 months. 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 
21.3.13. 
Visual Field 
Visual field examinations will be performed using a static or dynamic perimeter (Humphrey, 
Octopus, or KOWA perimeter) without pupil dilation at Visit 1 (Screening), if it has not been 
performed within 3 months 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 
standard deviation, glaucoma hemifield test, and type of glaucomatous visual field loss). 
Visual field tests that, in the Investigator's opinion, indicate low subject reliability (e.g., due to 
fixation losses, false positive errors, or false negative errors) should be excluded. A copy of the 
computer printout from the visual field test(s) will be attached to the subject's source documents. 
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21.3.14. 
Ophthalmoscopy (Fundus) Examination 
The ophthalmoscopy (fundus) examination will be performed for each eye at Visit 1, Visit 2, 
Visit 5, and Visit 6 Study Exit/Early Termination, and graded as described below. If investigator 
performs ophthalmoscopy under dilation based on his/her decision, please dilate pupil and 
perform 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 
21.3.15. 
Saliva Sample for Pharmacogenomics/genomics Study 
At sites which elect to participate and for subjects who agree to provide a saliva sample, an 
exploratory biomarker laboratory research study will be performed to evaluate the association of 
possible genetic biomarkers with the study drug(s) and/or ophthalmologic conditions. 
Approximately 2 mL of saliva will be collected for genetic analysis from the subject and stored 
in a refrigerator or room temperature until shipment. Please refer to the separate Central 
Laboratory Services manual for sample handling, storage, and shipment. The samples will be 
coded to protect the participants' private information. Nucleic acids will be extracted from saliva 
sample and stored in the repository for future pharmacogenomics/genomics studies performed by 
appropriate assay platforms such as PCR (Polymerase Chain Reaction), hybridization, and 
sequencing on the genes involved in the study drug(s) and/or ophthalmologic conditions. 
Individual subjects' results from the research testing on their samples will not be communicated 
to them. 
Samples collected and stored, and relevant documents (the list of screening/registration of 
subjects only for documents to be retained by the medical institution) will be retained for the 
period agreed in the IC. Upon completion of analyses or the retention period, they will be 
anonymized and disposed. If the subject withdraws the consent, samples will be immediately 
disposed, and the applicable subject will be informed in writing. 
For any other matters not specified in the protocol, a written procedure will be defmed 
separately. 
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21.4. 
Appendix D - Latanoprost Ophthalmic Solution, 0.005% Package 
Insert 
HIGHLIGHTS OJ' PRISC'RIBING INJI'ORMATION 
1'1iele.. 
J" ..... DDt ilcJudt. ... tnr.f'I!!M!dM ~ 
.. ••X4L.A1"4N taf«b'-~tly.SN 
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lor XAIA.TAN. 
XAIA.TArfA(II 
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..,.._._.__.. __ 
M~wllbXALATAN.Jf 
fULL fRESCIUBING JNro 
IA110N: 
CON'I'EN'J'S• 
J INDICATIONS AND 'VSAGB 
2 DOSAGE AND ADMINISTRADON 
3 DOSAGE FORMS AND STR£NGTBS 
.. CONTRAINDICATIONS 
5 WARNINGS AND PRECAUTIONS 
S.t~oa 
S.2 Byellsb Clwl&es 
SJ Jntraoeular Inflemmwrioa 
SA Macular Edema 
S.S Hapetie Kaalitis 
5.6 Baderial Kera1itis 
5.1 Use with~ Laucs 
6 ADVERSE REA.CDONS 
6.1 Clinical Trials Bxperiencc 
6.2 ~F.xpaien.ee 
7 DRUG INTERACI'IONS 
I USE IN SPECIJIC POPULA nONS 
8.1 PrepaDcy 
1.3 Nl.lniq Molbm 
8.4 Pedilltic Use 
8.5 Oeriab:ic Ute 
..... 
.,.~~~~~~~, 1hq ihould ltc: -- iJia'c(llt 1C11515 
aninws..-.(1) 
S.1'7 rPA'IUl'tt 
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lO OV&RDOSAGE 
1 
12 CLOOCAL PIIARMACOLOGY 
12.1 Mecb111:ism of Aetioo 
12.2 Pbaumacodynamics 
123~ 
13 NONCUNICAL TOXICOLOGY 
:UIJDI~ 
13.1 c.dDoseaesil, Mutagmais. Jmpairmcut 
of FercDity 
l4CLINICAL~ 
14. I Elevated Baseliae lOP 
14.2 P'rogRssioo. of~ 
Iris Pi~ 
16 HOW SUPPLIED/STORAGE AND 
IIANDUNG 
1'1 PATIENT COUNSELING INFORMATION 
17.1 POtemial for~ 
17.2 PobldaJ Cor Eyclub Cblmaet 
17.3 Haodlins de Contaioer 
17.4 Wbca to Sect Physician Advice 
t 7.S Use with Contact LcoscJ 
17.6 Use wi1h Other Ophthalmic Drugs 
• Sec:dc:liU or wbtodiom ~ 
6vm ~ 
AaU 
Jlftll:ribilll infomaation- DGt listed. 
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Protocol 012601IN 
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JIJO)JC.A.TIONS .lt.ND USAGE 
XALATAN Slaile ()p'htud•ic SOJutioa is indicated for the nduclioa. olekwatecJ. iDilaOOUlar peaaueia 
patients wi1h ape1H1DI.te ,__..or ocular b)'pate.aioa. 
2 DOSAGE Aim ADMINIS'I'RATION 
Tbe,.,....,ended dosage II one drop in tho atfccted C,C(i) oacccJaiJy ia 'llaetmndas.lf one dole is 
mfMod, tnatmcat sho1dd ~ 
wlthtte next d.o• asaormal. 
The dosage ofXALATAN lhould:ootcxoood om:e daily; the COIIIbJald uae oftwo or more 
~. 
orpmstaa,_ctin aaalopinc1•Miins XALA1'A'Ni8 .-JWOOmlnondoct.lt be boca 1bowD 
u.t ~of*-~dnlapod\ti.Um.oteddncmeo daily Dllf Ucruse the 
iatraocular ~(lOP) lowaiq e.tl'lctar .._ paradmdcal elmdi.oDsia lOP. 
Reducnioa of'the lOP-approximaldy 3104 houn aftcrldmildstndimlaudtbe max.bman effect is 
lCICbcd. ala: 8 to '12 boan. 
XALATAN maybelJIIOd ooacomltdly wllh otbe.ttopical CJ)Idbalmic dtua .~to 
lower IOP.If 
mtftthm 08C topical OJhtldmic drua is baiDi used, tbe*9 sltoukl.be ..tmjnistereflltleutfive. (5) 
lllinuiiiS aparL Caatact 1lalll should be:reiDO'Ved. pdot to tho ldminlllralion ofXALATAN. and may bo 
Rlimerted U·llliJulelaftor~ 
3DOMGE JORMS AND STIU!NGTBS 
Sterile apltthelmic 101Uiioft 00Dfai1aiD1 50nt.CJ(mL ~ 
4 CONI'ItAINDICATIONS 
KDowa ~dvitym ~ 
blllr.alko.aiumc:hlari&W, or myothlr~ iDdlisprod.uct. 
5 WABNJNGSAND PIIBCAVDONS 
S.tPip•IMie• 
XALATAN bubeea.repDited to oaatoc1wtaesto~tdnol. 1he most ~·mpollld 
chtd&ttluwobeen ~ 
pipladatioaofthe. periodtitd issue (eplidhudqeluhn. 
Pi8J"'"'''ioaiscxpected to U..Ou Joaa• ~ 
tsadlniailleRd. 
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ofJ~pi~of1heirisii 
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receive ....... lhouW be iafbtmecJ,oflbc 
poaibilit)' ofin«ccsod pi...-cltioo. Beyond 5 )'aRb effects ofiacmuld piplafa1ioD _,,DOt. 
kuwnfa• ailril:tll Stvdla (14..2)]. 
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Protocol 012601IN 
DE-126 Ophthalmic Solution 
Iris color change 1111)' not be noticeable for sewra1 months to years. T)•pJcellyt the brown pia,mentalioa 
around die ..,,._,n Sl1fl*ls conceatricatly to-wards tbe periphe!y of1he iris and the entire iris or JJidS of the 
iris become IDON brownish. Neither nevi. oor freckles of the iris~ to be aft'ec1ed by treaJment.. 
WbiJe 1reltment with XALATAN CBD be COiltinucd in patienll who do\dop noticelbl)' increaeed iris 
JJiamcntation, 1besc: ~auld 
be examined reauJar1y [m Patltlll Counseling llformation (17.1)). 
5.2ByeluhCh...-
XALA TAN may padually clmnae eyelashes rmd wUas hair in 1he Veldd eye; 1bciC chaqcs include 
:increased lcqth. thicll:ocss. piamemadoo. 'dle number oflula or hairs, and misdirected lf'Owth of 
eyeluhe&. Eyelash dlanges are mually rewrsible upm disccmtinuatiol of trc:almCUt [lee Polient 
Cmms~ltng l'fli»'mtUitm (11.2)]. 
l,.""'u h•fDBWIIIIII 
XALATAN should be used with amtion in patieDis with a hbtcny o.fin 
itttJamnwttion 
(uitirfuveitis) aocl should pncra11y aot be used bt pedmtl with active iDtraocu1ar infllmmation boc&wso 
iDflammalion may be exacelbated. 
Macular edema. iocludiq cystoid m.aculltodcma. bas beea tq.Uted duriD& ttea1meD1 with XALATAN. 
XALATAN sbould be used with cautioaiaaphatic pili~ iD ~· 
patieata wifh a tom 
posterior Ia caps:ulc. or in pade;nU with btowD risk &cton :fi:lr macular edema. 
5.5 Herpede Kmdlil· 
lteactivalioa ofHelpes Simplex keratitis has been NpOJ1ed during tradmcat with XALATAN. 
XALAT AN sbouk1 be used witb ca~ in padeats with a history ofberpetic bratiiis. XALATAN 
sbou1cl be avoided ia cues of active be.rpea limplcx b:ralids becasc ioOamme.t:k'lo IIUl)' be ex.eerbact 
5.6 Badaial KerwtltiJ 
~haw ben rcpott!J.·ofbacletW b.tatitia .u:sociated with the use of multiple-dose CODiainen of 
topical. ophthalmic products. These cootaincr.s had been .iDadYertaJ.tly ~by 
patient~~ in 
DkiSt ~had 
11 ccrncunent comeel cliJeue or a disruption of the ocaJar epithelial surface [.!ft Potlml 
O>rm.tellrfg hr/ortllolltm ( 17.J)J. 
:5.7 UH 1rilll Co 
et Leata 
Ccmtact lcmcs should 1le removed prior to the~ 
ofXALATAN, md may be Ninseded IS 
minutes after aclm.inislratio. 
6 ADVERSE REACI10NS 
1'ht= fo.Jlowiq ldvene reactioDs W~nmpotted in postmatketina cxporicncc and .are diacUSied in JfCider 
detail in oCher ICCti<IG:toftho label: 
• Iris: pismentation. changes [see WGmings Dllll PreCillltil»u ($. /)) 
• Eyelid ikin dadtcoina [sec Warning~ tRKIPr-ecmmlm8 (j.J)] 
• Eyelash chimps fmCRIIIHCIIqtb.1hicbcss. ~and 
number of lashes) [see War-111"-P 
ad PrecalftitJtm (J.2)J 
• Jnlmocular inflmnmation (iritis/mriliJ) (SOC W~ 
mid PrtcaUiiOIJ$ (5.J}) 
• Maculu edema. inc1udiaa cystoid nuu:u1ar edema (see Warnbtgs andPrtu:au/IOM (l-1)] 
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6 .. 1 CIWul1'rlals E~ 
BecMge elird* triaiJ arc CODdLJcted 1iiDdar widely vary.iq co.nditiODBot theadver.ae ·~ 
ra~s 
e'blalwd. iD the aJilliaal studiO of a ..._CIJIDOt be directly~ 
10 rates 1ft the eliiiical ti:i41s of 
IIMiher d'tua andi mlf nOt docttho ~· obH.ned in cJmical pndice. 
XALATAN 'WitS studied in three mukice:Dter~ ~ 
contiODed. cliiliCid tdal8. hli4mts mccivad SO 
~XALATAN 
onoodaiJy or S qfmL acti~{dmolot)·twiceddy."Ihe·patlent 
populatkm sludild. had 8 miiUl age of65*lll)'UI& Sevm peteettt of~ 
wltbdttW ~ 
tht 
'-momh llldpoint. 
by 5-l!S% ofpalilllu nlllvfns! i:.:a.hlaopnu.t 
A._•.....,..Oaddt!aa(%)) 
Lataaopr.t 
Tlaiolol 
jsy.mptom!Pmdiae 
(~) 
(PI69) 
IF~ 
.body IIDII8ILtioD 
1.3 
8 
Pr.mdate epbhoUal keratopath)· 
JO 
' 
stiQing 
' 
l2 
Conjuncrivu~ · 
• 
8 
3 
BlUIRid vision 
8 
I 
[1ddnK 
8 
8 
l)uming 
7 
I 
lncfCascd piptealatiOli ofb iris 
1 
0 
I4s.- IU of the pMientl'lmU:Od w.ieh XALATAN l'llll.uired dilcoJdinuadon of therapy because of 
iotolcmiii:ID 10: eo:qjmletivallvpaemia. 
receiving Lataaop~~mt 
Advene Rcudou (bactdeaft! (o/o)} 
IAt&Doprod 
1'im.W 
(a-4Qf) 
(il.-.369} 
~eular E.atts/SlpiiDd Symptome 
Bl:casiive tariog 
• 
6 
W disO<n:nforl/p.!Qo 
4 
1 
Dry eye 
3 
3 
Eye pain 
l· 
3 
Lid c:rumng 
3 
3 
Lid tr)1hc:ma 
3 
2. 
Pbotophllma 
2 
1 
Lid edlililla 
1 
3 
~Ytbiiiilt :~vo ... 
Upper Rspiratoty 'bact 
3 
3 
WCtction!coJdfflu 
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Protocol 012601IN 
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A.dverle RdetJ.on.e (Jneld~u (•~)) 
IAtln.oprn&t 
11Dmlot 
(m=-4~) 
( .. r:e3691 
1 
o.s 
1 
0.3 
6.Z PolbnarltetittJ Ex(Jtriertee 
The foll.OwmJ~.have ~ 
idcmfifieddmi.ng postmarkedq ll$:' ofXALATA.N in cUHieal 
paetice. Becamothey are ro~ 
v.,I~Wily ,!tOm a Pl,putatioo o~unkDOwu siZe, cstimilcs of 
hqt~e:noy c~t be madei. The reaclioos, '9i.'hich have been~ fol' mct~on ~to either lheir 
soriov:ui~ ft'tqu.;y of~rting, ~~e 
causal~ 
1o XALATAN, 0£ a Cor.nhinatiPnbf~ 
:facton,) inclu~e: 
Ngypw System dif1j!Btm~ diZ1.ioe-. ~he, 
4.1Dd toxic epidecun&.1 J1e(:l'C'Jy;.is 
Eye Disolders~ ey~1ash m;d v~Uu.s l$ir.~.(in~r;d l ... 
lhiekne·~ pi~ 
.and~; 
keratitisi eomealodcmaarul ero$cfu;~ular inflamma!io_n (iritis/~);~· ~ 
.. includitta 
cystOid IWlCularedcnul; mhidirtl~ erie~lasb• ~~-~ng 
in eye.i:ni.tmion; peri~ ·aDd lid 
~·tmd~g in dcepeftina of the eyetid.sUicus 
· 
Re19lratoo:·lhoraclc agd M;djgtjuJ l)jmrdm:.uduna and ~M 
-of~; dyspnea 
$1cip apd SuJx#dam!qua·Usp pit!:!!dm;;: eyelid s1dn darJum.iD& 
lgfecliops apd ~tions: herpes kermitb 
7 DRUG .INTERACTIONS 
Jnviri studi~ ba~ •own 1hatpreclpitalion OOaD'8 •nere,~ps ~~-~r~ 
~ ~ 
with .XALATAN. If such chugs ~ nOd. they !ho11ld be :adl.niDistered at least. five (S) minute& ;put 
1b eombioed use; of~ o.rmo,re P"J~}p~ or~ 
analc:tgS ine11Kliq XALATAN is not 
reoomme~.lt. ~·been sbqwn 11mfld.tttinistia1ion of tbt:$e ~ 
q 
pi'od1:1tts more thari: 
om::t" dailyll'lay doc~ the fOP~-effect-ot cause puado:dcat .eJ~-tnlOP. 
B USE IN SPECUl.C 'POPULATIONS 
J.,lPNpbq 
Teratogenic Effects; ~y 
·Olr¢101)' C. 
ReprodUQti(ttt sUI6ies iaw been perf~ in mCE and. rabbit$; In:mbbUs, aniooick:nce ~f4 e>f 16 ~ 
had no Viilblc fc1Usc;s at a ·dOse that. was ~x,i~y 80 times the maximuJn 1mman dose, and the 
~eft nonenm,yaddal doSe iD.'nbbils was :ilp)Jto~y 15 ~ * ~ 
lnn:wm do~~e. 
There are DO adequate· and wcU~ttb'OUcd studies .IJI pre pant women. XALATAN ahould be U$Cd 
during p.re:pney ad.)' if the potenlial be:oefit justifies lb¢: poteoJ:fa] rl:sk to 1he (etus . 
.1.3 NIJ~IMqt~ 
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·~·~u. 
':~:~:~~lii~.:~t.··~~·~·~ 
:a~s ..... v_. 
··:::n~-·wety41!.~--·~:··~·~~-.~; 
·~ •OVJIU)OMGE 
B!:~··!l!ri!!AP 
,lf~--·~TAN~,.~::~b,ii~~~~ 
·0.:-lilk.'-QN:. 
:r ··~J if · · · ..... a!I11•Nt;M. v.,.;:adl · · · ·.-ltl ~--' · ' -· :t J~pr9pyJ..(Z)o7(ill~$.;.$$.): 
-~~~~·~~~~.~~~~.lt. .:~~ ... · .... 
:q' 
'"""·:::u_.::,'.a-;" ........ ::h. -~.:.-• -
....... -.:.;.a •. 
-~~~-~~~~~-~~~-~·~·~-· 
NO 
&-t'~~~i~~=:~J:r:.. 
:~ma~bt-~ll.Wilba.p9~o£.,~1i.7tid:·"' o~·ot~l-:Ut · 
, •• 
~.!t:4! 
·.u::CJJ1!1c~-v· 
w M.eell..ds~:~f~ 
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.Latano~ iJ. a pmsUJitoid selcctb~ FP ~ 
9r.Ust1blt iS bl!li.eved w reduce the intraoeaJ.ar 
preuure·OOP) by increasing the outtl~w of aqQeO.lis blRJl(l[· S~ 
ln ~ 
~ 
man suasest that de 
main meebiJD.ism of aetion i:s. in~ 
uveoscler'al outflow. Ele\'Rted lOP ~Scnls a~or risk helot 
fOr glaucomatous field los$. Th.O bilbcr the l~~i (;flOPs the Steatet the ·likellhaod of optic nmre: 
· 
damage: and ·..,isufd .field loss. 
1Z.2 Pfw'maoodyPm.kJ. 
R.educ:tiQD of the lO:P in mansmrt~.about 3-4.bcXlrs afteradrMnt~on and :maximum effect is reached 
aftc:r·s-12 bour~. JOP reduction is J)fesut:ror atieast :24 hours. 
l:D Phannaeuldnetb 
A~ 
on 
Latanoprost js abn"bed through~·~. wbm 1he isopmpyl ester prodrug is hydrolp.ed to .the acid 
(Q1:'1ll to beeome biolo,gicall)' active. 
pjiJribudon 
1'b; disWD\ltkJn Wlu;f~bin human~ iS 0~ 16 :LJl~Ol Llkg. 1le aeid Qfl~st 
C&Ul be~. 
ill 
oqueous h}.t[nordur.iog the first 4 ~;and m p~ 
~y d~ 
1he .:fii'St-dlir local 
administtation. StU(Iie.s in man indicate 1hat the .peak co0~timl m 
tlK; ·~~rumor is teached 
abo- W.ro hours atb:J: .lnp.ical a4mlnhtmdon. 
'MS!tl.bgUsm 
~.st, an isopR)p)~lester prrodnl& is ~drQI~ by~ 
in. ·abe ~-to~ biologically 
.aCtive acjd. Th.c aCtive acid of.Wano~lrt reachblg the systemic cireuJation is primarily tndaboli=d by 
1he fiver to. the 1.2-dbmr and 1-Z.l.~ Mbolil03 via tany·a.eid ~-oxidaticm. 
Eaillb!l 
'I'he·elimination ofthe acid oflatanopmst fimD hmmm plana is ntpid (tJn • 17 min) llfl:er both 
JntravcllQ\C lmd ~ 
~rds~tkm. ~Y~t~tic e~ 
;s ap'pl'Oxinia1dy 7 mLI~nlkg;F~UI)Witll 
bepatk· p-oxidadm.'dK .nietaboli~s are mainly eliminated.\'ia th.e kidneyS. Approximatei.Y 88% and 
98~ of~ adminilll!lmd ·dose·'are ~,·efecl in dle urine det10pi¢$.) Md. itttre.~us dosipg,. 
~:vef.y. 
13 NONCLJNICAL tOXICOLOGY 
IS. I C'llt'tl....,ealt,Mu:~U, Jmp•bmeat of Fertility 
~.pro&twas Dot~ 
in citba: m~ce QJ'l'a#Y,~ edm;nigt~ by oral. sa• ~ dqses of up 
bJ 179 m~dtly (~ly2800 tW.es 1be recollllllmdod mU~m.um b~ 
~) 
fOtttp ro·20 
and .24 ~ 
msPocti\'el)'. 
~t 
WM .not m_,tnt~ m ·~in 
D1ou.se. .lylnplumu. ~dn mause mi~ 
te$.1S. 
CbrOl:i.tOscmm ~ 
were: obsCrnd in 1Jitro whh .h'umQ. Jymphoeytes. AdditioDal in v/D'o &ruJ m 
vm_; swdieson ~DNA 
syn1h.esis ·in rats ·wen: DCplivo.. 
La.tmwprost haS not mn fo'I.Uld to have any effect oo tnlle. ot female fertili1y in BDimal studies. 
14 CLINI.CAL STUDIES 
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Protocol 012601IN 
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1~1 Elimdell BueliDeiOP 
Patiads with mua. 1aasel.inl JOPof14-25 mmHJ who wen ~rated for611'10Dd2s in m~. 
andamized, COidlrOlled tdals.demoAttntocJ6-Immlla iOductiOD1J in lOP .. This lOP Jedudiaa With 
XALATAN 0.005% dosocl OJDZ daiiJ \\iBS eqaivaleat to die eftict, oftimolol 0.5% d.olec1 twice daily. 
lU~oaaf.........._lriaPi:paeataiDD 
A 3·yw opea'"lebeJi pros_pecdvo safety ltud;r wilh a 2-yar IXllusioD phase was condudod to ewlaafe 
1bc~ 
ofil1cnaed his piame.ntati.cm. with cotdinumu1111 ofXA.LAT.AN oaoe-daily 111 
adjudve tt.r.py iD 519 pWenta Widao,....P ataucoma. 1be ~was 
based• ~ 
popUtkm ofthe 380palicaas wbo contiuucd In the extemioa phase. 
Besults showed--- ofaodccU)o increued ids Jlamellltbl OCl1lrled within the fuat yarof 
...... fottbo mfJority ofdle J)lldmts who develapdiiOBeable increued iris pifiiBidldon. ..... 
~ 
to·sbowsipsofiDcJeaalDa irfs.~1bfouabout tho &voycat~ of tho Defy. 
Oblervtdoaofiacreued ids piJmoa1atloodhlaotatrect 1M~ 
........ 01 sewdty ofadvme 
ewldl (athlr thaD i1aeaRc1 iris pipntltioa) ftiCIOidad mtbe study.JOPtedtdoa wu lim.ilat 
repnUess ofdledeveJopment ofiacreated iris piamemMiondtariDj tho ldudy. 
16 HOW SUPPUEDJITORAGE AND BANDLING 
XALATAN a. e. dear. ilo1oaic. buftCred, ~coladas 101ution of~Hmopmst O.OOS% ($0 
mcatmL). Jt a ..,&ed as a 2.5 mL IDiutioD in a.S mL dear low deDsitypolyetbyhme boule wkh • cJ. 
po~Jeaedropper1ip.a ~bipdcm.tlty 
po~Jceb.yleao ICIOWCieil\ aac1 a ~cl_. 
low dal'ty po)yc1bylono owtcap. 
2.S mL fiB, O.OOS% (~OmcsfmL): ,_.of I boUle: NDC 00134S03..o4 
2J mL fin. oms" (50·•JimL): Multi-,.c.k or3 boll1es: Nne ootl-8303-0l 
Stomp: Protect fmmupt. Slore~ 
bolle(s) under I:Oiiipndoa at2a to rc{WtoWP). 
Dudna shipment to tho patio.ot the 1JoU1e may be nudntained at ...,_...ns up· to 400C (1040fl)for a 
period DOt "'"'"'in~ I days. Cnce a bottle is opened Cot WIC, it mq lie 8tOI'ed at mom tempotal\Ue up to 
15°C (T70f) for6 weeb. 
11 PATIENT OOIJNSELING IIDOIIMATION 
17.1P...uJfor ...... fldlu 
AdvJie ,.,... .. about lbo 1)0ICOii81 tor illcrtasid blown piamatatioD ofthe iris, which may be 
pll'IIIIDIDt.lafmm pdieats about tbepoaibility of eyelid .. ~ 
which 8Uiy bo fCNCftlldoalcr 
diSC'.ominPadcJA ofXALATAN (.m W~-~ 
(S.l)]. 
17.,2Potealdlw~Cb.ua«t 
laform patieats of the poaihllily of eyelash .t 
voUua balr ana- in tt. tretdldeyo durioa trcaiiDcnt 
wldlXALATAN. 1'helo cbqcl may Malt. in.adispaity between .,a in 1.,ab, tbi.ckDess, 
piam~ 
D1.11llbcr ofeyelubes or wJJus hairs, mlfor dinetkm of eye1e.sh 8ft)Wtla. E)'eluh ctaaqa 
are umallyJeYaBibi&UJOil~ oftreetmerd. 
t7.3 lludJiaa • am..._. 
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Instruct paticnli 1o avoid ilEowma the tip of'dic ~ 
(lie)i21a\not to oon'Laet 1ho eye orsurrotmdina 
structures because tbis could eause die tip to become toolamioated by common bacteria !koowD to cause 
ocular infoeliollt. SetiOU$ damaae to abe eye mtd. ubsequem Joas ot \lision may result fio:m us1n,g 
~talllioa!cd soJuticm.s [see Wm?Jings and Precaations (J. ~). 
l"T.4 Whea to SerikPIQJidau Adftce 
Advise paticnU that if they develop am interew:rent ocular oondition (e~&·~ uuma or infection) or have 
ooular sargery, or devdop any ocular :raetion.s, particularly WIQunelhitisii.Dd eyelid md.ont. they 
should ilnmedWely M!lek their physician's advice eoncenUA.g tl.te continued use of the multiple-dose 
comainer. 
11.5 V~e11rith Coatad Leun 
Advise patients that XALA.TAN contains benzalb:mium chloride, which may be absorbed by cootact 
lc:nscs. Contact. ICOJCS should be removed prior to admiliiitldon of tbc IOlutloa. Le:ata may be 
reinserted 1 S miDuta fo11owift8 adminimtion ofXALATAN. 
17*6 Use ~itb Olber 0 hthalnd" D·rup 
If~ than one topic.! opb1haJmio dm& is being usod. the dt:uss should be adminiltemi at least five (S) 
minutes apart. 
Pfizer Manufaoturina Bclsium NV 
Pu~Belgium 
J..AB.Oll.S..I l.O 
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22. 
PROTOCOL AMENDMENT 1 SUMMARY OF CHANGES 
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Table 4: 
Protocol Amendment 1 Summary of Changes (Continued) 
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Table 4: 
Protocol Amendment 1 Summary of Changes (Continued) 
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Table 4: 
Protocol Amendment 1 Summary of Changes (Continued) 
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Table 4: 
Protocol Amendment 1 Summary of Changes (Continued) 
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Table 4: 
Protocol Amendment 1 Summary of Changes (Continued) 
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Table 4: 
Protocol Amendment 1 Summary of Changes (Continued) 
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Table 4: 
Protocol Amendment 1 Summary of Changes (Continued) 
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Protocol012601TIN 
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Table 4: 
Protocol Amendment 1 Summary of Changes (Continued) 
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Table 4: 
Protocol Amendment 1 Summary of Changes (Continued) 
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