Conditions: Primary Open-angle Glaucoma and Ocular Hypertension
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 107
Healthy volunteers: no

Brief summary:
Santen will evaluate the intraocular pressure (IOP) lowering effect and efficacy of DE-117 ophthalmic solution 0.002% in latanoprost low/non-responder subjects diagnosed with POAG or OHT

Detailed description:

Arms:
arm 1: Interventional treatment will be made with DE-117 Ophthalmic Solution 0.002% once daily in the evening for the duration of the 3 month treatment period.

Interventions: intervention 1: DE-117 Ophthalmic Solution
Intervention descriptions: intervention 1: Interventional treatment will be made with DE-117 Ophthalmic Solution 0.002% once daily in the evening for the duration of the 3 month treatment period.

Protocol document:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:   
An Open-Label, Multicenter Study Assessing the Efficacy and 
Safety of DE-117 Ophthalmic Solution 0.002% in Latanoprost 
Low/Non-Responder Subjects Diagnosed with Primary Open-Angle 
Glaucoma or Ocular Hypertension - Spectrum 5 Study 
 
 
NCT Number:  
NCT03697811 
 
Date of the document: 
 18 JULY 2018 
 
 
 


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DE-117 Protocol 
Study 011711IN 
 
 
TITLE:  An Open-Label, Multicenter Study Assessing the Efficacy and Safety of DE-117 
Ophthalmic Solution 0.002% in Latanoprost Low/Non-Responder Subjects Diagnosed 
with Primary Open-Angle Glaucoma or Ocular Hypertension - Spectrum 5 Study 
SPONSOR: 
SANTEN Inc. 
6401 Hollis St, Suite 125 
Emeryville, CA 94608 USA 
STUDY DRUG:  
DE-117 Ophthalmic Solution 0.002% 
I have read the 011711IN protocol and agree to conduct the study as outlined. I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol. I will not initiate the study until I have obtained written approval by the appropriate 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and have complied 
with all financial and administrative requirements of the governing body of the clinical 
institution and Santen as the Sponsor. I will obtain written informed consent from each study 
subject prior to performing any study-specific procedures. I understand that my electronic 
signature on an electronic case report form (eCRF) indicates that the data therein has been 
reviewed and accepted by me as the Investigator.  
 
INVESTIGATOR: 
Date:             
_________________________________ 
 
Signature: 
_________________________________ 
 
Name:                _________________________________ 
 
Address:             _________________________________ 
 
 
_________________________________ 
 
Phone: 
_________________________________ 
This study will be conducted in accordance with applicable Good Clinical Practices (GCP), 
United States Code of Federal Regulations, International Conference on Harmonization (ICH) 
guidelines, and the Declaration of Helsinki. 


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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Santen Inc. 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608, USA 
Name of Investigational Product: DE-117 Ophthalmic Solution 0.002% 
Name of Active Ingredient:  
Glycine, N-[6-[[[[4-(1H-pyrazol-1-yl)phenyl]methyl](3-pyridinylsulfonyl)amino]methyl]-2-
pyridinyl]-, 1-methylethyl ester 
Propan-2-yl 2-[[6-[[(4-pyrazol-1-ylphenyl)methyl-pyridin-3-ylsulfonylamino]methyl]pyridin-2-
yl]amino]acetate 
Title of Study:  
An Open-Label, Multicenter Study Assessing the Efficacy and Safety of DE-117 Ophthalmic 
Solution 0.002% in Latanoprost Low/Non-Responder Subjects Diagnosed with Primary Open-
Angle Glaucoma or Ocular Hypertension- Spectrum 5 Study 
Protocol Number: 011711IN 
Number of Subjects (planned): Approximately 150 subjects with Primary Open-Angle 
Glaucoma (POAG) or Ocular Hypertension (OHT) will be enrolled into the Treatment Period 
with DE-117 ophthalmic solution 0.002%  
Number of Sites (planned): Approximately 25 Sites  
Study Period: Approximately 13 months 
Primary objective:  
To evaluate the intraocular pressure (IOP) lowering effect of DE-117 ophthalmic solution 
0.002% in latanoprost low/non-responder subjects diagnosed with POAG or OHT. Specifically, 
the primary efficacy endpoint is the change from baseline (Day 1, Visit 4) in mean diurnal IOP 
at Month 3 (Visit 7). 
Secondary objectives:  
To evaluate the IOP lowering efficacy (change, percent change and proportion of responders) of 
DE-117 ophthalmic solution 0.002% in latanoprost low/non-responder subjects diagnosed with 
POAG or OHT at each timepoint.  
Safety objective:  
To evaluate the safety of DE-117 ophthalmic solution 0.002% in latanoprost low/non-responder 


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subjects diagnosed with POAG or OHT.  
Duration of Treatment: 8-Week Run-in Period with latanoprost ophthalmic solution 0.005% 
and 3-month Treatment Period with DE-117 ophthalmic solution 0.002% 
Methodology: 
This is an open-label multi-center study. Subjects diagnosed with POAG or OHT who  meet the 
eligibility criteria at Visit 1 (Screening) will enter a Washout Period, the duration of which is 
determined by their current topical IOP-lowering medication(s) if any. After completing the 
required Washout Period, subjects will return for Visit 2 (Week -8, start of the Run-in Period). 
Subjects who remain qualified will start a Run-in Period dosing with latanoprost ophthalmic 
solution 0.005% once daily in the evening in both eyes, and then return for Visit 3 (Week -4, 
midpoint of the Run-in Period) and Visit 4 (Baseline, Day 1), to confirm ongoing eligibility.  
Subjects who meet all eligibility criteria at Visit 4 (Baseline, Day 1), will enter the Treatment 
Period and will be treated with DE-117 ophthalmic solution 0.002 % once daily in the evening 
in both eyes for 3 months. During the 3-month Treatment Period, three follow-up visits will be 
scheduled: Visit 5 (Week 2), Visit 6 (Week 6) and Visit 7 (Month 3). 
Approximately 150 subjects with POAG or OHT who meet all eligibility criteria are planned to 
enter the Treatment Period and be treated with DE-117 ophthalmic solution 0.002%. 
Study Design 
 
 
This study will consist of a Screening Period which includes a Washout Period of up to 35 days 
(28 days + 7 days window) and an additional 8-Week Latanoprost Run-in Period; followed by a 
3-month Open-Label Treatment Period with DE-117 0.002% ophthalmic solution. 
At Visit 1 (Screening; start of the Washout Period [if applicable]), subjects will be screened 
against the inclusion and exclusion criteria. Eligible subjects will be instructed to discontinue 
use of all IOP-lowering medications during the 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 


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 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandins Analogs (PGA): 28 days 
 Rho kinase inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will be 
used. 
During the required washout period, subjects who discontinue their current treatment, may, if 
the investigator deems it necessary, be treated with a short-acting IOP lowering agent, topical 
Carbonic Anhydrase Inhibitor (CAI), e.g., brinzolamide or dorzolamide eye drops, one drop 
twice daily. Topical CAI treatment must be stopped at the latest 1 week before Visit 2  
(Week -8, start of the Run-in Period). An interim safety visit may be performed during the 
washout period, Visit 1a (optional, mid-washout visit), if in the Investigator’s opinion, a 
subject’s IOP may be of concern. If subjects are treated with a topical CAI during the washout 
period, Visit 1a (optional, mid-washout visit) is recommended to be performed.  
Subjects who have not used an IOP-lowering medication for the last 28 days, will need a wait 
period of ≥ 1 day before Visit 2 (Week -8, start of the Run-in Period). 
At Visit 2 (Week -8, start of the Run-in Period), continuing eligibility will be determined based 
on non-treated IOP: 
 IOP ≥ 22 mmHg in at least one eye 
 IOP ≤ 34 mmHg in both eyes at all measurement time points 
Subjects who are qualified at Visit 2, will begin the 8-Week Run-in Period, dosing with 
one drop of latanoprost ophthalmic solution 0.005% every evening at 20:00 (±60min) in 
both eyes. 
Visit 3 will take place at Week -4 (midpoint of the Run-in Period) to check the following IOP 
criteria:  
 The same eye meeting criteria at Visit 2 (Week -8, start of the Run-in Period), must 
meet the following criteria: percent decrease of IOP from Visit 2 (Week -8, start of 
the Run-in Period) of  ≤ 25% at all measurement time points 
 Visit 3 8:00 IOP should be compared with Visit 2 8:00 IOP;  
 Visit 3 12:00 IOP should be compared with Visit 2 12:00 IOP;  
 Visit 3 16:00 IOP should be compared with Visit 2 16:00 IOP.   
 IOP in both eyes of ≤ 34 mmHg at all measurement time points  
Subjects who are qualified at Visit 3 (Week -4, midpoint of the Run-in Period), will 
complete the remainder of the 8-Week Run-in Period, continuing dosing with one drop 
of latanoprost ophthalmic solution 0.005% every evening at 20:00 (±60min) in both 
eyes.  
Visit 4 (Baseline, Day 1) will take place at the end of the Run-in Period and is considered the 


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baseline for the analyses. The following criteria have to be met to initiate the Treatment Period 
with DE-117 ophthalmic solution 0.002%: 
 The same eye meeting criteria at Visit 3 (Week -4, midpoint of the Run-in Period) 
must meet the following criteria: percent decrease of IOP from Visit 2 (Week -8, 
start of the Run-in Period) of ≤ 15% at all measurement time points 
 Visit 4 8:00 IOP should be compared with Visit 2 8:00 IOP; 
 Visit 4 12:00 IOP should be compared with Visit 2 12:00 IOP; 
 Visit 4 16:00 IOP should be compared with Visit 2 16:00 IOP.   
 IOP in both eyes of ≤ 34 mmHg at all measurement time points 
Subjects who are qualified at Visit 4 (Baseline, Day 1), will be enrolled into study and 
begin the 3-month Treatment Period, dosing with one drop of DE-117 ophthalmic 
solution 0.002% every evening at 20:00 (±60min) in both eyes. Follow-up visits will be 
scheduled at Week 2 (Visit 5), Week 6 (Visit 6) and Month 3 (Visit 7). 
IOP will be measured at 8:00, 12:00 and 16:00 (±60 min) at all visits except at Visit 1 
(Screening) and Visit 1a (optional, mid-washout visit) when one measurement at any time will 
suffice. The study eye will be the eye that qualifies per eligibility criteria through Visit 4 
(Baseline, Day 1). If both eyes meet the eligibility criteria, the eye with the higher diurnal IOP 
(calculated as the average of IOP measurements at 3 time points) at Visit 4 (Baseline, Day 1) 
will be designated as the study eye. If both eyes meet the eligibility criteria and have the same 
mean diurnal IOP, the right eye will be designated as the study eye.  
At the scheduled visits, query of adverse events (AEs), best-corrected visual acuity (BCVA) 
and slit lamp biomicroscopy will be performed before the first IOP measurement. 
Ophthalmoscopy (fundus examination) will be performed after the last IOP measurement for 
the day. Additional procedures are explained in Section 7.4. 
Pharmacogenomics/Genomics: 
Subjects who consent to the optional pharmacogenomics/genomics laboratory study will 
provide a blood sample for future testing after subject is enrolled and study drug, DE-117 
ophthalmic solution 0.002%, dosing has begun. The purpose of this exploratory research is to 
identify possible genetic markers associated with the study medication(s) and/or ocular 
conditions. 
Masking:  
This is an open label study; masking will not be applied.  
Inclusion Criteria: 
At Visit 1 (Screening, start of the Washout Period), the subject must meet all of the following 
inclusion criteria: 
1. Provide signed written informed consent on the Institutional Review Board (IRB)/Ethics 
Committee (EC) approved Informed Consent Form (ICF). 
2. Be 18 years of age or older on the date of signing the ICF and be able and willing to 


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comply with all treatment and follow-up study procedures. 
3. If a subject is female of childbearing potential (i.e., not post-menopausal [within 12 
months since the last menses] or not surgically sterile [less than 6 months from date of 
surgery]), subject must have a negative urine pregnancy test and must use at least one of 
the following acceptable contraceptive methods during the study (as well as for 4 weeks 
following last dose in study). 
 Abstinence 
 Hormonal contraceptive method (including oral or transdermal contraceptives, 
injectable progesterone, progestin subdermal implants, progesterone-releasing 
intrauterine devices [IUDs]) initiated at least 28 days prior 
 Placement of a copper-containing IUD 
 Condom with spermicidal foam/gel/film/cream/suppository 
 Vasectomized male partner (surgery at least 6 months prior)  
Male subjects capable of fathering children should use or practice an acceptable contraceptive 
method, such as abstinence, condom or vasectomy (surgery at least 6 months prior) or other 
contraceptive method deemed adequate by the investigator throughout the course of the study 
(as well as for 12 weeks following last dose in study). 
4. Must have a diagnosis of POAG or OHT in both eyes, or one eye with POAG and the 
other with OHT. 
5. BCVA of +0.60 logMAR (Snellen equivalent 20/80) or better in each eye. 
6. Central corneal thickness ≥ 480 m and ≤ 600 m in each eye. 
7. Anterior chamber angle grade ≥ 2 (Shaffer scale) in each eye. 
At Visit 2 (Week -8, start of the Run-in Period), the subject must meet the following criteria: 
8. Completed the required wait/washout period. 
9. At all time points of IOP measurements (08:00, 12:00 and 16:00 ± 60 min), have IOP of 
≥ 22 mmHg in at least one eye (the same eye), and ≤ 34 mmHg in both eyes. 
At Visit 3 (Week -4, midpoint of the Run-in Period) the following IOP criteria have to be met: 
10. Percent decrease in IOP from Visit 2 (Week -8, start of the Run-in Period) of ≤ 25% at 
all measurement time points in the eye meeting criteria at Visit 2 (Week -8, start of the 
Run-in Period).  
11. IOP in both eyes ≤ 34 mmHg at all measurement time points. 
At Visit 4 (Baseline, Day 1) the following IOP criteria have to be met: 
12. Percent decrease in IOP from Visit 2 (Week -8, start of the Run-in Period) of ≤ 15% at 
all measurement time points in the eye meeting criteria at Visit 3 (Week -4, midpoint of 
the Run-in Period).  
13. IOP in both eyes ≤ 34 mmHg at all measurement time points. 


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Exclusion Criteria: 
From Visit 1 (Screening) to Visit 4 (Baseline, Day 1), subjects 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 4 weeks prior to Visit 1 (Screening) or at any time during this 
trial. 
4. Subjects who have been exposed to DE-117 prior to Visit 1 (Screening). 
Medications / Therapies 
5. Usage of more than two active ingredients to lower IOP prior to Washout Period. 
6. Intended or current use of the following prohibited medications/therapies during the 
study: 
 All ocular medications other than: sodium chloride/potassium chloride ophthalmic 
solution; cataract treatment agents (e.g., glutathione, pirenoxine); Vitamin B12 
formulation (e.g., cyanocobalamine); over-the-counter dry eye artificial tears/drops; 
and study medications. 
 All systemic medications for ocular hypotensive (e.g., oral or intravenous CAI, oral 
glycerol). 
 Any ocular, periocular, inhaled, nasal or systemic corticosteroids including joint 
injection, etc. 
 Lacrimal/punctal occlusion via plug(s) or cautery.  
7. Subjects who cannot safely discontinue use of ocular hypotensive medications during 
the wait/washout period. 
8. Subjects who will be required to initiate or modify any systemic or topical medication 
known to affect IOP (e.g., β-adrenergic antagonists, α-adrenergic agonists, calcium 
channel blockers, angiotensin-converting enzyme [ACE] inhibitors, and angiotensin II 
receptor blockers [ARB]). Subjects using the above medications must have a stable dose 
use for at least 30 days prior to Visit 1 (Screening) and throughout the study. 
9. Use of contact lenses within 2-3 weeks prior to Visit 2 (Week -8, start of the Run-in 
Period) until end of treatment in either eye (2 weeks for soft contact lens wearers, and 3 
weeks for rigid contact lens wearers). 
10. Any ocular surgery or ocular laser treatment within 180 days prior to Visit 1 (Screening) 
and throughout the study in either eye. 
11. History of ocular surgery specifically intended to lower IOP (e.g. laser trabeculoplasty, 
filtering surgery, tube shunt, Minimally Invasive Glaucoma Surgery (MIGS), or 


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trabeculotomy) in either eye. 
12. History of keratorefractive surgery (e.g. Radial Keratotomy [RK], Refractive 
Keratectomy [PRK], Laser-Assisted-in-Situ Keratomileusis [LASIK]) in either eye.  
13. Allergy, hypersensitivity or contraindications to latanoprost, EP2 receptor agonists, 
benzalkonium chloride (BAK) or any other components of the study medications, or 
other study related procedures/medications. 
Diseases 
14. Presence of advanced glaucoma (e.g., visual field mean deviation worse than -12 dB) in 
either eye. 
15. Presence of any corneal abnormality or other conditions interfering with or preventing 
reliable Goldmann applanation tonometry (e.g., Fuch’s dystrophy or significant corneal 
surface abnormality) in either eye. 
16. Presence of any active severe external ocular disease, inflammation, or infection of the 
eye and/or eyelids in either eye. 
17. Presence or history of macular edema or known risk factors for macular edema in either 
eye. 
18. History of severe ocular trauma in either eye. 
19. History of iritis and/or uveitis, 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. 
20. History of retinal detachment, proliferative diabetic retinopathy, or any retinal disease 
that may be progressive during the time course of the study in either eye. 
21. Presence or history of any disease or condition that in the opinion of the study 
Investigator may put the subject at significant risk, may confound study results, or may 
interfere significantly with the subject’s participation in the study (e.g., recurrent corneal 
erosion syndrome, uncontrolled cardiovascular disease etc.). 
22. Any decision by the Investigator or Medical Monitor to terminate a subject in screening 
or declare any subject ineligible for any sound medical reason. 
Investigational product, dosage and mode of administration:  
During the 8-Week Run-in Period, all subjects will dose with one drop of latanoprost 
ophthalmic solution 0.005% in both eyes once daily in the evening at 20:00 (±60min). During 
the 3-month Treatment Period, all subjects will dose one drop of DE-117 ophthalmic solution 
0.002% in both eyes once daily in the evening at 20:00 (±60min).   
Product to be used during Run-in Period: 
Latanoprost ophthalmic solution 0.005% (Greenstone®)  
Investigational Product: 
DE-117 ophthalmic solution contains 0.002% DE-117. Each 2.5 mL bottle of DE-117 
ophthalmic solution 0.002% contains 50 μg of DE-117. In additio


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Route of Administration of Investigational Product: Topical ocular 
Duration of the Study: The study duration includes a Screening Period which includes a 
Washout Period of up to 35 days (28 days + 7 days window) and an additional 8-Week Run-in 
with Latanoprost; followed by a 3-month Open-Label Treatment Period with DE-117 0.002% 
ophthalmic solution. 
Criteria for Evaluation: 
Efficacy: 
Efficacy will be assessed by evaluating IOP at each scheduled time point as follows: 08:00, 
12:00, and 16:00 (± 60 min) at the scheduled visits with the exception of Visit 1 (Screening) 
and Visit 1a (optional, mid-washout visit).  
Safety: 
Safety assessments will be composed of AEs, BCVA, slit-lamp biomicroscopy, 
ophthalmoscopy, and iris color/eyelash/eyelid examination.  
Other: 
Subject demographics, baseline characteristics, medical history, concomitant medications, 
exposure to study medication, and pregnancy for females of childbearing potential will be 
summarized. 
Efficacy Endpoints: 
Primary Efficacy Endpoint 
 Change from baseline in mean diurnal IOP at Month 3 (Visit 7) 
Secondary Efficacy Endpoints  
 Percent change from baseline in mean diurnal IOP at Month 3 (Visit 7) 
 Change and percent change from baseline (Visit 4) in mean diurnal IOP at Week 2 
(Visit 5) and 6 (Visit 6)  
 Change and percent change from baseline in IOP for each post-baseline 
timepoint/visit 
 Having a mean diurnal IOP reduction ≥ 10%, ≥ 15%, ≥ 20%, ≥ 25%, or ≥ 30% from 
baseline (Visit 4) at Month 3 (Visit 7)  


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 Having a mean diurnal IOP ≤ 18 mmHg at Month 3 (Visit 7) 
Safety Endpoints 
Safety will be evaluated by the following parameters: 
 Incidence of ocular and systemic AEs 
 BCVA 
 Slit-lamp biomicroscopy findings: anterior chamber cells, anterior chamber flare, lid 
hyperemia, lid edema, conjunctival hyperemia, conjunctival chemosis, corneal 
edema, corneal staining, keratic precipitates, lens, anterior synechiae of iris, 
posterior synechiae of iris 
 Ophthalmoscopy  
 Iris color/eyelash/eyelid 
Statistical Methods: 
Using one sample t-test with a significance level of 5%, a sample size of 150 will have 90% 
power to detect a mean diurnal IOP reduction of 1.0 mmHg from baseline with a standard 
deviation of 3.5 mmHg, after taking into account of up to 12% dropouts. 
 
 
 


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Washout Period 
Run- in Period 
Treatment Period 
Visit 1 
(Screening) 
Washout 
Period 
(up to 4 
weeks) 
Optional 
Visit 1a b 
Visit 2 
Week -8 
(Day  
-56±3) 
Visit 3 
Week -4 
(Day  
-28±3) 
Visit 4 
Baseline 
(Day 1) 
Visit 5 
Week 2 
(Day 
15±3) 
Visit 6 
Week 6 
(Day 
43±5) 
Visit 7 
Month 3 
(Day 91±7) 
Exit or 
Early 
Termination 
Informed Consent(s) including 
the consent for 
pharmacogenomics / genomics 
laboratory research studya 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria  
X 
 
X 
X 
X 
 
 
 
Demographics and Medical 
History, including prior PGAc 
X 
 
 
 
 
 
 
 
Concomitant Medications/ 
Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
Dosing Compliance 
 
 
 
X 
X 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testd 
X 
 
 
 
X 
 
 
X 
Refractione 
X 
 
 
 
 
 
 
 
BCVAe 
X 
X 
X (08:00) X (08:00) X (08:00) X (08:00) X (08:00) 
X (08:00) 
Biomicroscopyf 
X 
X 
X (08:00) X (08:00) X (08:00) X (08:00) X (08:00) 
X (08:00) 
IOPg 
X 
(any time) 
X 
(any time) 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
Pachymetryh 
X 
 
 
 
 
 
 
 
Iris color, eyelash, eyelidi 
 
 
 
 
X (photo) 
 
 
X (photo) 
Gonioscopyj 
X 
 
 
 
 
 
 
 
Visual Fieldk 
X 
 
 
 
 
 
 
 
Ophthalmoscopyl 
X (pupil 
dilation) 
 
 
 
X (16:00) 
 
 
X (16:00, 
pupil 
dilation) 
Blood Sampling for 
Pharmacogenomics/genomicsm 
 
 
 
 
 
X 
Dispense Study Medication 
 
 
X 
X 
X 
 
X 
 
Collect Study Medication 
 
 
 
X 
X 
 
X 
X 
Phone call to remind subject to 
take evening dose on the day 
before each visit 
 
 
 
X 
X 
X 
X 
X 
 


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a. 
Informed Consent Form must be signed and dated before study procedures are performed. Informed consent for 
the optional pharmacogenomics/genomics laboratory research study may be obtained at any visit prior to study 
exit. 
b. An interim safety visit may be performed during the washout period Visit 1a (optional, mid-washout visit), if in 
the Investigator’s opinion a subject’s IOP may be of concern. If subjects are treated with a topical CAI during 
the washout period, Visit 1a (optional, mid-washout visit) is recommended to be performed. 
c. 
The previous use of prostaglandin analogs should be confirmed by either subject’s medical records or subject 
history. 
d. A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
e. 
Refraction will be performed at the screening visit. If more than 10 letters in BCVA are lost compared to the 
screening visit, then refraction should be performed again. BCVA examination will be completed before IOP 
measurement at 08:00 (±60 min).  
f. 
Biomicroscopy examination must be completed before IOP is measured at 08:00 (±60 min). Aqueous flare and 
cell evaluation will be performed before fluorescein instillation.  
g. IOP measurements will be performed at 08:00, 12:00 and 16:00 (±60 min) at all visits except for Visit 1 
(Screening) and Visit 1a (optional, mid-washout visit).  
h. Pachymetry will be performed after IOP measurement at Visit 1 (Screening). 
i. 
Eye photograph will be taken at Visits 4 (Baseline, Day 1) and 7 (Month 3). 
j. 
If gonioscopy was performed within 3 months (90 days) prior to screening and was documented in the subject’s 
records, no additional screening gonioscopy examination is necessary. Gonioscopy will be performed after IOP 
measurement at Visit 1 (Screening). 
k. If visual field test was performed within 3 months (90 days) prior to screening and was documented in the 
subject’s records, no additional screening visual field test is necessary.  
l. 
Ophthalmoscopy will be performed at Visits 1, 4 and 7 (i.e., Screening, Baseline and Month 3) after the 16:00 
IOP measurements. Ophthalmoscopy will be performed with pupil dilation at Screening and Visit 7 (Month 
3)/Study Exit or Early Termination. Dilation of the pupil will be performed after the 16:00 IOP measurement. 
m. Blood sampling for the pharmacogenomics/genomics laboratory research study may be performed at any visit 
after pharmacogenomics/genomics informed consent is obtained, subject is enrolled and study drug, DE-117 
ophthalmic solution 0.002%, dosing has begun. 
 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
 
TABLE OF CONTENTS 
1. 
PROCEDURES IN CASE OF EMERGENCY ............................................................3 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............15 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................20 
5. 
INTRODUCTION ......................................................................................................23 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................25 
6.1. 
Primary Objective .......................................................................................................25 
6.2. 
Secondary Objectives .................................................................................................25 
6.3. 
Safety Objective ..........................................................................................................25 
7. 
INVESTIGATIONAL PLAN .....................................................................................26 
7.1. 
Overall Study Design ..................................................................................................26 
7.2. 
Number of Subjects ....................................................................................................28 
7.3. 
Treatment Assignment ................................................................................................28 
7.4. 
Schedule of Events and Procedures ............................................................................29 
7.4.1. 
Visit 1 (Screening) ......................................................................................................30 
7.4.2. 
Visit 1a (optional, mid-washout visit) ........................................................................32 
7.4.3. 
Visit 2 (Week -8, start of the Run-in Period) ..............................................................32 
7.4.4. 
Visit 3 (Week -4, midpoint of the Run-in Period) ......................................................33 
7.4.5. 
Visit 4 (Baseline, Day 1) ............................................................................................34 
7.4.6. 
Visit 5 (Week 2, Day 15 ± 3) ......................................................................................36 
7.4.7. 
Visit 6 (Week 6, Day 43 ± 5) ......................................................................................36 
7.4.8. 
Visit 7 (Month 3, Day 91 ± 7) Study Exit/Early Termination ....................................37 
7.5. 
Study Termination ......................................................................................................38 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................39 
8.1. 
Subject Inclusion Criteria ...........................................................................................39 
8.2. 
Subject Exclusion Criteria ..........................................................................................40 
8.3. 
Subject Withdrawal Criteria .......................................................................................42 
9. 
TREATMENT OF SUBJECTS ..................................................................................43 


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9.1. 
Description of Study Medication ................................................................................43 
9.2. 
Concomitant Medications or Therapies ......................................................................43 
9.2.1. 
Prohibited Medications or Therapies ..........................................................................43 
9.3. 
Treatment Compliance ................................................................................................44 
9.4. 
Randomization and Masking ......................................................................................45 
10. 
STUDY MEDICATION MATERIALS AND MANAGEMENT .............................46 
10.1. 
Study Medication ........................................................................................................46 
10.1.1. 
Investigational Product ...............................................................................................46 
10.1.2. 
Product to be used during Run-in Period ....................................................................46 
10.2. 
Study Medication Packaging and Labeling ................................................................46 
10.3. 
Study Medication Storage ...........................................................................................46 
10.4. 
Study Medication Preparation ....................................................................................47 
10.5. 
Study Medication Administration...............................................................................47 
10.6. 
Study Medication Accountability ...............................................................................47 
10.7. 
Study Medication Handling and Disposal ..................................................................47 
10.8. 
Study Supplies ............................................................................................................48 
11. 
ASSESSMENT OF EFFICACY ................................................................................49 
11.1. 
Efficacy Parameter ......................................................................................................49 
12. 
ASSESSMENT OF SAFETY .....................................................................................50 
12.1. 
Adverse Events and Serious Adverse Events .............................................................50 
12.1.1. 
Definition of Adverse Events .....................................................................................50 
12.1.1.1. 
Assessment of Adverse Events ...................................................................................50 
12.1.1.2. 
Reporting Adverse Events ..........................................................................................51 
12.1.2. 
Serious Adverse Events ..............................................................................................52 
12.1.2.1. 
Assessment of Serious Adverse Events ......................................................................52 
12.1.2.2. 
Reporting Serious Adverse Events .............................................................................53 
12.1.2.3. 
Expedited Reporting of Serious Adverse Events ........................................................53 
12.1.3. 
Events of Special Interest ...........................................................................................53 
12.1.4. 
Follow-up of Adverse Events .....................................................................................54 
12.1.5. 
Manual Back-Up Reporting Procedures .....................................................................54 
12.2. 
Safety Parameters .......................................................................................................55 
12.2.1. 
Ocular Assessments ....................................................................................................55 
13. 
OTHER ASSESSMENTS ..........................................................................................56 


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13.1. 
Demographic, Baseline Characteristics and Other Assessments ................................56 
14. 
STATISTICAL METHODS .......................................................................................57 
14.1. 
Interim Analysis ..........................................................................................................57 
14.2. 
Final Analysis .............................................................................................................57 
14.3. 
General Considerations ...............................................................................................57 
14.3.1. 
Sample Size ................................................................................................................57 
14.3.2. 
Statistical Hypotheses and Level of Significance .......................................................57 
14.4. 
Study Populations .......................................................................................................58 
14.4.1. 
Safety Population ........................................................................................................58 
14.4.2. 
Full Analysis Set .........................................................................................................58 
14.4.3. 
Per-Protocol Set ..........................................................................................................58 
14.5. 
Handling of Missing Values .......................................................................................58 
14.6. 
Demographic and Baseline Characteristics ................................................................58 
14.7. 
Efficacy Analyses .......................................................................................................59 
14.7.1. 
Analysis of Primary Efficacy Endpoint ......................................................................59 
14.7.2. 
Analysis of Secondary Efficacy Endpoints ................................................................59 
14.7.2.1. 
Secondary Efficacy Endpoints ....................................................................................59 
14.8. 
Safety Analyses ..........................................................................................................59 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................60 
15.1. 
Study Monitoring ........................................................................................................60 
15.2. 
Audits and Inspections ................................................................................................61 
15.3. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................61 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................62 
16.1. 
Quality Control ...........................................................................................................62 
16.2. 
Quality Assurance .......................................................................................................62 
17. 
ETHICS ......................................................................................................................63 
17.1. 
Ethics Review .............................................................................................................63 
17.2. 
Ethical Conduct of the Study ......................................................................................63 
17.3. 
Written Informed Consent ..........................................................................................63 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................64 
18.1. 
Inspection of Records .................................................................................................64 
18.2. 
Retention of Records ..................................................................................................64 
18.2.1. 
Source Documents ......................................................................................................64 


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18.2.2. 
Source Data .................................................................................................................64 
18.2.3. 
Data Collection ...........................................................................................................65 
19. 
PUBLICATION POLICY ..........................................................................................66 
20. 
REFERENCES ...........................................................................................................67 
20.1. 
Literature .....................................................................................................................67 
20.2. 
Study Data ..................................................................................................................68 
21. 
APPENDICES ............................................................................................................70 
21.1. 
Appendix A - Obligations of Investigators .................................................................70 
21.2. 
Appendix B - Elements of Informed Consent ............................................................72 
21.3. 
Appendix C - Procedures for Assessments .................................................................74 
21.3.1. 
Demographics, Medication/Therapy and Medical History ........................................74 
21.3.2. 
Pregnancy Test ............................................................................................................74 
21.3.3. 
Iris color, Eyelash, Eyelid ...........................................................................................74 
21.3.3.1. 
Iris Color .....................................................................................................................75 
21.3.3.2. 
Eyelash ........................................................................................................................75 
21.3.3.3. 
Eyelid ..........................................................................................................................75 
21.3.4. 
Refraction ...................................................................................................................75 
21.3.5. 
Best-Corrected Visual Acuity .....................................................................................75 
21.3.5.1. 
ETDRS Visual Acuity Scoring ...................................................................................76 
21.3.6. 
Slit-lamp Biomicroscopy ............................................................................................77 
21.3.7. 
Intraocular Pressure ....................................................................................................79 
21.3.7.1. 
Goldmann Applanation Tonometer Calibration .........................................................80 
21.3.8. 
Pachymetry (Central Corneal Thickness) ...................................................................81 
21.3.9. 
Gonioscopy .................................................................................................................81 
21.3.10. 
Visual Field .................................................................................................................81 
21.3.11. 
Ophthalmoscopy (Fundus) Examination ....................................................................81 
21.3.12. 
Blood Sample for Pharmacogenomics/genomics Study .............................................82 
21.5. 
Appendix D - Latanoprost Ophthalmic solution 0.005% Package Insert ...................83 
LATANOPROST- latanoprost solution  Greenstone LLC ............................................................83 
 
 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................20 
Table 3: 
LogMAR Scoring Grid for ETDRS Eye Chart...........................................................76 
 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................26 
Figure 2: 
DE-117 Structure ........................................................................................................43 
 
 
 


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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 
ACE 
Angiotensin-Converting Enzyme 
AE 
Adverse Event 
AGIS 
Advanced Glaucoma Intervention Study 
ARB 
Angiotensin II Receptor Blockers 
ATC 
Anatomical Therapeutic Chemical 
BAK 
Benzalkonium Chloride 
BCVA 
Best-Corrected Visual Acuity 
CAI 
Carbonic Anhydrase inhibitor 
CV 
Curriculum Vitae 
dB 
Decibel 
DUES 
Deepening of the Upper Eyelid Sulcus 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMGT 
Early Manifest Glaucoma Trial 
EP2 
Prostaglandin E receptor Subtype 2 
ESI 
Events of Special Interest 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FP 
Prostaglandin F Receptor 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IUDs 
Intrauterine Devices 


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Table 2: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Definition 
LASIK 
Laser-Assisted-in-Situ Keratomileusis 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram 
µm 
Micrometer 
mg 
Milligram 
MIGS 
Minimally Invasive Glaucoma Surgery  
min 
Minute 
mL 
Milliliter 
mmHg 
Millimeters of Mercury 
N 
Number of subjects 
NDA 
New Drug Application 
OAG 
Open-Angle Glaucoma 
OCT 
Optical Coherence Tomography 
OD 
Right Eye 
OHT 
Ocular Hypertension 
OHTS 
Ocular Hypertension Treatment Study 
OS 
Left Eye 
OU 
Both Eyes 
PACG 
Primary Angle Closure Glaucoma 
PCR 
Polymerase Chain Reaction 
PG 
Prostaglandin 
PGA 
Prostaglandin Analogue 
PGE2 
Prostaglandin E2  
POAG 
Primary Open-Angle Glaucoma 
PPS 
Per-Protocol Set 
PRK 
Refractive Keratectomy 
PT 
Preferred Term 
QD 
Once a day 
RK 
Radial Keratotomy 
SAE 
Serious Adverse Event 


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Table 2: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Definition 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SUN 
Standardization of Uveitis Nomenclature 
UKGTS 
United Kingdom Glaucoma Treatment Study 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 
 


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5. 
INTRODUCTION 
Glaucoma represents a group of related diseases frequently associated with elevated IOP. When 
left untreated, glaucoma can lead to retinal ganglion cell death and optic nerve damage, resulting 
in progressive and irreversible loss of vision. Glaucoma is the second leading cause of blindness 
worldwide. In 2013, the global prevalence of glaucoma for population aged 40 to 80 years was 
3.54%. The number of people (aged 40 to 80 years) with glaucoma worldwide was estimated to 
be 64.3 million, increasing to 76.0 million in 2020 and 111.8 million in 2040 (Tham et al., 2014). 
It affects one in two hundred people aged fifty or younger and one in ten over the age of eighty 
(Resnikoff et al., 2004). 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 (Iwase et al., 2004; Yamamoto et al., 2005). 
Although currently there is no cure for open-angle glaucoma (OAG), results from multiple 
studies, including the Advanced Glaucoma Intervention Study (AGIS) (AGIS_Investigators, 
2000), the Ocular Hypertension Treatment Study (OHTS) (Kass et al., 2002), and the Early 
Manifest Glaucoma Trial (EMGT) (Leske et al., 2003), and United Kingdom Glaucoma 
Treatment Study (UKGTS) (Garway-Heath et al., 2015) have demonstrated that treating elevated 
IOP with topical ocular hypotensive agents is effective in delaying or preventing disease 
progression. The lowering of IOP is currently the only method for reducing the risk of 
glaucomatous visual field loss and remains the primary goal of therapy. 
Several classes of ocular hypotensive medications exist today and are differentiated by their 
mechanism of action at the cellular/molecular level. These include miotics, β-adrenergic receptor 
antagonists (β-blockers), CAIs, -adrenergic receptor agonists (-agonists), and prostaglandin 
analogues (PGAs). The pharmacodynamic effect of these medications can differ substantially, as 
some affect aqueous humor production (β-blockers, -agonists, and CAIs) while others affect the 
outflow pathway (miotics, PGs, and -agonists). In general, PGAs are recommended as the first 
choice agent for most eyes with OHT and OAG. However as disease progresses and maintaining 
target IOP becomes difficult, more than one drug is needed to achieve optimum benefit and reach 
target IOP. Surgical interventions, including laser surgery, shunting of aqueous humor to an 
appropriate locale, and filtering surgery, are available options for treating insufficiently 
controlled IOP. In such instances pharmacotherapy may be continued as well. 
While adequate IOP-lowering can be achieved by currently available pharmacotherapies in some 
patients, not all patients are adequately treated and additional IOP-lowering may provide for 
further slowing of disease progression. In some patients, treatment with a single IOP-lowering 
compound is not sufficient to obtain optimal IOP control. Adjunctive or combination therapy 
using different classes of drugs is often employed in order to achieve additional IOP-lowering 
effects. Moreover, consistent lowering of IOP over a 24 hour period has not yet been fully 
realized. If achieved, this could also contribute to slowing of disease progression. Therefore, new 
pharmacologic agents with new mechanism of action are needed. 
Santen has developed an ophthalmic topical formulation of omidenepag isopropyl (UR-7385) for 
the reduction of elevated IOP in patients with OHT or OAG. DE-117 is a pro-drug of the 
pharmacologically active acid metabolite, UR-7276, a synthetic non-prostanoid agonist of 
prostaglandin E2 (PGE2) receptor, subtype 2 (EP2). PGE2 has been shown to markedly reduce 
IOP when applied topically to human and animal eyes (Bito, 2001). PGE2, its analogues and 


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receptor agonists are thought to mediate the IOP-lowering effect by relaxing the ciliary muscle 
and increasing outflow of aqueous humor through the uveo-scleral pathway (Yamaji et al., 2005). 
Very recently, Fuwa et al., demonstrated that DE-117 lowers the IOP through a novel 
meachnism of action: that is, through both conventional and uveoscleral outflows (Fuwa et al., 
2017).Currently approved IOP- lowering medications such as latanoprost (latanoprost 
ophthalmic solution, 0.005%; NDA 20-597) lower IOP by enhancing uveoscleral outflow only, 
but do so through effects on a receptor for PGF2α. Unlike latanoprost and other approved 
prostaglandin F receptor (FP) agonists that are synthetic prostanoid analogues, DE-117 is a non-
prostanoid chemical compound. 
To date, Santen has completed seven clinical studies including three clinical studies (33-001,  
33-002, 33-003) in the U.S. and four clinical studies (01171502, 01171503, 01171504, 
01171506) in Japan with DE-117 in healthy adult subjects, or subjects with OAG or OHT to 
evaluate the efficacy and safety of DE-117. DE-117 ophthalmic solution 0.002% appeared to be 
well tolerated and efficacious in IOP lowering. As a result, it was chosen to advance into the 
phase III clinical development program in the US.  
Additional information on DE-117 ophthalmic solution, including the results of nonclinical and 
clinical studies can be found in the Investigator’s Brochure. 
The proposed study is an open-label, multi-center study. The total duration of this study is 13 
months. The objective is to investigate the efficacy and safety of DE-117 ophthalmic solution 
0.002% in latanoprost low/non-responder subjects diagnosed with POAG or OHT. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To evaluate the intraocular pressure (IOP) lowering effect of DE-117 ophthalmic solution 
0.002% in latanoprost low/non-responder subjects diagnosed with POAG or OHT. Specifically, 
the primary efficacy endpoint is the change from baseline (Day 1, Visit 4) in mean diurnal IOP at 
Month 3 (Visit 7). 
6.2. 
Secondary Objectives 
To evaluate the IOP lowering efficacy (change, percent change and proportion of responders) of 
DE-117 ophthalmic solution 0.002% in latanoprost low/non-responder subjects diagnosed with 
POAG or OHT at each timepoint. 
6.3. 
Safety Objective 
To evaluate the safety of DE-117 ophthalmic solution 0.002% in latanoprost low/non-responder 
subjects diagnosed with POAG or OHT.  


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is an open-label and multi-center study investigating the efficacy and safety of DE-117 
ophthalmic solution 0.002% in latanoprost low/non-responder subjects diagnosed with POAG or 
OHT. 
See the study design diagram in Figure 1. This study will consist of a Screening Period which 
includes a Washout Period of up to 35 days (28 days + 7 days window) and an additional  
8-Week Latanoprost Run-in Period; followed by a 3-month Open-Label Treatment Period with 
DE-117 0.002% ophthalmic solution.  
Approximately 150 subjects with POAG or OHT who meet all eligibility criteria are planned to 
enter the Treatment Period and be treated with DE-117 ophthalmic solution 0.002%. 
 
Figure 1: 
Study Design 
 
 
At Visit 1 (Screening; start of the Washout Period [if applicable]), subjects will be screened 
against the inclusion and exclusion criteria. Eligible subjects will be instructed to discontinue use 
of all IOP-lowering medications during the Washout Period as follows (up to +7 days as a 
window is allowed):  
 Miotics: 7 days 
 Oral/topical Carbonic Anhydrase Inhibitors (CAIs): 7 days 
 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandins Analogs (PGA): 28 days 
 Rho kinase inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will be 
used.


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During the required washout period, subjects who discontinue their current treatment, may, if the 
investigator deems it necessary, be treated with a short-acting IOP lowering agent, topical 
Carbonic Anhydrase Inhibitor (CAI), e.g., brinzolamide or dorzolamide eye drops, one drop 
twice daily. Topical CAI treatment must be stopped at the latest 1 week before Visit 2 (Week -8, 
start of the Run-in Period). An interim safety visit may be performed during the washout period 
Visit 1a (optional, mid-washout visit) if, in the Investigator’s opinion, a subject’s IOP may be of 
concern.  If subjects are treated with a topical CAI during the washout period, Visit 1a (optional, 
mid-washout visit) is recommended to be performed. 
Subjects who have not used an IOP-lowering medication for the last 28 days, will need a wait 
period of ≥ 1 day before their Visit 2 (Week -8, start of the Run-in Period). 
At Visit 2 (Week -8, start of the Run-in Period), continuing eligibility will be determined based 
on non-treated IOP:  
 IOP ≥22 mmHg in at least one eye and ≤34 mmHg in both eyes at all measurement 
time points  
Subjects who are qualified at Visit 2, will begin the 8-Week Run-in Period, dosing with 
one drop of latanoprost ophthalmic solution 0.005% every evening at 20:00 (±60min) in 
both eyes. 
Visit 3 will take place at Week -4 (midpoint of the Run-in Period), to check the following IOP 
criteria:  
 The same eye meeting criteria at Visit 2 (Week -8, start of the Run-in Period), must 
meet the following criteria: percent decrease of IOP from Visit 2 (Week -8, start of 
the Run-in Period) of  ≤ 25% at all measurement time points 
 Visit 3 8:00 IOP should be compared with Visit 2 8:00 IOP;  
 Visit 3 12:00 IOP should be compared with Visit 2 12:00 IOP;  
 Visit 3 16:00 IOP should be compared with Visit 2 16:00 IOP.   
 IOP in both eyes of  ≤ 34 mmHg at all measurement time points  
Subjects who are qualified at Visit 3 (Week -4, midpoint of the Run-in Period), will 
complete the remainder of the 8-Week Run-in Period, continuing dosing with one drop of 
latanoprost ophthalmic solution 0.005% QD at 20:00 (±60min) in both eyes.  
Visit 4 (Baseline, Day 1) will take place at the end of the Run-in Period and is considered the 
baseline for the analyses. The following criteria have to be met to initiate the Treatment Period 
with DE-117 ophthalmic solution 0.002%: 
 The same eye meeting criteria at Visit 3 (Week -4, midpoint of the Run-in Period) 
must meet the following criteria: percent decrease of IOP from Visit 2 (Week -8, start 
of the Run-in Period) of ≤ 15% at all measurement time points 
o Visit 4 8:00 IOP should be compared with Visit 2 8:00 IOP; 
o Visit 4 12:00 IOP should be compared with Visit 2 12:00 IOP; 
o Visit 4 16:00 IOP should be compared with Visit 2 16:00 IOP.   
 IOP in both eyes of ≤ 34 mmHg at all measurement time points 


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Subjects who are qualified at Visit 4 (Baseline, Day 1), will be enrolled into study and begin the 
3-month Treatment Period, dosing with one drop of DE-117 ophthalmic solution 0.002% every 
evening at 20:00 (±60min) in both eyes. Follow-up visits will be scheduled at Week 2 (Visit 5), 
Week 6 (Visit 6) and Month 3 (Visit 7). 
IOP will be measured at 8:00, 12:00 and 16:00 (± 60 min) at all visits except at Visit 1 
(Screening) and Visit 1a (optional, mid-washout visit) when one measurement at any time may 
suffice. The study eye will be the eye that qualifies per eligibility criteria through Visit 4 
(Baseline, Day 1). If both eyes meet the eligibility criteria, the eye with the higher diurnal IOP 
(calculated as the average of IOP measurements at 3 time points) at the end of the Run-in Period 
(Visit 4) will be designated as the study eye. If both eyes meet the eligibility criteria and have the 
same mean diurnal IOP, the right eye will be designated as the study eye.  
At the scheduled visits, query of AEs, BCVA and slit lamp biomicroscopy will be performed 
before the first IOP measurement. Ophthalmoscopy (fundus examination) will be performed after 
the last IOP measurement for the day. Additional procedures are explained in Section 7.4. 
Pharmacogenomics/genomics: 
Subjects who consent to the optional pharmacogenomics/genomics laboratory study will provide 
a blood sample for future testing after subject is enrolled and study drug, DE-117 ophthalmic 
solution 0.002%, dosing has begun. The purpose of this exploratory research is to identify 
possible genetic markers associated with the study medication(s) and/or ocular conditions. 
7.2. 
Number of Subjects 
Approximately 150 subjects are planned to be enrolled into the Treatment Period with DE-117 
ophthalmic solution 0.002%. 
7.3. 
Treatment Assignment 
All subjects will receive the following study medications: 
 8-Week Run-in Period: latanoprost ophthalmic solution 0.005% QD (20:00 ±60min) 
 3-month Treatment Period: DE-117 ophthalmic solution 0.002% QD (20:00 ±60min)  
 
 
 


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7.4. 
Schedule of Events and Procedures 
 
Washout Period 
Run-in Period 
Treatment Period 
Visit 1 
(Screening) 
Washout 
Period 
(up to 4 
weeks) 
Optional 
Visit 1ab 
Visit 2 
Week -8 
(Day -56±3) 
Visit 3 
Week -4 
(Day -28±3) 
Visit 4 
Baseline 
(Day 1) 
Visit 5 
Week 2 
(Day 15±3) 
Visit 6 
Week 6 
(Day 43±5) 
Visit 7 
Month 3 
(Day 91±7) 
Exit or 
Early 
Termination 
Informed Consent(s) including 
the consent for 
pharmacogenomics / genomics 
laboratory research studya 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria  
X 
 
X 
X 
X 
 
 
 
Demographics and 
Medical History, including 
prior PGAc 
X 
 
 
 
 
 
 
 
Concomitant Medications/ 
Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
Dosing Compliance 
 
 
 
X 
X 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testd 
X 
 
 
 
X 
 
 
X 
Refractione 
X 
 
 
 
 
 
 
 
BCVAe 
X 
X 
X (08:00) 
X (08:00) X (08:00) X (08:00) X (08:00) X (08:00) 
Biomicroscopyf 
X 
X 
X (08:00) 
X (08:00) X (08:00) X (08:00) X (08:00) X (08:00) 
IOPg 
X 
(any time) 
X 
(any time) 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
Pachymetryh 
X 
 
 
 
 
 
 
 
Iris color, eyelash, eyelidi 
 
 
 
 
X (photo) 
 
 
X (photo) 
Gonioscopyj 
X 
 
 
 
 
 
 
 
Visual Fieldk 
X 
 
 
 
 
 
 
 
Ophthalmoscopyl 
X (pupil 
dilation) 
 
 
 
X (16:00) 
 
 
X (16:00, 
pupil 
dilation) 
Blood Sampling for 
Pharmacogenomics/genomicsm 
 
 
 
 
 
X 
Dispense Study Medication 
 
 
X 
X 
X 
 
X 
 
Collect Study Medication 
 
 
 
X 
X 
 
X 
X 
Phone call to remind subject to 
take evening dose on the day 
before each visit 
 
 
 
X 
X 
X 
X 
X 
 
 


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a. 
Informed Consent Form must be signed and dated before study procedures are performed. Informed consent for 
the optional pharmacogenomics/genomics laboratory research study may be obtained at any visit prior to study 
exit. 
b. An interim safety visit may be performed during the washout period Visit 1a (optional, mid-washout visit), if in 
the Investigator’s opinion a subject’s IOP may be of concern. If subjects are treated with a topical CAI during 
the washout period, Visit 1a (optional, mid-washout visit) is recommended to be performed. 
c. 
The previous use of prostaglandin analogs should be confirmed by either subject’s medical records or subject 
history. 
d. A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
e. 
Refraction will be performed at the screening visit. If more than 10 letters in BCVA are lost compared to the 
screening visit, then refraction should be performed again. BCVA examination will be completed before IOP 
measurement at 08:00 (±60 min).  
f. 
Biomicroscopy examination must be completed before IOP is measured at 08:00 (±60 min). Aqueous flare and 
cell evaluation will be performed before fluorescein instillation.  
g. IOP measurements will be performed at 08:00, 12:00 and 16:00 (±60 min) at all visits except for Visit 1 
(Screening) and Visit 1a (optional, mid-washout visit).  
h. Pachymetry will be performed after IOP measurement at Visit 1 (Screening). 
i. 
Eye photograph will be taken at Visits 4 (Baseline, Day 1) and 7 (Month 3). 
j. 
If gonioscopy was performed within 3 months (90 days) prior to screening and was documented in the subject’s 
records, no additional screening gonioscopy examination is necessary. Gonioscopy will be performed after IOP 
measurement at Visit 1 (Screening). 
k. If visual field test was performed within 3 months (90 days) prior to screening and was documented in the 
subject’s records, no additional screening visual field test is necessary.  
l. 
Ophthalmoscopy will be performed at Visits 1, 4 and 7 (i.e. Screening, Baseline and Month 3) after the 16:00 
IOP measurements. Ophthalmoscopy will be performed with pupil dilation at Screening and Visit 7 (Month 3)/ 
Study Exit or Early Termination. Dilation of the pupil will be performed after the 16:00 IOP measurement. 
m. Blood sampling for the pharmacogenomics/genomics laboratory research study may be performed at any visit 
after pharmacogenomics/genomics informed consent is obtained, subject is enrolled and study drug, DE-117 
ophthalmic solution 0.002%, dosing has begun. 
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 
pharmacogenomics/genomics laboratory research study may be obtained at any visit 
prior to blood sampling. Ensure the subject understands that participation in the 
optional pharmacogenomics/genomics laboratory research will not influence 
participation in the main study. 
 Prepare the list of screening/registration of subjects. 
 Obtain demographics. 
 Obtain medications including prior prostaglandin analog use, procedures/therapies 
and medical history including all lifetime ocular medical history to the extent 
possible, non-ocular medical history within 5 years, diagnosis, ocular surgical history, 
current ocular and systemic conditions. 
 Obtain urine and perform urine pregnancy test, if the subject is female of child-
bearing potential. 
 Perform the following procedures or assessments (all ophthalmic procedures to be 
performed in both eyes): 
 Refraction  


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 BCVA (before IOP measurement) 
 Visual field (will be performed if this has not been performed in the previous 
three months) 
 Gonioscopy (will be performed after IOP measurement if this has not been 
performed in the previous three months) 
 Biomicroscopy (before IOP measurement) 
 IOP 
 Pachymetry (after IOP measurement)  
 Ophthalmoscopy with pupil dilation (after IOP measurement) 
 Determine if the subject meets eligibility criteria. 
 If the subject meets eligibility criteria and is still willing to continue the study, 
discontinue any current IOP-lowering medication according to the following schedule 
(up to +7 days as a window is allowed): 
 Miotics: 7 days 
 Oral/topical Carbonic Anhydrase Inhibitors (CAIs): 7 days 
 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandins Analogs (PGA): 28 days 
 Rho kinase inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will 
be used. 
 During the required washout period, subjects who discontinue their current treatment 
may, if the Investigator deems it necessary for safety, be treated with a topical CAI, 
e.g., brinzolamide or dorzolamide eye drops, one drop twice daily. Topical CAI 
treatment must stop 1 week before Visit 2 (Week -8, start of the Run-in Period).   
 An interim safety visit may be performed during the washout period Visit 1a 
(optional, mid-washout visit) if in the Investigator’s opinion, a subject’s IOP may be 
of concern. If subjects are treated with a topical CAI in the week before Visit 2 
(Week -8, start of the Run-in Period), Visit 1a (optional, mid washout visit) is 
recommended to be performed. 
 Subjects who have not used an IOP-lowering medication for the last 28 days, will 
need a wait period of ≥ 1 day before their Visit 2 (Week -8, start of the Run-in 
Period). 


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 If a subject does not require washout from an IOP-lowering medication, but they 
use contact lenses in either eye, they will need a wait period of ≥ 2-3 weeks (2 
weeks for soft contact lens wearers, and 3 weeks for rigid contact lens wearers) 
with no contact use before their Visit 2 (Week -8). 
 Schedule the eligible subject to return for Visit 2 (Week -8) 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 1a (optional, mid-washout visit) 
 Visit 1a is an interim safety visit (referred to as mid-washout visit) that may be 
performed during the washout period if, in the Investigator’s opinion, a subject’s IOP 
causes any safety concern. If subjects are treated with a topical CAI in the week 
before Visit 2 (Week -8, start of the Run-in Period), Visit 1a (optional, mid-washout 
visit) is recommended to be performed. 
 Update concomitant medications and procedures/therapies. 
 Query the subject regarding AEs. 
 Perform the following procedures or assessments (all ophthalmic procedures to be 
performed in both eyes): 
 BCVA (before IOP measurement) 
 Biomicroscopy (before IOP measurement) 
 IOP 
7.4.3. 
Visit 2 (Week -8, start of the Run-in Period) 
 Confirm the subject has complied with the required wait/washout period for ocular 
hypotensive medication(s), or contact lenses use, if required. 
 Update concomitant medications and procedures/therapies. 
 Query the subject regarding AEs. 
 Perform the following procedures or assessments immediately before the 08:00  
(± 60 min) IOP measurement (all ophthalmic procedures to be performed in both 
eyes): 
 BCVA 
 If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Biomicroscopy 
 Perform IOP measurement at 08:00 (±60 min). 
 If subject meets the 08:00 (±60 min) IOP eligibility requirements, schedule additional 
IOP measurements at 12:00 (±60 min). 


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 Perform IOP measurement at 12:00 (±60 min). 
 If subject meets the 08:00 and 12:00 (±60 min) IOP eligibility requirements, schedule 
additional IOP measurements at 16:00 (±60 min). 
 Perform IOP measurement at 16:00 (±60 min). 
 Perform final review of eligibility criteria after the 16:00 (±60 min) IOP measurement. 
 If the subject meets all eligibility criteria upon completion of the above procedures 
and assessments, the subject will be assigned a treatment kit via Interactive Response 
Technology. A study staff member will: 
 Dispense one (1) bottle of latanoprost ophthalmic solution 0.005% from the 
assigned kit to the subject 
 Give the subject verbal and written instructions for proper instillation of the study 
medication, the dosing regimen, and study medication storage.  
 Schedule the subject to return for Visit 3 (Week -4, midpoint of the Run-in Period) 
 Inform the subjects they will be reminded of the evening instillation of the study 
medication the day before Visit 3 through a phone call.  
 Remind the subject to bring all study medication at Visit 3 (Week -4, midpoint of the 
Run-in Period).  
 A subject who does not meet eligibility criteria or will not otherwise continue in the 
study is considered a screen failure. 
7.4.4. 
Visit 3 (Week -4, midpoint of the Run-in Period) 
 Update concomitant medications and procedures/therapies. 
 Collect study medication 
 Query the subject regarding dosing compliance.  
 Query the subject regarding AEs. 
 Perform the following procedures or assessments immediately before the 08:00 (± 60 
min) IOP measurement (all ophthalmic procedures to be performed in both eyes): 
 BCVA  
 If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Biomicroscopy   
 Perform IOP measurement at 08:00 (±60 min). 
 If subject meets the 08:00 (±60 min) IOP eligibility requirements, schedule additional 
IOP measurements at 12:00 (±60 min). 
 Perform IOP measurement at 12:00 (±60 min). 


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 If subject meets the 08:00 and 12:00 (±60 min) IOP eligibility requirements, schedule 
additional IOP measurements at 16:00 (±60 min). 
 Perform IOP measurement at 16:00 (±60 min). 
 Determine if subject meets eligibility criteria after the 16:00 IOP measurement.  
 If the subject meets all eligibility criteria upon completion of the above procedures 
and assessments, the subject will be assigned a treatment kit via Interactive Response 
Technology. A study staff member will:   
 Dispense one (1) bottle of latanoprost ophthalmic solution 0.005% from the 
assigned kit to the subject 
 Give the subject verbal and written instructions for proper instillation of the study 
medication, the dosing regimen, and study medication storage.  
 Schedule the subject to return on Visit 4 (Baseline, Day 1). 
 
Inform the subjects they will be reminded of the evening instillation of the study medication 
the day before Visit 4 through a phone call.  
 Remind the subject to bring all study medication at Visit 4 (Baseline, Day 1). 
 A subject who does not meet eligibility criteria or will not otherwise continue in the 
study is considered a screen failure. 
7.4.5. 
Visit 4 (Baseline, Day 1) 
 Update concomitant medications and procedures/therapies. 
 Collect study medication  
 Query the subject regarding dosing compliance.  
 Query the subject regarding AEs. 
 Obtain urine and perform urine pregnancy test, if the subject is female of child-
bearing potential. 
 Perform the following procedures or assessments immediately before the 08:00 (±60 
min) IOP measurement (all ophthalmic procedures to be performed in both eyes): 
 BCVA   
 If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Biomicroscopy   
 Perform IOP measurement at 08:00 (±60 min). 
 If subject meets the 08:00 IOP eligibility requirements, schedule additional IOP 
measurements at 12:00 (±60 min). 
 Perform IOP measurement at 12:00 (±60 min). 


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 If subject meets the 08:00 and 12:00 (±60 min) IOP eligibility requirements, schedule 
additional IOP measurements at 16:00 (±60 min). 
 Perform IOP measurement at 16:00 (±60 min). 
 Perform ophthalmoscopy in both eyes immediately after the 16:00 (±60 min) IOP 
measurement. 
 Perform iris color, eyelash, eyelid assessment at any time during this visit, with sets 
of front view and side view photographs of each eye individually. The following six 
(6) photos are required at this visit as follows: 
 Perform final review of eligibility criteria after the 16:00 (±60 min) IOP 
measurement. A subject who does not meet eligibility criteria or will not otherwise 
continue in the study is considered a screen failure. 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 enrolled in the study, via 
Interactive Response Technology. 
 The study eye will be the eye that qualifies per eligibility criteria at Visit 4 
(Baseline, Day 1). If both eyes meet the eligibility criteria, the eye with the higher 
mean diurnal IOP at Visit 4 (Baseline, Day 1) will be designated as the study eye. 
If both eyes meet the eligibility criteria and have the same mean diurnal IOP, the 
right eye will be designated as the study eye.  
 After the subject has been enrolled and assigned a treatment kit through the 
Interactive Response Technology, a study staff member must: 
 Dispense two (2) bottles of study drug DE-117 ophthalmic solution 0.002% from 
the assigned kit to the subject  
 Give the subject verbal and written instructions for proper instillation of the study 
medication, the dosing regimen, and study medication storage.  
 Schedule the subject to return on Day 15 ± 3 for Visit 5 (Week 2). 


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 Inform the subjects they will be reminded of the evening instillation of the study 
medication the day before Visit 5 through a phone call.  
7.4.6. 
Visit 5 (Week 2, Day 15 ± 3)  
 Update concomitant medications and procedures/therapies. 
 Query the subject regarding dosing compliance. 
 Query the subject regarding AEs. 
 Perform the following procedures or assessments immediately before the 08:00 (±60 
min) IOP measurement (all ophthalmic procedures to be performed in both eyes): 
 BCVA   
 If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
Biomicroscopy   
 Perform IOP measurement at 08:00, 12:00, and 16:00 (±60 min). 
 If the subject provided written consent to provide a blood sample for a future 
pharmacogenomics/genomics laboratory research study, the sample may be collected 
at this visit or at future visits. 
 Remind the subject of proper instillation of the study medication, the dosing regimen, 
and study medication storage.  
 Inform the subjects they will be reminded of the evening instillation of the study 
medication the day before Visit 6 through a phone call.  
 Schedule the subject to return on Day 43 ± 5 for Visit 6 (Week 6). 
 Remind the subject to bring all study medication at Visit 6. 
7.4.7. 
Visit 6 (Week 6, Day 43 ± 5) 
 Update concomitant medications and procedures/therapies. 
 Collect study medication. 
 Query the subject regarding dosing compliance.  
 Query the subject regarding AEs. 
 Perform the following procedures or assessments immediately before the 08:00 (±60 
min) IOP measurement (all ophthalmic procedures to be performed in both eyes): 
 BCVA   
 If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Biomicroscopy   
 Perform IOP measurement at 08:00, 12:00, and 16:00 (±60 min). 


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 If the subject provided written consent to provide a blood 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. 
 Dispense two (2) bottles of study drug DE-117 ophthalmic solution 0.002% from the 
assigned kit to the subject  
 Give the subject verbal and written instructions for proper instillation of the study 
medication, the dosing regimen, and study medication storage.  
 Schedule the subject to return on Day 91 ± 7 for Visit 7 (Month 3). 
 Inform the subjects they will be reminded of the evening instillation of the study 
medication the day before Visit 7 through a phone call.  
 Remind the subject to bring all study medication at Visit 7. 
7.4.8. 
Visit 7 (Month 3, Day 91 ± 7) Study Exit/Early Termination 
 Update concomitant medications and procedures/therapies. 
 Collect all study medication. 
 Query the subject regarding dosing compliance.  
 Query the subject regarding AEs. 
 Obtain urine and perform urine pregnancy test, if the subject is female of child-
bearing potential. 
 Perform the following procedures or assessments immediately before the 08:00 (±60 
min) IOP measurement (all ophthalmic procedures to be performed in both eyes): 

BCVA   

If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 

Biomicroscopy   
 Perform IOP measurement at 08:00, 12:00, and 16:00 (±60 min). 
 Assess any changes from baseline in iris color, eyelash, eyelid and take front view 
and side view photographs of each eye individually. The following six (6) photos are 
required at this visit as follows: 


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 Perform pupil dilation in both eyes after the 16:00 (±60 min) IOP measurement. 
 Perform ophthalmoscopy with pupil dilation in both eyes immediately after the 16:00 
IOP measurement. 
 If the subject provided written consent to provide a blood sample for a future 
pharmacogenomics/genomics laboratory research study, the sample must be collected 
at this visit, if not collected at the previous visits. 
 Exit the subject from the study. 
Note: If a subject’s study participation is terminated prior to Visit 7, then, to the extent 
possible, all scheduled Visit 7 procedures will be performed at the earliest visit or on the 
day of early termination. 
Note: If subject requires an unscheduled visit, procedures and assessments will be 
performed as needed. 
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 Section 8.1 and 
Section 8.2. 
8.1. 
Subject Inclusion Criteria 
At Visit 1 (Screening, start of the Washout Period), the subject must meet all of the following 
inclusion criteria: 
1. Provide signed written informed consent on the Institutional Review Board (IRB)/Ethics 
Committee (EC) approved Informed Consent Form (ICF). 
2. Be 18 years of age or older on the date of signing the ICF and be able and willing to 
comply with all treatment and follow-up study procedures. 
3. If a subject is female of childbearing potential (i.e., not post-menopausal [within 12 
months since the last menses] or not surgically sterile [less than 6 months from date of 
surgery]), subject must have a negative urine pregnancy test and must use at least one of 
the following acceptable contraceptive methods during the study (as well as for 4 weeks 
following last dose in study). 
 Abstinence 
 Hormonal contraceptive method (including oral or transdermal contraceptives, 
injectable progesterone, progestin subdermal implants, progesterone-releasing 
intrauterine devices [IUDs]) initiated at least 28 days prior 
 Placement of a copper-containing IUD 
 Condom with spermicidal foam/gel/film/cream/suppository 
 Vasectomized male partner (surgery at least 6 months prior)  
Male subjects capable of fathering children should use or practice an acceptable 
contraceptive method, such as abstinence, condom or vasectomy (surgery at least 6 
months prior) or other contraceptive method deemed adequate by the investigator 
throughout the course of the study (as well as for 12 weeks following last dose in study). 
4. Must have a diagnosis of POAG or OHT in both eyes, or one eye with POAG and the 
other with OHT. 
5. BCVA of +0.60 logMAR (Snellen equivalent 20/80) or better in each eye. 
6. Central corneal thickness ≥ 480 m and ≤ 600 m in each eye. 
7. Anterior chamber angle grade ≥ 2 (Shaffer scale) in each eye. 
At Visit 2 (Week -8, start of the Run-in Period), the subject must meet the following criteria: 
8. Completed the required wait/washout period. 
9. At all time points of IOP measurements (08:00, 12:00 and 16:00 ±60 min), have IOP of  
≥ 22 mmHg in at least one eye (the same eye), and ≤ 34 mmHg in both eyes. 


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At Visit 3 (Week -4, midpoint of the Run-in Period) the following IOP criteria have to be met: 
10. Percent decrease in IOP from Visit 2 (Week -8, start of the Run-in Period) of ≤ 25% at all 
measurement time points in the eye meeting criteria at Visit 2 (Week -8, start of the Run-
in Period). 
11. IOP in both eyes ≤ 34 mmHg at all measurement time points. 
At Visit 4 (Baseline, Day 1) the following IOP criteria have to be met: 
12. Percent decrease in IOP from Visit 2 (Week -8, start of the Run-in Period) of ≤15% at all 
measurement time points in the eye meeting criteria at Visit 3 (Week -4, midpoint of the 
Run-in Period). 
13. IOP in both eyes ≤34 mmHg at all measurement time points.  
8.2. 
Subject Exclusion Criteria 
From Visit 1 (Screening) to Visit 4 (Baseline, Day 1), subjects 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 4 weeks prior to Visit 1 (Screening) or at any time during this 
trial. 
4. Subjects who have been exposed to DE-117 prior to Visit 1 (Screening). 
Medications / Therapies 
5. Usage of more than two active ingredients to lower IOP prior to Washout Period. 
6. Intended or current use of the following prohibited medications/therapies during the 
study: 
 All ocular medications other than: sodium chloride/potassium chloride ophthalmic 
solution; cataract treatment agents (e.g., glutathione, pirenoxine); Vitamin B12 
formulation (e.g., cyanocobalamine); over-the-counter dry eye artificial tears/drops; 
and study medications. 
 All systemic medications for ocular hypotensive (e.g., oral or intravenous CAI, oral 
glycerol). 
 Any ocular, periocular, inhaled, nasal or systemic corticosteroids including joint 
injection, etc. 
 Lacrimal/punctal occlusion via plug (s) or cautery.  
7. Subjects who cannot safely discontinue use of ocular hypotensive medications during the 
wait/washout period. 


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8. Subjects who will be required to initiate or modify any systemic or topical medication 
known to affect IOP (e.g., β-adrenergic antagonists, α-adrenergic agonists, calcium 
channel blockers, angiotensin-converting enzyme [ACE] inhibitors, and angiotensin II 
receptor blockers [ARB]). Subjects using the above medications must have a stable dose 
use for at least 30 days prior to Visit 1 (Screening) and throughout the study. 
9. Use of contact lenses within 2-3 weeks prior to Visit 2 (Week -8, start of the Run-in 
Period) until end of treatment in either eye (2 weeks for soft contact lens wearers, and 3 
weeks for rigid contact lens wearers). 
10. Any ocular surgery or ocular laser treatment within 180 days prior to Visit 1 (Screening) 
and throughout the study in either eye. 
11. History of ocular surgery specifically intended to lower IOP (e.g., laser trabeculoplasty, 
filtering surgery, tube shunt, Minimally Invasive Glaucoma Surgery (MIGS), or 
trabeculotomy) in either eye. 
12. History of keratorefractive surgery (e.g., Radial Keratotomy [RK], Refractive 
Keratectomy [PRK], Laser-Assisted-in-Situ Keratomileusis [LASIK]) in either eye.  
13. Allergy, hypersensitivity or contraindications to latanoprost, EP2 receptor agonists, 
benzalkonium chloride (BAK) or any other components of the study medications, or 
other study related procedures/medications. 
Diseases 
14. Presence of advanced glaucoma (e.g., visual field mean deviation worse than -12 dB) in 
either eye. 
15. Presence of any corneal abnormality or other conditions interfering with or preventing 
reliable Goldmann applanation tonometry (e.g., Fuch’s dystrophy or significant corneal 
surface abnormality) in either eye. 
16. Presence of any active severe external ocular disease, inflammation, or infection of the 
eye and/or eyelids in either eye. 
17. Presence or history of macular edema or known risk factors for macular edema in either 
eye. 
18. History of severe ocular trauma in either eye. 
19. History of iritis and/or uveitis, 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. 
20. History of retinal detachment, proliferative diabetic retinopathy, or any retinal disease 
that may be progressive during the time course of the study in either eye. 
21. Presence or history of any disease or condition that in the opinion of the study 
Investigator may put the subject at significant risk, may confound study results, or may 
interfere significantly with the subject’s participation in the study (e.g., recurrent corneal 
erosion syndrome, uncontrolled cardiovascular disease etc.). 


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22. Any decision by the Investigator or Medical Monitor to terminate a subject in screening 
or declare any subject ineligible for any sound medical reason. 
8.3. 
Subject Withdrawal Criteria 
An early termination occurs when a subject who provides written informed consent ceases 
participation in the study after enrollment (Visit 4 Baseline [Day 1]), regardless of 
circumstances, and before the completion of the study. Subjects may be voluntarily discontinued 
from study medication or withdrawn from the study at any time for any reason. In addition, the 
Principal Investigator or Medical Monitor may discontinue the study drug administration or 
terminate a subject’s study participation due to any of the following reasons: 
 AE (e.g., not compatible with study continuation) 
 Non-compliance with study drug 
 Lack of efficacy (e.g., IOP exceeds 34 mmHg in either eye after enrollment) 
 Progressive disease 
 Protocol deviation (e.g., not fulfilling eligibility criteria) 
 Pregnancy 
 Voluntary withdrawal by subject at any time for any reason 
 Lost to follow-up (e.g., no contact is possible) 
 Death 
 Other 
If DE-117 study drug administration is discontinued prior to last scheduled visit, Visit 7, the 
subject should be encouraged to continue participating in all remaining follow-up study 
visits/procedures on an observational basis.  
If subject participation is terminated prior to Visit 7, then to the extent possible, all Visit 7 
procedures will be performed on the day of early termination or at the earliest opportunity 
possible. Subjects who are terminated from the study early will not be replaced. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Medication 
DE-117 ophthalmic solution 0.002% is an aqueous solution containing DE-117. Benzalkonium 
chloride 0.005% is added as a preservative. 
 
Figure 2: 
DE-117 Structure 
 
Investigational Product: 
 DE-117 ophthalmic solution 0.002% contains 0.02 mg/mL DE-117 
Product to be used during Run-in Period: 
 Latanoprost ophthalmic solution 0.005% (Greenstone®) contains the active ingredient, 
latanoprost 0.05 mg/mL. See Section 21.5. 
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 besides the study medication during the study duration will be 
considered as a concomitant treatment. The information of concomitant treatment must be 
recorded in the subject’s source documents and on the eCRF.  
 Concomitant medication: name of medication, route of administration, treated eye(s) 
(if applicable), dose, frequency, indication, start date and stop date. 
 Concomitant therapy: name of therapy, treated eye(s) (if applicable), indication, start 
date and stop date. 
9.2.1. 
Prohibited Medications or Therapies 
 All ocular medications other than: sodium chloride/potassium chloride ophthalmic 
solution; cataract treatment agents (e.g., glutathione, pirenoxine); Vitamin B12 


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formulation (e.g., cyanocobalamine); over-the-counter dry eye artificial tears/drops; 
and study medications during the study duration. 
 If artificial sodium chloride/potassium chloride ophthalmic solution; cataract 
treatment agents; Vitamin B12 formulation; over-the-counter dry eye artificial 
tears/drops are concomitantly used, there must be an interval of at least 5 
minutes between use of these ocular medications and use of the study medication. 
 All systemic medications for ocular hypotensive (e.g., oral or intravenous CAI, oral 
glycerol) during the study duration. 
 Any ocular, periocular, inhaled, nasal or systemic corticosteroids including joint 
injection, etc. during the study duration. 
 Lacrimal/punctal occlusion via plug (s) or cautery during the study duration.  
 Initiate or modify any systemic or topical medication known to affect IOP (e.g.,  
β-adrenergic antagonists, α-adrenergic agonists, calcium channel blockers, ACE 
inhibitors, and ARB) within the first 30 days prior to Visit 1 (Screening) and during 
the study duration. 
 Contact lenses within 2-3 weeks prior to Visit 2 (Week -8, start of the Run-in Period) 
until end of treatment in either eye (2 weeks for soft contact lens wearers, and 3 
weeks for rigid contact lens wearers). 
 Any ocular surgery or ocular laser treatment within 180 days prior to Visit 1 
(Screening) and throughout the study in either eye. 
 Participation in any other clinical trial involving an investigational product within 
4 weeks prior to Visit 1 (Screening) and during the study. 
The decision to administer a prohibited medication or therapy should be made with the safety of 
the subject as the primary consideration. Whenever possible, Medical Monitor should be notified 
before any prohibited medication or therapy is administered. There may be additional prohibited 
therapies not mentioned above. Medical Monitor should be contacted if the permissibility of a 
specific medication or therapy is in question. 
9.3. 
Treatment Compliance 
To obtain reliable efficacy and safety data, the following precautions will be taken to ensure 
compliance with the treatment regimen during the study: 
 Subjects will receive verbal and written instructions for proper instillation of the 
study medication, the dosing regimen, and the conditions of the study medication 
storage.  
 Subjects will be reminded at study visits to consistently dose at the same time of the 
day. 
 once daily at 20:00 [±60min] through Visit 2 to 7.  


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 Subjects will be reminded of the evening instillation of the study drug on the days 
before Visit 3 (Week -4, midpoint of the Run-in Period) through Visit 7/Early 
Termination respectably. 
 Since subjects must have a diagnosis of POAG or OHT in both eyes, both eyes should 
be treated for the duration of the study, even if only one eye is eligible per IOP 
inclusion criteria. 
 Subjects will be queried regarding compliance with the protocol’s dosing regimen at 
Visit 3 (Week -4, midpoint of the Run-in Period) through Visit 7/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 
(Week -4, midpoint of the Run-in Period) through Visit 7/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 
This is an open label study; masking will not be applied. There will be no randomization for this 
study.  


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10.
STUDY MEDICATION MATERIALS AND MANAGEMENT 
10.1.
Study Medication 
10.1.1.
Investigational Product 
DE-117 ophthalmic solution contains 0.002% DE-117. Each 2.5 mL bottle of DE-117 
ophthalmic solution 0.002% contains 50 μg of DE-117. In addition,
10.1.2.
Product to be used during Run-in Period 
The product to be used during the Run-in Period, latanoprost ophthalmic solution 0.005%, is 
supplied as a sterile, isotonic, buffered aqueous solution. 
Latanoprost ophthalmic solution 0.005% contains the active ingredient, latanoprost 0.05 mg/mL 
and the preservative BAK 0.02%. The inactive ingredients are: sodium chloride, sodium 
dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, and water for 
injection. The latanoprost solution has a pH of approximately 6.7 and an osmolality of 
approximately 267 mOsmol/kg. See Section 21.5. 
10.2.
Study Medication Packaging and Labeling 
DE-117 ophthalmic solution 0.002% will be supplied as 
 Each DE-117 eye drop bottle will be placed in a unit carton. Four 
eye drop bottles/unit cartons of study medication will be placed in one kit. The eye drop bottles, 
unit cartons, and the kit will be labeled with the protocol number, kit number, storage conditions, 
and dosing instructions. 
Latanoprost ophthalmic solution 0.005% will be supplied as a 2.5 mL solution in a 5 mL clear 
low density polyethylene bottle with a clear polyethylene dropper tip, a turquoise high density 
polyethylene screw cap, and a tamper-evident clear low density polyethylene overcap. Each 
latanoprost eye drop bottle will be in a unit carton, consistent with commercial packaging. The 
unit carton will be labeled with the protocol number and kit number. 
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 8°C (36° to 46°F), protected from 
light and stored upright. During the refrigeration storage, the Investigator (or his/her designee) 


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will verify and record that the temperature was maintained at 2° to 8°C (36° to 46°F) using 
temperature recorder at least once every seven days at the investigational site, until the last 
subject has exited the study at the site. In the event of a temperature excursion or any study 
medications damaged during storage, the Investigator (or his/her designee) will notify Santen (or 
designee) and will not dispense the study medications until obtaining authorization from Santen 
(or designee). 
Subjects will be reminded to store all dispensed eye drop bottles under refrigeration, protected 
from light and kept in unit cartons in an upright position. Study medications should not be 
frozen. 
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 20:00 (±60min) 
daily for a total of 5 months. During the 8-Week Latanoprost Run-in Period, subjects will dose 
with one drop of latanoprost ophthalmic solution 0.005% every evening at 20:00 (±60min) in 
both eyes. During the 3-month Open-Label Treatment Period, subjects will dose one drop of  
DE-117 ophthalmic solution 0.002% every evening at 20:00 (±60min) in both eyes. 
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 
8°C (36° to 46°F) during transit. In the event of a temperature excursion or any study 
medications damaged during transit, the Investigator (or his/her designee) will notify Santen (or 
designee) and will not dispense the study medications until obtaining authorization from Santen 
(or designee). The receipt of clinical supplies form should be completed, signed, dated, and 
returned as directed. A copy must be maintained at the site for the Investigator’s records.  
The Investigator (or his/her designee) will keep a current record of the inventory, storage 
conditions and dispensing of all study medications. This record will be made available to Santen 
(or designee) for the purpose of accounting for all clinical supplies. Any significant discrepancy 
and/or deficiency must be recorded with an explanation. 
All supplies sent to the investigational site must be accounted for and in no case will study 
medications be used in any unauthorized situation. It is the responsibility of the Investigator to 
ensure that any used and unused supplies are available to Santen (or designee) for accountability 
purposes throughout the study. 
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 


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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 and customized blood 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 IOP (mmHg) measured in the study eye (identified at the baseline visit) is the efficacy 
measure for this study. The IOP at each scheduled time point (08:00, 12:00 and 16:00 ±60 min) 
will be evaluated at each post-baseline visit. Besides observed IOP measurements, change from 
baseline in IOP, and percent changes from baseline in IOP at each scheduled time point as well 
as the change from baseline in mean diurnal IOP will also be derived 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 medication. For this study, the 
investigational products are DE-117 and latanoprost. Regardless of relationship to the study 
medication, an AE can be a clinically relevant unintended sign (including an abnormal laboratory 
finding), symptom, or disease.  
Any significant change in a subject’s condition from the time that written informed consent is 
obtained, regardless of causality, is to be considered an AE. A clinically significant worsening in 
severity, intensity, or frequency of a pre-existing condition may indicate an AE. 
An elective surgical procedure scheduled or planned prior to study entry that does not require 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 a serious adverse event (SAE). 
The lack of efficacy of the study medication for the condition being investigated is not 
considered an AE unless a clinically significant change is assessed by the Investigator. 
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. 
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) 


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mechanisms of action e) biologic plausibility f) confounding risk factors (i.e., medical history, 
concomitant medications) g) temporal relationship h) dechallenge/rechallenge and i) lack of 
alternative explanation. 
 The event may be recorded as Related to investigational product 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 subject withdrawal or the scheduled exit visit, must be 
recorded. To improve the quality and precision of acquired AE data, Investigators should 
observe the following guidelines: 
 Whenever possible, use recognized medical terms when recording.  Do not use 
colloquialisms and/or abbreviations. 
 If known, record the diagnosis (i.e., disease or syndrome) rather than component 
signs and symptoms and /or laboratory or test findings (e.g., record congestive heart 
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). 


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 If the diagnosis is not known, then record the leading component sign, symptom or 
test finding and describe the other clinically related findings in the narrative 
description of the case. A suspected diagnosis can be used and described as such (e.g., 
record suspected or probable myocardial infarction); this has to be updated in the 
clinical database once the diagnosis is confirmed.  
AEs occurring secondary to other events (e.g., sequelae) should be identified by the 
primary cause. A primary AE, if clearly identifiable, generally represents the most 
accurate clinical term.  If a primary AE is recorded, events occurring secondary to the 
primary event should be described in the narrative description of the case. For 
example: 
The subject developed orthostatic hypotension and subsequently fainted and fell to 
the floor wherein she experienced a head trauma and neck pain. 
The primary AE in this example is orthostatic hypotension. The fall, head trauma and 
neck pain should be described in the narrative description of the case.  
 For intermittent events (e.g., intermittent headache), the event onset date should be 
recorded as the date the subject first started to experience the event and resolution 
date should reflect when the last occurrence resolved or stopped.  Separate AEs for 
each event should not be recorded. For example, if a subject experienced headache on 
14SEP2015 lasting for three hours, then subsequently experienced intermittent 
episodes of headache every day for approximately 3 hours until 21SEP2015, then the 
AE date of onset is 14SEP2015 and the resolution date is 21SEP2015. 
 For intermittent events, record the maximum severity of the individual events.  For 
example, if a subject complains of intermittent headaches for one week and the 
severity of each headache ranges from mild to moderate, then the severity would be 
moderate. 
 For intermittent hospitalizations occurring for a primary AE (e.g., in a subject with 
multiple sclerosis, commonly known for its relapsing and remitting course, in some 
cases leading to multiple hospital confinements), the subsequent hospitalizations 
should be described in the narrative description of the case. 
 If treatment was initiated, include the treatment and duration of the medication(s) in 
the eCRF. 
12.1.2. 
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: 
 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). 


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 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. 
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. 
Events of Special Interest 
The following are considered events of special interests (ESIs) and should be reported on the 
appropriate eCRF with as much information as available within 24 hours of knowledge of the 
event:  
 Pregnancy: 
 There are no controlled data with the investigational product in human pregnancy. 
It is required that females of childbearing potential use effective contraception 
during the study and recommended for 4 weeks for female subjects of 
childbearing potential and 12 weeks for male subjects capable of fathering 
children after the completion of the study. Any pregnancy occurring during study 
treatment should be reported and the subject will be discontinued from the study. 
The subject should be followed until the end of pregnancy or until the end of the 
study, whichever is longer.   


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 Medication administration errors 
 Study medication administration errors determined to be significant by the 
Investigator will be reported and evaluated as ESIs. Examples of study medication 
administration errors may include, but are not limited to: incorrect dose of study 
medication and administration of study medication from an incorrect kit. An AE 
does not necessarily need to have occurred to count as a study medication 
administration error. A medication administration error is an unintended failure in 
the process of treatment with a medicinal product that leads to, or has the 
potential to lead to harm of the subject. 
 Macular edema (including cystoid macular edema):  
 Macular edema has been reported in some patients during the DE-117 clinical 
trials. Any cases of macular edema (including cystoid macular edema) should be 
reported in the ESI form in eCRF, or in case the electronic data capture (EDC) 
system is down, in the manual ESI form. Any cases of macular edema (including 
cystoid macular edema) will need to be followed until the event is determined to 
be resolved, irreversible, chronic, stable, the subject withdraws consent, or no 
further information can be reasonably obtained as per Section 12.1.4.   
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 with the following types of events should be followed by the Investigator 
until the event is determined to be resolved, irreversible, chronic, stable, the subject withdraws 
consent, or no further information can be reasonably obtained.  
 On-going SAEs issued after study medication treatment 
 On-going ESIs, including pregnancy, medication errors resulting in AE’s, and 
macular edema/cystoid macular edema issued after study medication treatment 
 Early termination and withdrawal from the study due to study medication related AEs 
In addition, on a case by case basis, Santen (or designee) may request follow up beyond the 
scheduled exit visit. 
The follow-up information on an individual SAE or AE (or ESI) will be entered into the eCRF 
prior to database lock. If the information requested by Santen is not part of the eCRF, or when 
database lock has already been completed, the site’s response to follow-up requests should be 
emailed to globalPVAmericas@santen.com or reported in writing and fax to +1-415-276-5882 
(in the US).  
12.1.5. 
Manual Back-Up Reporting Procedures 
This study is utilizing an EDC system for data entry. In the event that the EDC system is 
unavailable for electronic reporting, the manual back-up reporting procedures below should be 
followed. 
 Complete an AE Form, SAE Form, pregnancy Form, medication error Form, or ESI 
Form as appropriate. 


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 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 globalPVAmericas@santen.com or fax number +1-415-276-5882 (in the 
US). 
When the EDC system becomes available, the EDC system should be updated with all 
previously reported information. 
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: 
 BCVA 
 Slit-lamp biomicroscopy findings: anterior chamber cells, anterior chamber flare, lid 
hyperemia, lid edema, conjunctival hyperemia, conjunctival chemosis, corneal 
edema, corneal staining, keratic precipitates, lens, anterior synechiae of iris, posterior 
synechiae of iris 
 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, baseline characteristics, medical history, concomitant medications, 
exposure to study medication, and pregnancy test for females of childbearing potential will be 
summarized. 


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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. 
Interim Analysis 
There is no planned interim analysis for this study. 
14.2. 
Final Analysis 
The final analysis will be performed after all subjects completed Month 3 (Visit 7). The analysis 
will evaluate the efficacy and safety of DE-117 ophthalmic solution 0.002% once daily in 
latanoprost low/non-responders.  
14.3. 
General Considerations 
Descriptive statistics, unless otherwise noted, will include the number of subjects (n), mean, 
standard deviation, median, minimum, and maximum for continuous variables and frequency and 
percentage for categorical variables. 
The study eye will be defined as the eye that qualifies per eligibility criteria at Baseline (Visit 4). 
If both eyes qualify, the eye with the higher mean diurnal IOP at baseline will be the study eye. 
If both eyes have the same mean diurnal IOP at baseline, then the right eye will be designated as 
the study eye. 
The statistical testing will be conducted at a significance level of 0.05 (two-sided) and the 95% 
confidence interval will be shown, unless specified otherwise.  No statistical testing will be 
conducted for safety measures. 
More details on the statistical methods will be described in the SAP. 
14.3.1. 
Sample Size 
Using one sample t-test with a significance level of 5%, a sample size of 150 will have 90% 
power to detect a mean diurnal IOP reduction of 1.0mmHg from baseline with a standard 
deviation of 3.5 mmHg, after taking into account of up to 12% dropouts. 
14.3.2. 
Statistical Hypotheses and Level of Significance 
The primary endpoint (the mean diurnal IOP change from baseline at Month 3) will be evaluated 
according to the following testing hypotheses: 
H0: µi = µj 
versus 
H1: µi ≠ µj 
where µi and µj  are the mean diurnal IOP at Baseline and Month 3, respectively.    


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Paired t-test will be used to compare the difference in diurnal IOP between Baseline (Visit 4) and 
Month 3 (Visit 7). The mean difference in diurnal IOP will be reported along with 95% 
confidence intervals.   
14.4. 
Study Populations 
14.4.1. 
Safety Population 
The Safety Population will include all subjects who signed informed consent, met the eligibility 
criteria at baseline, and received at least one dose of the study medication. The safety analysis 
will be performed on the Safety Population. 
14.4.2. 
Full Analysis Set 
The Full Analysis Set (FAS) will include all Safety population who had at least one post-baseline 
IOP measurement. The efficacy analysis will be performed on the FAS or a subset of the FAS. 
14.4.3. 
Per-Protocol Set 
The Per-Protocol Set (PPS) is a subset of the FAS, restricted to the subjects who fulfill the 
protocol in the terms of the eligibility, interventions, and outcome assessment. It will be the 
analysis population for some sensitivity analyses. More details will be provided in the SAP.  
14.5. 
Handling of Missing Values 
The primary analysis of IOP will be based on observed cases. As a sensitivity analysis, missing 
IOP data at Month 3 will be imputed by last observed post-baseline IOP. Sensitivity analyses 
using other imputation methods may be performed and detailed in the SAP.  
For medical events including AEs and medical history, completely or partially missing onset and 
resolution dates will be imputed in a conservative fashion. Same rules will be followed to impute 
the completely or partially missing start and end dates of non-study medications. 
Additional details on handling of missing data will be provided in the SAP. 
14.6. 
Demographic and Baseline Characteristics 
Age, sex, race, ethnicity, iris color, and baseline IOP will be summarized with descriptive 
statistics. 
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 (SOC) and Preferred Term (PT) specified in the MedDRA. 
Subjects using any prior medications that has been used for OAG or OHT within 28 days before 
Visit 1 (Screening) will be tabulated by Anatomical Therapeutic Chemical (ATC) levels, and PT 
specified in the latest version of World Health Organization Drug Dictionary Enhanced (WHO-
DDE, 2011). 


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14.7. 
Efficacy Analyses  
14.7.1. 
Analysis of Primary Efficacy Endpoint  
The primary efficacy endpoint is the change from baseline in mean diurnal IOP at Month 3 (Visit 7).  
The primary analysis will be performed on the FAS. Paired t-test will be used to compare the difference 
in diurnal IOP between Baseline (Visit 4) and Month 3 (Visit 7). The mean difference in diurnal IOP will 
be reported along with the 95% confidence intervals.   
14.7.2. 
Analysis of Secondary Efficacy Endpoints 
14.7.2.1. Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be analyzed:  
 Percent change from baseline in mean diurnal IOP at Month 3 (Visit 7) 
 Change and percent change from baseline (Visit 4) in mean diurnal IOP at Week 2 
(Visit 5) and 6 (Visit 6) 
 Change and percent change from baseline in IOP for each post-baseline 
timepoint/visit 
 Having a mean diurnal IOP reduction ≥ 10%, ≥ 15%, ≥ 20%, ≥ 25%, or ≥ 30% from 
baseline (Visit 4) at Month 3 (Visit 7) 
 Having a mean diurnal IOP ≤ 18 mmHg at Month 3 (Visit 7) 
For change and percent change in mean diurnal IOP from baseline, descriptive statistics will be 
provided including the number of subjects (n), mean, standard deviation, median, minimum and 
maximum. For binary secondary efficacy endpoints, results will be tabulated using frequencies 
and percentages. 
14.8. 
Safety Analyses 
All safety outcome measures will be summarized descriptively for the Safety Population. The 
safety outcome measures include AEs, BCVA, slit-lamp biomicroscopy findings, 
ophthalmoscopy variables, and iris color, eyelash, eyelid. 
AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). Subjects with any AEs will be tabulated by primary SOC and PT specified in the 
MedDRA. Similarly, subjects with any ocular and non-ocular AEs will be tabulated separately. 
AEs, ocular and non-ocular will also be summarized by relationship to study drug and maximum 
severity. In addition, SAEs and AEs leading to discontinuations will be summarized. More 
details will be provided in the SAP.  
Safety parameters listed in Section 12.2.1 will be summarized using descriptive statistics. 
Changes from baseline in these ocular safety parameters will also be summarized. 


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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 IRB or IEC and other applicable regulatory agencies to inspect all study records, 
eCRFs, recruitment materials and corresponding portions of the subject’s medical records at 
regular intervals throughout the study. These inspections are for the purpose of verifying 
adherence to the protocol, completeness, and exactness of the data being entered onto the eCRF, 
and compliance with the 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 IRB or IEC. 
 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. 


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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 Santen (or designee) should the site 
be audited or inspected by the governing IRB or IEC, and applicable regulatory agencies. Santen 
(or designee) will also notify the investigational site of any known pending site audits or 
inspections planned by Santen (or designee), governing IRB or IEC and regulatory agencies. 
15.3. 
Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) 
The Principal Investigator must obtain IRB/IEC approval for the study. Initial IRB/IEC approval, 
and all materials approved by the IRB/IEC for this study including the subject consent form, 
written information provided to subjects, and recruitment materials must be maintained by the 
Principal Investigator and made available for inspection. 


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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 pharmacogenomics/genomics 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 blood samples for optional future pharmacogenomics/genomic 
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 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 blood samples for future pharmacogenomics/genomic 
research studies. If the subject does not wish to provide a blood 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 
 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 
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, 


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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 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. 
Bito, L. (2001).  A New Approach to the Medical Management of Glaucoma, from the Bench to 
the Clinic, and Beyond. Investigative Ophthalmology & Visual Science. 42(6):1126-33. 
 
3. 
Fuwa, M., Toris, C. B., Fan, S., Taniguchi, T., Ichikawa, M., Odani-Kawabata, N., Iwamura, R., 
Yoneda, K., Matsugi, T., Shams, N. K., Zhang, J.-Z. (2017).  ABSTRACT: ARVO 2018: Effects 
of a Novel Selective EP2 Receptor Agonist, Omidenepag Isopropyl, on Aqueous Humor 
Dynamics in Laser-induced Ocular Hypertensive Monkeys.2. 
 
4. 
Garway-Heath, D. F., Crabb, D. P., Bunce, C., Lascaratos, G., Amalfitano, F., Anand, N., 
Azuara-Blanco, A., Bourne, R. R., Broadway, D. C., Cunliffe, I. A., Diamond, J. P., Fraser, S. G., 
Ho, T. A., Martin, K. R., McNaught, A. I., Negi, A., Patel, K., Russell, R. A., Shah, A., Spry, P. 
G., Suzuki, K., White, E. T., Wormald, R. P., Xing, W., Zeyen, T. G. (2015).  Latanoprost for 
open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial. Lancet. 
385(9975):1295-304. doi: 10.1016/S0140-6736(14)62111-5. PubMed PMID: 25533656. 
 
5. 
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. 
 
6. 
Kass, M., Heuer, D., Higginbotham, E., Johnson, C., Keltner, J., Miller, J., Parrish, R., Wilson, 
M., Gordon, M. (2002).  The Ocular Hypertension Treatment Study: A Randomized Trial 
Determines That Topical Ocular Hypotensive Medication Delays or Prevents the Onset of 
Primary Open-Angle Glaucoma. Arch Ophthalmol. 120:701-13. 
 
7. 
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. 
 


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8. 
MedDRA.  Medical Dictionary for Regulatory Activities. 14.1. 
 
9. 
Resnikoff, S., Pascolini, D., Etya ale, D., Kocur, I., Pararajasegaram, R., Pokharel, G., Mariotti, 
S. (2004).  Global data on visual impairment in the year 2002. Bulletin of the World Health 
Organization. 82(11):844-52. 
 
10. 
Tham, Y., Li, X., Wong, T., Quigley, H., Aung, T., Cheng, C. (2014).  Global Prevalence of 
Glaucoma and Projections of Glaucoma Burden through 2040. Ophthalmology. 121(11):2081-90. 
 
11. 
WHO-DDE, W. H. O. (2011).  World Health Organization Drug Dictionary Enhanced. 
 
12. 
Yamaji, K., Yoshitomi, T., Ishikawa, H., Usui, S. (2005).  Prostaglandins E 1  and E 2 , but not F 
2  α  or Latanoprost, Inhibit Monkey Ciliary Muscle Contraction. Current Eye Research. 30:661-
5. 
 
13. 
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: Santen Study 33-001. A Phase I/II, Randomized, Observer-masked, 
Placebo-and-active-controlled, Parallel-group, Multi-center Study Assessing the Safety 
and Efficacy of DE-117 Ophthalmic Solution in Subjects with Primary Open-angle 
Glaucoma or Ocular Hypertension 
2. 
Data on File: Santen Study 33-002. A Phase II, Randomized, Observer-masked, Placebo-
and Active-controlled, Parallel-group, Multi-center Study Assessing the Safety and 
Efficacy of DE-117 Ophthalmic Solution Compared with Latanoprost and Placebo in 
Subjects with Primary Open-angle Glaucoma or Ocular Hypertension  
3. 
Data on File: Santen Study 33-003. A Phase IIb, Randomized, Observer-masked, Active-
controlled, Parallel-group, Multicenter Study Assessing the Safety and Efficacy of DE-
117 Ophthalmic Solution Compared with Latanoprost Ophthalmic Solution, 0.005% in 
Subjects with Primary Open-angle Glaucoma or Ocular Hypertension – SEE Study 


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4. 
Data on File: Santen Study 01171502. A Pharmacokinetic Study of DE-117 Ophthalmic 
Solution in Healthy Adult Male Subjects - Phase I Study - 
5. 
Data on File: Santen Study 01171503. A Study Assessing the Efficacy and Safety of DE-
117 Ophthalmic Solution in Subjects With Primary Open Angle Glaucoma or Ocular 
Hypertension -AYAME Study- 
6. 
Data on File: Santen Study 01171504. A Long-term Study of DE-117 Ophthalmic 
Solution Monotherapy and Concomitant Use of DE-117 Ophthalmic Solution With 
Timolol Ophthalmic Solution in Patients With OAG or OH: RENGE Study 
7. 
Data on File: Santen Study 01171506. A Study Assessing the Safety and Efficacy of DE-
117 in Subjects With POAG or OH Who Are Non-/Low-responders to Latanoprost: FUJI 
Study 
 


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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. 
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 of the IRB or IEC. 


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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. 
O. That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) 
will be granted direct access to the subject's original medical records for 
verification of clinical trial procedures and/or data, without violating the 
confidentiality of the subject, to the extent permitted by the applicable laws and 
regulations and that, by signing a written informed consent form, the subject or the 
subject's legally acceptable representative is authorizing such access. 
P. That records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available. If the results of the trial are published, the subject’s identity will remain 
confidential. 


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Q. That the subject or the subject's legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the 
subject's willingness to continue participation in the trial. 
R. The person(s) to contact for further information regarding the trial and the rights of 
trial subjects, and whom to contact in the event of trial-related injury. 
S. The foreseeable circumstances and/or reasons under which the subject's 
participation in the trial may be terminated. 
T. The expected duration of the subject's participation in the trial. 
U. The approximate number of subjects involved in the trial. 
V. Clinical trial information has been or will be available on 
http://www.clinicaltrials.gov. 
II. 
Additional Elements of Informed Consent for Optional Future 
Pharmacogenomics/genomics Laboratory Research Study  
The following information must be provided to each subject in obtaining informed consent 
for the future 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, Medication/Therapy and Medical History 
Demographics including age, sex, race, prostaglandin analogs naïve status, and ethnicity will be 
obtained through subject interviews at Visit 1 (Screening). 
Medications and 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 (Screening), 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 procedure/therapy that has been received for POAG or OHT within 28 
days before the date of Visit 1 (Screening), or any concomitant procedure/therapy, must be 
recorded in the subject’s source documents. 

Name of procedure/therapy, treated eye(s) (if applicable), indication, start date and 
stop date 
Medical history including all lifetime ocular medical history to the extent possible, non-ocular 
medical history within 5 years, diagnosis, ocular surgical history, current ocular and systemic 
conditions will be confirmed through subject interviews at Visit 1 (Screening) to determine if the 
subject meets eligibility criteria. Primary diagnosis 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 4 (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 4 (Baseline, Day 1), and Visit 7 Study Exit/Early Termination for all females 
of childbearing potential. A female is considered of childbearing potential unless she is post-
menopausal (at least 12 months since last menses occurred), is without a uterus or without both 
ovaries, or has had a bilateral tubal ligation. To perform the pregnancy test, follow instructions 
provided by the manufacturer of the urine pregnancy test kit. 
21.3.3.
Iris color, Eyelash, Eyelid  
Please take photographs of the iris, eyelids and eyelashes of each eye at Visit 4 (Baseline, Day 1), and 
Visit 7 (Month 3), Study Exit/Early Termination. Six (6) photos are required at each visit as follows:   


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The photographs taken at Visit 4 (Baseline, Day 1) 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, eyelashes and eyelids at Visit 7 (Month 3) Study Exit/Early 
Termination. For any changes from baseline in deepening of the upper eyelid sulcus (DUES), the 
response will be YES or NO.  
Each photograph will be labeled with subject number, OD or OS, and Visit number, and kept 
with the subject’s source document. 
21.3.3.1. Iris Color 
The Investigator will assess the iris color and any change (e.g., pigmentation) at Visit 7 (Month 
3) Study Exit/Early Termination using the photographs obtained at Visit 4 (Baseline, Day 1). 
21.3.3.2. Eyelash 
The Investigator will assess eyelash change at Visit 7 (Month 3) Study Exit/Early Termination 
(e.g., length, thickness, pigmentation and number) using the photographs obtained at Visit 4 
(Baseline, Day 1). 
21.3.3.3. Eyelid 
The Investigator will assess eyelid change at Visit 7 (Month 3) Study Exit/Early Termination 
(e.g., pigmentation, hair growth and deepening of the upper eyelid sulcus) using the photographs 
obtained at Visit 4 (Baseline, Day 1). For any changes from baseline in deepening of the upper 
eyelid sulcus (DUES), the response will be YES or NO.  
21.3.4. 
Refraction 
Refraction will be performed for each eye at Visit 1 (Screening). At Visits 2 to 7, if more than 10 
letters in BCVA were lost compared to the screening visit, then refraction should be performed. 
21.3.5. 
Best-Corrected Visual Acuity 
BCVA (Best-Corrected Visual Acuity) will be measured for each eye prior to the 08:00 (±60 
min) IOP measurement at all visits except for Visit 1 (Screening) and Visit 1a (optional, mid-
washout visit). For Visit 1 (Screening) and Visit 1a (optional, mid-washout visit), BCVA will be 
performed prior to IOP measurement.  BCVA will be measured under normal room illumination 


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using visual acuity chart (ETDRS chart) and the logMAR scoring will be recorded in the 
subject’s source document. If ETDRS chart is used, the following procedure should be followed. 
21.3.5.1. ETDRS Visual Acuity Scoring 
The Examiner records each letter identified correctly by circling the corresponding letter on an 
appropriate visual acuity worksheet. The Examiner records a letter read incorrectly, or a letter for 
which the subject made no guess, by crossing the letter out with an “x” or a line. Each letter read 
incorrectly is scored as one point. The last line in which a letter is read correctly will be taken as 
the Base logMAR line. 
The total number of letters that have an “x” or a line through them (letters read incorrectly or not 
at all) down to and including the Base logMAR line, and multiply the total number by 0.02. Add 
this value to the Base logMAR value to obtain the logMAR score. 
Example: 
Subject correctly reads 4 of 5 letters on the +0.2 line, and 2 of 5 letters on the +0.1 line, and 
zero letters on the 0.0 line 
Base logMAR value = +0.1 (last line in which a letter was read correctly) 
Total number of letters missed = 4 (number of letters missed on the +0.2 line plus the number 
missed on the +0.1 line) 
LogMAR score = +0.1 + (4 x 0.02) = 0.18 
Table 3: 
LogMAR Scoring Grid for ETDRS Eye Chart 
 
Total Number of Letters Missed 
Snellen 
Base 
LogMAR 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
20/200 
+1.0 
1.00 
1.02 
1.04 
1.06 
1.08 
--- 
--- 
--- 
--- 
--- 
--- 
20/160 
+0.9 
0.90 
0.92 
0.94 
0.96 
0.98 
1.00 
1.02 
1.04 
1.06 
1.08 
1.10 
20/125 
+0.8 
0.80 
0.82 
0.84 
0.86 
0.88 
0.90 
0.92 
0.94 
0.96 
0.98 
1.00 
20/100 
+0.7 
0.70 
0.72 
0.74 
0.76 
0.78 
0.80 
0.82 
0.84 
0.86 
0.88 
0.90 
20/80 
+0.6 
0.60 
0.62 
0.64 
0.66 
0.68 
0.70 
0.72 
0.74 
0.76 
0.78 
0.80 
20/63 
+0.5 
0.50 
0.52 
0.54 
0.56 
0.58 
0.60 
0.62 
0.64 
0.66 
0.68 
0.70 
20/50 
+0.4 
0.40 
0.42 
0.44 
0.46 
0.48 
0.50 
0.52 
0.54 
0.56 
0.58 
0.60 
20/40 
+0.3 
0.30 
0.32 
0.34 
0.36 
0.38 
0.40 
0.42 
0.44 
0.46 
0.48 
0.50 
20/32 
+0.2 
0.20 
0.22 
0.24 
0.26 
0.28 
0.30 
0.32 
0.34 
0.36 
0.38 
0.40 
20/25 
+0.1 
0.10 
0.12 
0.14 
0.16 
0.18 
0.20 
0.22 
0.24 
0.26 
0.28 
0.30 
20/20 
0.0 
0.00 
0.02 
0.04 
0.06 
0.08 
0.10 
0.12 
0.14 
0.16 
0.18 
0.20 
20/16 
-0.1 
-0.10 
-0.08 
-0.06 
-0.04 
-0.02 
0.00 
0.02 
0.04 
0.06 
0.08 
0.10 
20/12.5 
-0.2 
-0.20 
-0.18 
-0.16 
-0.14 
-0.12 
-0.10 
-0.08 
-0.06 
-0.04 
-0.02 
0.00 
20/10 
-0.3 
-0.30 
-0.28 
-0.26 
-0.24 
-0.22 
-0.20 
-0.18 
-0.16 
-0.14 
-0.12 
-0.10 


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21.3.6. 
Slit-lamp Biomicroscopy 
As described below, slit-lamp biomicroscopy examinations will be performed and graded 
immediately prior to the 08:00 (±60 min) IOP measurement at all visits except for Visit 1 
(Screening) and Visit 1a (optional, mid-washout visit). For Visit 1 (Screening) and Visit1a 
(optional, mid-washout visit), the biomicroscopy examinations should be performed prior to IOP 
measurement. If an Investigator decides to evaluate a subject with pseudophakic eye(s) for 
possible tears in the posterior lens capsule by biomicroscopy under dilation at Visit 1 (Screening), 
pupil dilation must occur 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 
(4) = >50 cells 
 
      Anterior Chamber Flare  
(0) = None 
(1) = Faint 
(2) = Moderate (iris/lens details clear) 
(3) = Marked (iris/lens details hazy) 
(4) = Intense (fibrin/plastic aqueous) 
The lid, conjunctiva, cornea, lens, and iris will be observed and graded on a 4-point scale (0-3 
scale).  
Lid Hyperemia 
None 
(0) = Normal 
Mild 
(1) = Redness of most or all the lid(s) margin OR skin 
Moderate (2) = Redness of most or all the lid(s) margin AND skin 
Severe 
(3) =  Marked diffuse redness of both lid(s) margin AND skin  
Lid Edema 
None 
(0) = Normal 
Mild 
(1) = Localized to a small region of the lid(s) 


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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 
None 
(0) = Normal 
Mild 
(1) = Slight localized swelling 
Moderate (2) = Mild/medium localized swelling or mild diffuse swelling 
Severe 
(3) = Moderate diffuse swelling 
Corneal Edema 
None 
(0) = Normal 
Mild 
(1) = Mild, diffuse stromal haze 
Moderate (2) = Dense, diffuse stromal haze or bullae 
Severe 
(3) = Dense, diffuse bullae or stromal haze AND stromal edema 
Corneal Staining (with fluorescein) 
None 
(0) = Normal 
Mild 
(1) = Localized, occasional punctate staining 
Moderate (2) = Localized, dense OR diffuse occasional punctate staining 
Severe 
(3) = Diffuse, dense punctate staining which may be confluent staining 
Keratic Precipitate 
None 
(0) = Normal 
Mild 
(1) = Slight pigmentation or keratic precipitate 
Moderate (2) = Moderate pigmentation or keratic precipitate  
Severe 
(3) = Dense pigmentation or keratic precipitate 
Lens 
The lens will be noted as phakic, aphakic, or pseudophakic. Phakic lens will be graded as 
described below: 
None 
(0) = No lens discoloration nor opacification 


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Mild 
(1) = Yellow lens discoloration or small lens opacity (axial or peripheral) 
Moderate (2) = Amber lens discoloration or medium lens opacity (axial or peripheral) 
      Severe 
(3) = Brunescent lens discoloration or complete lens opacification (no red   reflex) 
Anterior Synechiae of Iris 
None 
(0) = No anterior synechiae of iris is found 
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 
21.3.7. 
Intraocular Pressure 
IOP will be performed at each visit. At Visit 1 (Screening) and Visit 1a (optional, mid-washout 
visit), IOP can be measured at any time. For Visit 2 to Visit 7 Study Exit/Early Termination, IOP 
measurements will be scheduled for 08:00 (±60min), 12:00 (±60min) and 16:00 (±60min). 
IOP will be measured using calibrated manual Goldmann applanation tonometer. Measurement 
will be performed preferably by the same Investigator (operator) and the same authorized study 
staff member (recorder) throughout the study. Investigator (operator) who performs the IOP 
measurement must have at least 2 years of experience in IOP measurement. 
The right eye is always tested first. At least two, and sometimes three, consecutive measurements 
are made to obtain a determination of IOP. Each IOP measurement and the clock time of IOP 
measurement will be recorded in the subject’s source document. 
A single measurement is made as follows: 
 The Investigator adjusts the force on the tonometer dial to an initial setting 
corresponding to 10 mmHg. The slit-lamp magnification is set at 10X. The light 
source is positioned at an angle of approximately 45º, and the aperture is maximally 
opened. A cobalt blue filter is employed. 
 After instillation of a topical anesthetic, a fluorescein paper strip is placed near the 
lateral canthus in the lower conjunctival sac. Once the lacrimal fluid is sufficiently 
colored, the paper strip is removed. Alternatively, one drop of premixed fluorescein 
and anesthetic (Fluress, Barnes Hind) may be instilled. The Investigator should use 
the same technique each time, be it a paper strip or a pre-mixed eye drop. 
 The subject and slit-lamp are adjusted so that the subject’s head is firmly positioned 
on the chin rest and against the forehead rest without leaning forward or straining. 


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Tight-fitting neckwear is loosened. The subject is asked to look straight ahead at a 
distant object or fixation target. If it is necessary to hold the eyelids open, the 
Investigator holds the eyelids against the orbit rim, taking care not to apply any 
pressure to the globe. The subject is cautioned not to hold his breath. 
 The Investigator looks through the slit-lamp and gently brings the tip of the prism into 
contact with the center of the cornea. The mires are well-focused, centered 
horizontally, and positioned vertically so that they are of equal circumference above 
and below the horizontal dividing line. If the mires are narrower than approximately 
1/10 their diameter, additional fluorescein is instilled. 
 The Investigator adjusts the measuring drum until the inner borders of the two mires 
just touch each other or, if pulsation is present, until the mires separate a given 
distance during systole and overlap the same distance during diastole. 
 The Investigator removes the tip from the cornea, and the authorized study staff 
(recorder) records the reading on the dial, rounded to the next highest integer. For 
example, if the measurement indicated is between 16 and 17, then 17 is recorded as 
the measurement in the subject’s source document. 
 The Investigator may also be the recorder instead of an authorized study staff 
member, if a study staff member was not assigned. 
 If corneal astigmatism is greater than 3.0 D, the prism is rotated so that the red line 
corresponds to the orientation of the longer axis of the elliptical applanated area. 
The above procedure is then repeated for the same eye, and that second measurement is also 
recorded in the subject’s source document. 
 If the two measurements differ by less than 3 mmHg, then the average of the two 
measurements becomes the recorded IOP. For example, if the two measurements are 
22 and 23, then 22.5 is the final recorded IOP. 
 However, if the two measurements differ by 3 mmHg or more, then a third 
measurement is made, and the median of the three measurements becomes the 
recorded IOP (the median is the middle measurement after ordering the 
measurements from low to high). For example, if the three measurements are 15, 19, 
and 16, then 16 is the final recorded IOP. 
The IOP in the left eye is then measured using the same technique. 
21.3.7.1. Goldmann Applanation Tonometer Calibration 
It is mandatory for every tonometer used in the study to be calibrated for accuracy before the 
first subject undergoes screening. Thereafter, the calibration must be checked monthly until the 
last subject has exited the study. For calibration checks, the manufacturer’s instructions should 
be followed. If the variation is within ±2 mmHg, the tonometer is considered adequately 
calibrated. However, if the variation exceeds this amount, the tonometer should be sent for repair 
and a different, adequately calibrated instrument should be used for IOP measurement. The date 
of each calibration, along with the name and signature (or initials) of the person who performed 


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the calibration, will be documented. The tonometer calibration record will be retained as a part of 
the study record. 
21.3.8. 
Pachymetry (Central Corneal Thickness) 
The central corneal thickness (µm) of each eye using any pachymeter including optical 
pachymeter, ultrasound pachymeter, OCT (optical coherence tomography) etc. will be measured 
and recorded after IOP measurement at Visit 1 (Screening). Pachymetry should be performed 
after IOP measurement. The same pachymeter should be used during the course of the study. 
21.3.9. 
Gonioscopy 
Gonioscopy will be performed to examine the angle of the anterior chamber after IOP 
measurement at Visit 1 (Screening), if it has not been performed within 3 months (90 days). The 
Shaffer scale will be used to rate the degree of angle closure. 
(0) = approximately 5 degrees or less, complete or partial closure 
(1) = approximately 10 degrees 
(2) = approximately 20 degrees 
(3) = approximately 30 degrees 
(4) = approximately 40 degrees or more 
21.3.10. 
Visual Field 
Visual field examinations will be performed using a static or dynamic perimeter (Humphrey or 
Octopus) without pupil dilation at Visit 1 (Screening), if this has not been performed within 3 
months (90 days) or the previous visual field test(s) indicates low subject reliability (e.g., due to 
fixation losses, false positive errors, or false negative errors). Glaucomatous visual field loss will 
be evaluated by the Investigator as presence or absence (mean deviation, pattern SD, glaucoma 
hemifield test, and type of glaucomatous visual field loss). 
Visual field tests that, in the Investigator's opinion, indicate low subject reliability (e.g., due to 
fixation losses, false positive errors, or false negative errors) should be excluded. A copy of the 
computer printout from the visual field test(s) will be attached to the subject’s source documents. 
21.3.11. 
Ophthalmoscopy (Fundus) Examination 
The ophthalmoscopy (fundus) examination will be performed for each eye at Visit 1 (Screening), 
Visit 4 (Baseline, Day 1), and Visit 7 Study Exit/Early Termination, and graded as described 
below. Ophthalmoscopy will be performed under dilation at Visit 1 (Screening) and Visit 7 
Study Exit/Early Termination. Pupil dilation must be performed after all other ocular procedures 
have been completed. Cup to disc ratio and abnormality in retina, macula, choroid, and vitreous 
will also be evaluated. 
Glaucomatous Optic Nerve Findings 
The optic nerve will be evaluated using a 4-point scale (0-3 scale). 
None 
(0) = No damage 


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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 
21.3.12. 
Blood Sample for Pharmacogenomics/genomics Study 
For sites which elect to participate and for subjects who agree to provide a blood sample, an 
exploratory biomarker laboratory research study will be performed to evaluate the association of 
possible genetic biomarkers with the study drug(s) and/or ophthalmologic conditions. 
Approximately 10 mL of blood will be collected for genetic analysis from the subject and stored 
in a refrigerator until shipment. Please refer to the separate procedure manual for sample 
handling, storage, and shipment. The samples will be coded to protect the participants’ private 
information. Nucleic acids will be extracted from blood sample and stored in the repository for 
future pharmacogenomics/genomics studies performed by appropriate assay platforms such as 
PCR (Polymerase Chain Reaction), hybridization, and sequencing on the genes involved in the 
study drug(s) and/or ophthalmologic conditions. Individual subjects’ results from the research 
testing on their samples will not be communicated to them. 
Samples collected and stored, and relevant documents (the list of screening/registration of 
subjects only for documents to be retained by the medical institution) will be retained for the 
period agreed in the ICF. Upon completion of analyses or the retention period, they will be 
anonymized and discarded. If the subject withdraws the consent, samples will be immediately 
disposed, and the applicable subject will be informed in writing. 
For any other matters not specified in the protocol, a written procedure will be defined 
separately. 
 
 


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21.5. 
Appendix D - Latanoprost Ophthalmic solution 0.005% Package 
Insert 
LATANOPROST- latanoprost solution  
Greenstone LLC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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HIGHLIGHTS OF PRESCRIBING 
INFORMATION 
These highlights do not include all the 
information needed to use latanoprost 
ophthalmic solution safely and effectively. See 
full prescribing information for latanoprost 
ophthalmic solution.  
 
Latanoprost ophthalmic solution 0.005%  
Initial U.S. Approval: 1996 
INDICATIONS AND USAGE 
Latanoprost ophthalmic solution is a prostaglandin 
F2α analogue indicated for the reduction of elevated 
intraocular pressure in patients with open-angle 
glaucoma or ocular hypertension. (1)  
DOSAGE AND 
ADMINISTRATION 
One drop in the affected eye(s) once daily in the 
evening. (2)  
DOSAGE FORMS AND 
STRENGTHS 
Ophthalmic solution containing 50 mcg/mL 
latanoprost (0.005%). (3)  
CONTRAINDICATIONS 
Known hypersensitivity to latanoprost, 
benzalkonium chloride, or any other ingredients in 
this product. (4)  
WARNINGS AND 
PRECAUTIONS 
 
Pigmentation: pigmentation of the iris, 
periorbital tissue (eyelid) and eyelashes can 
occur. Iris pigmentation likely to be permanent. 
(5.1) 
 
Eyelash Changes: gradual change to eyelashes 
including increased length, thickness and 
number of lashes. Usually reversible. (5.2) 
ADVERSE REACTIONS 
Most common adverse reactions (≥4%) from 
clinical trials are blurred vision, burning and 
stinging, conjunctival hyperemia, foreign body 
sensation, itching, increased pigmentation of the 
iris, punctate keratitis, and upper respiratory tract 
infection/nasopharyngitis/influenza. (6)  
 
To report SUSPECTED ADVERSE 
REACTIONS, contact Greenstone LLC at 1-
800-438-1985 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch.  
DRUG INTERACTIONS 
In vitro studies have shown that precipitation occurs 
when eye drops containing thimerosal are mixed 
with latanoprost ophthalmic solution. If such drugs 
are used, they should be administered at least 5 
minutes apart. (7)  
See 17 for PATIENT COUNSELING 
INFORMATION. 
Revised: 5/2017 
 


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FULL PRESCRIBING INFORMATION: 
CONTENTS* 
1 INDICATIONS AND USAGE 
2 DOSAGE AND ADMINISTRATION  
3 DOSAGE FORMS AND STRENGTHS 
4 CONTRAINDICATIONS 
5 WARNINGS AND PRECAUTIONS 
5.1 Pigmentation 
5.2 Eyelash Changes 
5.3 Intraocular Inflammation 
5.4 Macular Edema 
5.5 Herpetic Keratitis 
5.6 Bacterial Keratitis 
5.7 Use with Contact Lenses 
6 ADVERSE REACTIONS 
6.1 Clinical Trials Experience 
6.2 Postmarketing Experience 
7 DRUG INTERACTIONS 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
8.3 Nursing Mothers 
8.4 Pediatric Use 
8.5 Geriatric Use 
10 OVERDOSAGE 
11 DESCRIPTION 
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
12.2 Pharmacodynamics 
12.3 Pharmacokinetics 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment 
of Fertility 
14 CLINICAL STUDIES 
14.1 Elevated Baseline IOP 
14.2 Progression of Increased Iris Pigmentation 
16 HOW SUPPLIED/STORAGE AND 
HANDLING 
17 PATIENT COUNSELING INFORMATION 
* 
Sections or subsections omitted from the 
full prescribing information are not listed. 
FULL PRESCRIBING INFORMATION 
1 INDICATIONS AND USAGE 
Latanoprost is indicated for the reduction of elevated intraocular pressure in patients with open-angle 
glaucoma or ocular hypertension. 
2 DOSAGE AND ADMINISTRATION  
The recommended dosage is one drop in the affected eye(s) once daily in the evening. If one dose is 
missed, treatment should continue with the next dose as normal. 
The dosage of latanoprost ophthalmic solution should not exceed once daily; the combined use of two or 
more prostaglandins, or prostaglandin analogs including latanoprost ophthalmic solution is not 


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recommended. It has been shown that administration of these prostaglandin drug products more than once 
daily may decrease the intraocular pressure (IOP) lowering effect or cause paradoxical elevations in IOP. 
Reduction of the IOP starts approximately 3 to 4 hours after administration and the maximum effect is 
reached after 8 to 12 hours. 
Latanoprost ophthalmic solution may be used concomitantly with other topical ophthalmic drug products 
to lower IOP. If more than one topical ophthalmic drug is being used, the drugs should be administered at 
least five (5) minutes apart. Contact lenses should be removed prior to the administration of latanoprost 
ophthalmic solution, and may be reinserted 15 minutes after administration. 
3 DOSAGE FORMS AND STRENGTHS 
Sterile ophthalmic solution containing 50 mcg/mL latanoprost.  
4 CONTRAINDICATIONS 
Known hypersensitivity to latanoprost, benzalkonium chloride, or any other ingredients in this product. 
5 WARNINGS AND PRECAUTIONS 
5.1 Pigmentation 
Latanoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most 
frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid), and 
eyelashes. Pigmentation is expected to increase as long as latanoprost ophthalmic solution is 
administered. 
The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase 
in the number of melanocytes. After discontinuation of latanoprost, pigmentation of the iris is likely to be 
permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be 
reversible in some patients. Patients who receive treatment should be informed of the possibility of 
increased pigmentation. Beyond 5 years the effects of increased pigmentation are not known [see Clinical 
Studies (14.2)]. 
Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation 
around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the 
iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While 
treatment with latanoprost ophthalmic solution can be continued in patients who develop noticeably 
increased iris pigmentation, these patients should be examined regularly [see Patient Counseling 
Information (17)]. 
5.2 Eyelash Changes 
Latanoprost ophthalmic solution may gradually change eyelashes and vellus hair in the treated eye; these 
changes include increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected 
growth of eyelashes. Eyelash changes are usually reversible upon discontinuation of treatment [see 
Patient Counseling Information (17)]. 


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5.3 Intraocular Inflammation 
Latanoprost ophthalmic solution should be used with caution in patients with a history of intraocular 
inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular 
inflammation because inflammation may be exacerbated. 
5.4 Macular Edema 
Macular edema, including cystoid macular edema, has been reported during treatment with latanoprost 
ophthalmic solution. Latanoprost ophthalmic solution should be used with caution in aphakic patients, in 
pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for 
macular edema. 
5.5 Herpetic Keratitis 
Reactivation of Herpes Simplex keratitis has been reported during treatment with latanoprost ophthalmic 
solution. Latanoprost ophthalmic solution should be used with caution in patients with a history of 
herpetic keratitis. Latanoprost ophthalmic solution should be avoided in cases of active herpes simplex 
keratitis because inflammation may be exacerbated. 
5.6 Bacterial Keratitis 
There have been reports of bacterial keratitis associated with the use of multiple-dose containers of 
topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in 
most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface [see Patient 
Counseling Information (17)]. 
5.7 Use with Contact Lenses 
Contact lenses should be removed prior to the administration of latanoprost ophthalmic solution, and may 
be reinserted 15 minutes after administration. 
6 ADVERSE REACTIONS 
The following adverse reactions were reported in postmarketing experience and are discussed in greater 
detail in other sections of the label: 
 
Iris pigmentation changes [see Warnings and Precautions (5.1)] 
 
Eyelid skin darkening [see Warnings and Precautions (5.1)] 
 
Eyelash changes (increased length, thickness, pigmentation, and number of lashes) [see Warnings and 
Precautions (5.2)] 
 
Intraocular inflammation (iritis/uveitis) [see Warnings and Precautions (5.3)] 
 
Macular edema, including cystoid macular edema [see Warnings and Precautions (5.4)] 
6.1 Clinical Trials Experience 
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed 
in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug 
and may not reflect the rates observed in clinical practice. 


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Latanoprost ophthalmic solution was studied in three multicenter, randomized, controlled clinical trials. 
Patients received 50 mcg/mL latanoprost ophthalmic solution once daily or 5 mg/mL active-comparator 
(timolol) twice daily. The patient population studied had a mean age of 65±10 years. Seven percent of 
patients withdrew before the 6-month endpoint. 
Table 1: Ocular Adverse Reactions and Ocular Signs/Symptoms Reported by 5–15% of 
Patients Receiving Latanoprost 
Adverse Reactions (incidence (%)) 
Symptom/Finding 
Latanoprost 
(n=460) 
Timolol 
(n=369) 
Foreign body sensation 
13 
8 
Punctate keratitis 
10 
9 
Stinging 
9 
12 
Conjunctival hyperemia 
8 
3 
Blurred vision 
8 
8 
Itching  
8 
8 
Burning 
7 
8 
Increased pigmentation of the Iris 
7 
0 
Less than 1% of the patients treated with latanoprost ophthalmic solution required discontinuation of 
therapy because of intolerance to conjunctival hyperemia. 
Table 2: Adverse Reactions That Were Reported in 1–5% of Patients Receiving 
Latanoprost 
Adverse Reactions (incidence (%)) 
 
Latanoprost 
(n=460) 
Timolol 
(n=369) 
Ocular Events/Signs and Symptoms 
  Excessive tearing 
4 
6 
  Eyelid discomfort/pain 
4 
2 
  Dry eye 
3 
3 
  Eye pain 
3 
3 
  Eyelid margin crusting 
3 
3 
  Erythema of the eyelid 
3 
2 
  Photophobia  
2 
1 
  Eyelid edema 
1 
3 
Systemic Events 


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  Upper respiratory tract infection/nasopharyngitis/influenza 
3 
3 
  Myalgia/arthralgia/back pain 
1 
0.5 
  Rash/allergic skin reaction 
1 
0.3 
The ocular event/signs and symptoms of blepharitis have been identified as "commonly 
observed" through analysis of clinical trial data. 
6.2 Postmarketing Experience 
The following reactions have been identified during postmarketing use of latanoprost ophthalmic 
solution in clinical practice. Because they are reported voluntarily from a population of unknown 
size, it is not always possible to reliably estimate their frequency or establish a causal 
relationship to drug exposure. The reactions, which have been chosen for inclusion due to either 
their seriousness, frequency of reporting, possible causal connection to latanoprost ophthalmic 
solution, or a combination of these factors, include: 
Nervous System Disorders: Dizziness; headache; toxic epidermal necrolysis  
Eye Disorders: Eyelash and vellus hair changes of the eyelid (increased length, thickness, 
pigmentation, and number of eyelashes); keratitis; corneal edema and erosions; intraocular 
inflammation (iritis/uveitis); macular edema, including cystoid macular edema; trichiasis; 
periorbital and lid changes resulting in deepening of the eyelid sulcus; iris cyst; eyelid skin 
darkening; localised skin reaction on the eyelids; conjunctivitis; pseudopemphigoid of the ocular 
conjunctiva 
Respiratory, Thoracic and Mediastinal Disorders: Asthma and exacerbation of asthma; dyspnea  
Skin and Subcutaneous Tissue Disorders: Pruritus 
Infections and Infestations: Herpes keratitis 
Cardiac Disorders: Angina; palpitations; angina unstable 
General Disorders and Administration Site Conditions: Chest pain 
7 DRUG INTERACTIONS 
In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are 
mixed with latanoprost ophthalmic solution. If such drugs are used, they should be administered 
at least five (5) minutes apart. 
The combined use of two or more prostaglandins, or prostaglandin analogs including latanoprost 
ophthalmic solution is not recommended. It has been shown that administration of these 
prostaglandin drug products more than once daily may decrease the IOP lowering effect or cause 
paradoxical elevations in IOP. 


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8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
Teratogenic Effects: Pregnancy Category C. 
Reproduction studies have been performed in rats and rabbits. In rabbits, an incidence of 4 of 16 
dams had no viable fetuses at a dose that was approximately 80 times the maximum human dose, 
and the highest nonembryocidal dose in rabbits was approximately 15 times the maximum 
human dose. 
There are no adequate and well-controlled studies in pregnant women. Latanoprost ophthalmic 
solution should be used during pregnancy only if the potential benefit justifies the potential risk 
to the fetus. 
8.3 Nursing Mothers 
It is not known whether this drug or its metabolites are excreted in human milk. Because many 
drugs are excreted in human milk, caution should be exercised when latanoprost ophthalmic 
solution is administered to a nursing woman. 
8.4 Pediatric Use 
Safety and effectiveness in pediatric patients have not been established. 
8.5 Geriatric Use 
No overall differences in safety or effectiveness have been observed between elderly and 
younger patients. 
10 OVERDOSAGE 
Intravenous infusion of up to 3 mcg/kg in healthy volunteers produced mean plasma 
concentrations 200 times higher than during clinical treatment and no adverse reactions were 
observed. Intravenous dosages of 5.5 to 10 mcg/kg caused abdominal pain, dizziness, fatigue, hot 
flushes, nausea, and sweating. 
If overdosage with latanoprost ophthalmic solution occurs, treatment should be symptomatic. 
11 DESCRIPTION 
Latanoprost is a prostaglandin F2α analogue. Its chemical name is isopropyl-(Z)-
7[(1R,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate. 
Its molecular formula is C26H40O5 and its chemical structure is: 


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Latanoprost is a colorless to slightly yellow oil that is very soluble in acetonitrile and freely 
soluble in acetone, ethanol, ethyl acetate, isopropanol, methanol, and octanol. It is practically 
insoluble in water. 
Latanoprost ophthalmic solution 0.005% is supplied as a sterile, isotonic, buffered aqueous 
solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 
mOsmol/kg. Each mL of latanoprost ophthalmic solution contains 50 mcg of latanoprost. 
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. One drop contains approximately 1.5 mcg of latanoprost. 
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
Latanoprost is a prostanoid selective FP receptor agonist that is believed to reduce the intraocular 
pressure (IOP) by increasing the outflow of aqueous humor. Studies in animals and man suggest 
that the main mechanism of action is increased uveoscleral outflow. Elevated IOP represents a 
major risk factor for glaucomatous field loss. The higher the level of IOP, the greater the 
likelihood of optic nerve damage and visual field loss. 
12.2 Pharmacodynamics 
Reduction of the IOP in man starts about 3–4 hours after administration and maximum effect is 
reached after 8–12 hours. IOP reduction is present for at least 24 hours. 
12.3 Pharmacokinetics 
Absorption 
Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to 
the acid form to become biologically active. 
Distribution 
The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can be measured 
in aqueous humor during the first 4 hours, and in plasma only during the first hour after local 
administration. Studies in man indicate that the peak concentration in the aqueous humor is 
reached about two hours after topical administration. 
Metabolism 


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Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the 
biologically active acid. The active acid of latanoprost reaching the systemic circulation is 
primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid 
β-oxidation. 
Excretion 
The elimination of the acid of latanoprost from human plasma is rapid (t1/2 = 17 min) after both 
intravenous and topical administration. Systemic clearance is approximately 7 mL/min/kg. 
Following hepatic β-oxidation, the metabolites are mainly eliminated via the kidneys. 
Approximately 88% and 98% of the administered dose are recovered in the urine after topical 
and intravenous dosing, respectively. 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at 
doses of up to 170 mcg/kg/day (approximately 2800 times the recommended maximum human 
dose) for up to 20 and 24 months, respectively. 
Latanoprost was not mutagenic in bacteria, in mouse lymphoma, or in mouse micronucleus tests. 
Chromosome aberrations were observed in vitro with human lymphocytes. Additional in vitro 
and in vivo studies on unscheduled DNA synthesis in rats were negative. 
Latanoprost has not been found to have any effect on male or female fertility in animal studies. 
14 CLINICAL STUDIES 
14.1 Elevated Baseline IOP 
Patients with mean baseline IOP of 24 – 25 mmHg who were treated for 6 months in multi-
center, randomized, controlled trials demonstrated 6 – 8 mmHg reductions in IOP. This IOP 
reduction with latanoprost ophthalmic solution 0.005% dosed once daily was equivalent to the 
effect of timolol 0.5% dosed twice daily. 
14.2 Progression of Increased Iris Pigmentation 
A 3-year open-label, prospective safety study with a 2-year extension phase was conducted to 
evaluate the progression of increased iris pigmentation with continuous use of latanoprost 
ophthalmic solution once-daily as adjunctive therapy in 519 patients with open-angle glaucoma. 
The analysis was based on observed-cases population of the 380 patients who continued in the 
extension phase. 
Results showed that the onset of noticeable increased iris pigmentation occurred within the first 
year of treatment for the majority of the patients who developed noticeable increased iris 
pigmentation. Patients continued to show signs of increasing iris pigmentation throughout the 
five years of the study. Observation of increased iris pigmentation did not affect the incidence, 
nature, or severity of adverse events (other than increased iris pigmentation) recorded in the 


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study. IOP reduction was similar regardless of the development of increased iris pigmentation 
during the study. 
16 HOW SUPPLIED/STORAGE AND HANDLING 
Latanoprost ophthalmic solution is a clear, isotonic, buffered, preserved colorless solution of 
latanoprost 0.005% (50 mcg/mL). It is supplied as a 2.5 mL solution in a 5 mL clear low density 
polyethylene bottle with a clear polyethylene dropper tip, a turquoise high density polyethylene 
screw cap, and a tamper-evident clear low density polyethylene overcap. 
2.5 mL fill, 0.005% (50 mcg/mL): Package of 1 bottle: NDC 59762-0333-2 
Storage: Protect from light. Store unopened bottle(s) under refrigeration at 2° to 8°C (36° to 
46°F). During shipment to the patient, the bottle may be maintained at temperatures up to 40°C 
(104°F) for a period not exceeding 8 days. Once a bottle is opened for use, it may be stored at 
room temperature up to 25°C (77°F) for 6 weeks. 
17 PATIENT COUNSELING INFORMATION 
Potential for Pigmentation 
Advise patients about the potential for increased brown pigmentation of the iris, which may be 
permanent. Inform patients about the possibility of eyelid skin darkening, which may be 
reversible after discontinuation of latanoprost ophthalmic solution [see Warnings and 
Precautions (5.1)]. 
Potential for Eyelash Changes 
Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during 
treatment with latanoprost ophthalmic solution. These changes may result in a disparity between 
eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of 
eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment. 
Handling the Container 
Instruct patients to avoid allowing the tip of the dispensing container to contact the eye or 
surrounding structures because this could cause the tip to become contaminated by common 
bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of 
vision may result from using contaminated solutions [see Warnings and Precautions (5.6)]. 
When to Seek Physician Advice 
Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection) or 
have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid 
reactions, they should immediately seek their physician's advice concerning the continued use of 
the multiple-dose container. 
Use with Contact Lenses 
Advise patients that latanoprost ophthalmic solution contains benzalkonium chloride, which may 
be absorbed by contact lenses. Contact lenses should be removed prior to administration of the 


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solution. Lenses may be reinserted 15 minutes following administration of latanoprost 
ophthalmic solution. 
Use with Other Ophthalmic Drugs 
If more than one topical ophthalmic drug is being used, the drugs should be administered at least 
five (5) minutes apart. 
This product's label may have been updated. For current full prescribing information, please visit 
www.greenstonellc.com. 
 
LAB-0430-5.0 
Revised: 6/2017 
  



SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:  
An Open-Label, Multicenter Study Assessing the Efficacy and 
Safety of DE-117 Ophthalmic Solution 0.002% in Latanoprost 
Low/Non-Responder Subjects Diagnosed with Primary Open-Angle 
Glaucoma or Ocular Hypertension - Spectrum 5 Study 
 
 
NCT Number:  
NCT03697811 
 
Date of the document:
 08 Feb 2022 
 
 
 


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STATISTICAL ANALYSIS PLAN 
DE-117 SPECTRUM 5 
 
 
 
Protocol Title: 
An Open-Label, Multicenter Study Assessing the Efficacy and Safety of DE-
117 Ophthalmic Solution 0.002% in Latanoprost Low/Non-Responder Subjects 
Diagnosed with Primary Open-Angle Glaucoma or Ocular Hypertension – 
Spectrum 5 Study 
 
 
Product: 
DE-117  
 
 
Protocol Number:  
011711IN 
 
 
Sponsor: 
Santen Inc. 
 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608 
USA 
 
 
Date:  
February 08, 2022 
 
 
Status:  
Version 1.0 
 
CONFIDENTIAL 
 
The information in this document is considered privileged and confidential by Santen Inc. and 
may not be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by Federal and State Laws.  Persons to 
whom this information is disclosed must be informed that this information is privileged and 
confidential and that it should not be further disclosed. 
 
 


Confidential 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ........................................................................................................8 
2. 
OBJECTIVES AND ENDPOINTS ..............................................................................9 
2.1. 
Objectives .....................................................................................................................9 
2.1.1. 
Primary Objectives .......................................................................................................9 
2.1.2. 
Secondary Objectives ...................................................................................................9 
2.1.3. 
Safety Objective ............................................................................................................9 
2.2. 
Endpoints ......................................................................................................................9 
2.2.1. 
Primary Efficacy Endpoint ...........................................................................................9 
2.2.2. 
Secondary Efficacy Endpoints ......................................................................................9 
2.2.3. 
Safety Endpoints ...........................................................................................................9 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
General Study Design .................................................................................................11 
3.2. 
Randomization and Masking ......................................................................................12 
3.3. 
Sample Size Planning .................................................................................................12 
3.4. 
Visits and Assessments ...............................................................................................12 
4. 
TIME-RELATED TERMS .........................................................................................14 
4.1. 
Baseline Visit ..............................................................................................................14 
4.2. 
Study Periods, Treatment Start Date, and Treatment End Date .................................14 
4.3. 
Study Day ...................................................................................................................14 
4.4. 
Analysis Visit and Analysis Window .........................................................................15 
4.5. 
Analysis Timepoint and Analysis Timepoint Window ..............................................15 
4.6. 
Extent of Exposure .....................................................................................................16 
5. 
GENERAL CONSIDERATIONS ..............................................................................17 
5.1. 
Adjustments for Covariates ........................................................................................17 
5.2. 
Handling of Missing Data ...........................................................................................17 
5.2.1. 
Efficacy Measures ......................................................................................................17 
5.2.2. 
Safety Measures ..........................................................................................................17 
5.2.3. 
Dates for Medical Events and Medications ................................................................17 
5.3. 
Multi-Center Studies ...................................................................................................19 
5.4. 
Multiple Comparisons / Multiplicity ..........................................................................19 
5.5. 
Interim Analysis ..........................................................................................................19 


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6. 
STUDY POPULATION .............................................................................................20 
6.1. 
Safety Population ........................................................................................................20 
6.2. 
Full Analysis Set .........................................................................................................20 
6.3. 
Per-Protocol Set ..........................................................................................................20 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................21 
7.1. 
Subject Disposition .....................................................................................................21 
7.2. 
Demographics and Baseline Characteristics ...............................................................21 
7.3. 
Medical and Surgical History .....................................................................................22 
7.4. 
Protocol Deviations ....................................................................................................22 
7.5. 
Impact of the COVID-19 Pandemic ...........................................................................22 
7.6. 
Prior and Concomitant Medications ...........................................................................22 
7.7. 
Treatment Compliance ................................................................................................23 
7.8. 
Exposure to Study Medication ....................................................................................24 
8. 
EFFICACY ANALYSES ...........................................................................................25 
8.1. 
Efficacy-Related Definitions ......................................................................................25 
8.1.1. 
Study Eye and Fellow Eye ..........................................................................................25 
8.1.2. 
Baseline Score ............................................................................................................25 
8.1.3. 
Change and Percent Change from Baseline ................................................................25 
8.1.4. 
Response Endpoint and Response Rate ......................................................................25 
8.2. 
Analyses of Primary Endpoint and Secondary Endpoints ..........................................25 
8.2.1. 
Primary Analyses ........................................................................................................26 
8.2.2. 
Sensitivity Analyses ....................................................................................................26 
8.2.3. 
Analyses of Secondary Efficacy Endpoints ................................................................26 
8.3. 
Subgroup Analyses .....................................................................................................27 
9. 
SAFETY ANALYSES ...............................................................................................28 
9.1. 
Safety-Related Definitions ..........................................................................................28 
9.1.1. 
Adverse Event .............................................................................................................28 
9.1.2. 
Safety Measures ..........................................................................................................29 
9.2. 
Adverse Events ...........................................................................................................30 
9.2.1. 
Ocular Inflammation ...................................................................................................30 
9.2.2. 
Macular Edema ...........................................................................................................31 
9.2.3. 
Cosmetic Change(s) ....................................................................................................31 
9.3. 
Best-Corrected Visual Acuity .....................................................................................32 


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9.4. 
Slit-lamp Biomicroscopy ............................................................................................32 
9.5. 
Ophthalmoscopy .........................................................................................................32 
9.6. 
Eyelid Sulcus, Eyelid, Eyelash, and Iris Color ...........................................................32 
10. 
EXPLORATORY ANALYSES .................................................................................33 
10.1. 
Definitions ..................................................................................................................33 
10.1.1. 
Run-in Period Population ...........................................................................................33 
10.1.2. 
Time-Related Terms for Exploratory Analyses ..........................................................33 
10.1.3. 
Endpoint-Related Terms for Exploratory Analyses ...................................................33 
10.2. 
Summary of Run-in Period Population .......................................................................33 
10.2.1. 
Subject Disposition .....................................................................................................33 
10.2.2. 
Demographics .............................................................................................................33 
10.3. 
Exploratory Efficacy Analyses ...................................................................................34 
10.3.1. 
Analysis of Efficacy Measurements in the Run-in Period ..........................................34 
10.3.2. 
Other Exploratory Analyses .......................................................................................34 
10.4. 
Safety Analyses ..........................................................................................................34 
11. 
SUMMARY OF CHANGES TO THE PROTOCOL ................................................35 
11.1. 
Adding Exploratory Analyses .....................................................................................35 
11.2. 
Change in Handling Missing Data ..............................................................................35 
11.3. 
Change in Safety Population ......................................................................................35 
11.4. 
Change in Sample Size Planning ................................................................................35 
12. 
APPENDIX.................................................................................................................36 
 
 
 
 
 
 
 
 
 


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LIST OF TABLES 
Table 1: 
IOP-related Inclusion Criteria at the Specified Visits during Screening Phase ..........11 
Table 2: 
Assessment Schedule ..................................................................................................12 
Table 3: 
Definitions for Period Start and End Dates by Study Period ......................................14 
Table 4: 
Analysis Visit and Analysis Window .........................................................................15 
Table 5: 
Analysis Timepoint and Analysis Timepoint Window ..............................................16 
Table 6: 
Response Endpoints ....................................................................................................25 
Table 7: 
Overview of Primary and Sensitivity Analysis Methods ...........................................26 
Table 8: 
Safety Assessments .....................................................................................................29 
 
LIST OF FIGURES 
Figure 1: 
Study Design Diagram ................................................................................................11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Explanation 
ADR 
Adverse Drug Reaction 
AE(s) 
Adverse Event(s) 
ATC 
Anatomical-Therapeutic-Chemical 
BCVA 
Best-Corrected Visual Acuity 
CI 
Confidence Interval 
CM 
Concomitant Medications 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
ESI(s) 
Event(s) of Special Interest 
ET 
Early Termination 
FAS 
Full Analysis Set 
IOP 
Intraocular Pressure 
LOCF 
Last-observation-carried-forward 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Medical History 
mmHg 
Millimeter of Mercury 
OHT 
Ocular Hypertension 
OD 
Oculus Dexter (right eye) 
OS 
Oculus Sinister (left eye) 
OU 
Oculus Uterque (both eyes) 
POAG 
Primary Open-Angle Glaucoma 
PPS 
Per-Protocol Set 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
US 
United States 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the statistical methods to be implemented for the 
analysis of data collected from the SPECTRUM 5 study within the scope of Santen’s Protocol 
011711IN, “An Open-Label, Multicenter Study Assessing the Efficacy and Safety of DE-117 
Ophthalmic Solution 0.002% in Latanoprost Low/Non-Responder Subjects Diagnosed with 
Primary Open-Angle Glaucoma or Ocular Hypertension – Spectrum 5.” It applies to the study 
protocol version 1.0, dated 18 July 2018, and provides detailed instructions as to how each 
analysis will be performed. 
Results obtained from the analyses specified in the final approved version of the SAP will 
become the basis of the clinical study report (CSR) for this study.  Any deviations from the final 
approved version of the SAP must be substantiated by sound statistical reasoning and 
documented in the CSR. 


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2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
2.1.1. 
Primary Objectives 
To evaluate the intraocular pressure (IOP) lowering effect of DE-117 ophthalmic solution 
0.002% in latanoprost low/non-responder subjects diagnosed with Primary Open-Angle 
Glaucoma (POAG) or Ocular Hypertension (OHT). Specifically, the primary efficacy endpoint is 
the change from baseline (Day 1, Visit 4) in mean diurnal IOP at Month 3 (Visit 7). 
2.1.2. 
Secondary Objectives 
To evaluate the IOP lowering efficacy (change, percentage change and proportion of responders) 
of DE-117 ophthalmic solution 0.002% in latanoprost low/non-responder subjects diagnosed 
with POAG or OHT at each timepoint. 
2.1.3. 
Safety Objective 
To evaluate the safety of DE-117 ophthalmic solution 0.002% in latanoprost low/non-responder 
diagnosed with POAG or OHT. 
2.2. 
Endpoints 
2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline (Visit 4) in mean diurnal IOP at 
Month 3 (Visit 7). 
2.2.2. 
Secondary Efficacy Endpoints 
 Percent change from baseline (Visit 4) in mean diurnal IOP at Month 3 (Visit 7) 
 Change and percent change from baseline (Visit 4) in mean diurnal IOP at Week 2 
(Visit 5) and Week 6 (Visit 6) 
 Change and percent change from baseline (Visit 4) in IOP for each post-baseline 
timepoint/visit 
 Having a mean diurnal IOP reduction ≥ 10%, ≥ 15%, ≥ 20%, ≥ 25%, or ≥ 30% from 
baseline (Visit 4) at Month 3 (Visit 7) 
 Having a mean diurnal IOP ≤ 18 mmHg at Month 3 (Visit 7) 
2.2.3. 
Safety Endpoints 
The safety of DE-117 will be evaluated by: 
 Incidence of ocular and non-ocular adverse events (AEs) 
 Events of special interest (ESIs, which were defined to be macular edema, medication 
administration errors, and pregnancy) 
 Best-corrected visual acuity (BCVA) 


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 Slit-lamp biomicroscopy; severity scores for the following 12 parameters: anterior 
chamber cells, anterior chamber flare, lid hyperemia, lid edema, conjunctival 
hyperemia, conjunctival chemosis, corneal edema, corneal staining, keratic 
precipitates, lens, anterior synechiae of iris, posterior synechiae of iris 
 Ophthalmoscopy (cup-to-disc ratio, glaucomatous optic nerve severity score, and 
assessments of retina, macula, choroid, and vitreous) 
 Assessments for deepening of the upper eyelid sulcus (DUES) and other changes in 
eyelid, eyelash, and iris 


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3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is an open-label, multicenter study investigating the efficacy and safety of DE-117 
ophthalmic solution 0.002% in latanoprost low/non-responder subjects diagnosed with POAG or 
OHT. As shown in the study design diagram in Figure 1, subjects diagnosed with POAG or OHT 
who meet the eligibility criteria at Visit 1 (Screening) will enter a Washout Period of up to 35 
days (28 days + 7 days window) depending on their current topical IOP-lowering medication(s), 
if any. After completing the required Washout Period, subjects will return for Visit 2 (Week –8, 
start of a Run-in Period). Subjects who remain qualified will start a Run-in Period dosing 
latanoprost ophthalmic solution 0.005% once daily, and then return for Visit 3 (Week –4, mid-
point of the Run-in Period) and Visit 4 (Baseline, Day 1), to confirm ongoing eligibility. IOP 
will be measured at three timepoints (08:00, 12:00, and 16:00) at each scheduled visit. Table 1 
lists the IOP-related inclusion criteria at Visit 2, Visit 3 and Visit 4. 
Table 1: 
IOP-related Inclusion Criteria at the Specified Visits during Screening Phase 
Visit 
IOP at each scheduled timepoint 
(08:00, 12:00, and 16:00) 
Change in IOP at each scheduled 
timepoint (08:00, 12:00, and 16:00) from 
Visit 2 (Start of Run-in Period) 
Visit 2 (Start of 
Run-in Period) 
IOP in at least one eye ≥ 22 mmHg 
IOP in both eyes ≤ 34 mmHg 
 
Visit 3 
IOP in both eyes ≤ 34 mmHg 
Percent decrease of ≤ 25% 
Visit 4 (End of 
Run-in Period) 
IOP in both eyes ≤ 34 mmHg 
Percent decrease of ≤ 15% 
Subjects who meet all eligibility criteria at Visit 4 (Baseline, Day 1), will enter the Treatment 
Period and will be treated with DE-117 ophthalmic solution 0.002% for 3 months. 
Approximately 100 subjects with POAG or OHT who meet all eligible criteria are planned to 
enter the Treatment Period and be treated with DE-117 0.002% ophthalmic solution. 
 
Figure 1: 
Study Design Diagram 
  
 


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3.2. 
Randomization and Masking 
This is an open-label study; masking will not be applied. There will be no randomization for this 
study. 
3.3. 
Sample Size Planning 
Using one sample t-test with a significant level of 5%, a sample size of 100 will have 75% power 
to detect a mean diurnal IOP reduction of 1.0 mmHg from baseline with a standard deviation 3.5 
mmHg, after taking into account of up to 12% dropouts. 
3.4. 
Visits and Assessments 
There are 7 scheduled visits for each enrolled subject.  Assessments at each visit and the 
time/visit window for each post-baseline assessment are specified in the Assessment Schedule 
(Table 2). For subjects whose study participation is terminated prior to Visit 7 (Month 3), to the 
extent possible, all assessments scheduled for Visit 7 (Month 3) will be performed at the Exit 
Visit. 
Table 2: 
Assessment Schedule 
 
Washout Period 
Run-in Period 
Treatment Period 
Visit 1 
Screening 
Washout 
Period 
(up to 4  
weeks) 
Optional 
Visit 1ab 
Visit 2 
Week -8 
(Day-
56±3) 
Visit 3 
Week -4 
(Day-
28±3) 
Visit 4 
Baseline 
(Day 1) 
Visit 5 
Week 2 
(Day 
15±3) 
Visit 6 
Week 6 
(Day 43 ±5) 
Visit 7 
Month 3 
(Day 91±7) 
Exit or  
Early 
Termination 
Informed Consent(s) including 
the optional consent for 
pharmacogenomics/ genomics 
laboratory research study a 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
X 
X 
 
 
 
Demographics and 
Medical History, including 
prior PGA c 
X 
 
 
 
 
 
 
 
Concomitant Medications/ 
Therapies 
X 
X 
X 
X 
X 
X 
X 
X 
Dosing Compliance 
 
 
 
X 
X 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test d 
X 
 
 
 
X 
 
 
X 
Refraction e 
X 
 
 
 
 
 
 
 
BCVAe 
X 
X 
X (08:00) X (08:00) X (08:00) X (08:00) X (08:00) 
X (08:00) 
Biomicroscopy f 
X 
X 
X (08:00) X (08:00) X (08:00) X (08:00) X (08:00) 
X (08:00) 
IOP g 
X 
(any time) 
X 
(any 
time) 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 
08:00 
12:00 
16:00 


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Table 2: 
Assessment Schedule (Continued) 
 
Washout Period 
Run-in Period 
Treatment Period 
Visit 1 
Screening 
Washout 
Period 
(up to 4  
weeks) 
Optional 
Visit 1ab 
Visit 2 
Week -8 
(Day-
56±3) 
Visit 3 
Week -4 
(Day-
28±3) 
Visit 4 
Baseline 
(Day 1) 
Visit 5 
Week 2 
(Day 
15±3) 
Visit 6 
Week 6 
(Day 43 
±5) 
Visit 7 
Month 3 
(Day 91±7) 
Exit or  
Early 
Termination 
Pachymetry h 
X 
 
 
 
 
 
 
 
Iris color, eyelash, eyelid i 
 
 
 
 
X (photo) 
 
 
X (photo) 
Gonioscopy j 
X 
 
 
 
 
 
 
 
Visual Field k 
X 
 
 
 
 
 
 
 
Ophthalmoscopy l 
X (pupil 
dilation) 
 
 
 
X (16:00) 
 
 
X (16:00, 
pupil dilation) 
Blood Sampling for 
Pharmacogenomics/genomics m 
 
 
 
 
 
X 
Dispense Study Medication 
 
 
X 
X 
X 
 
X 
 
Collect Study Medication 
 
 
 
X 
X 
 
X 
X 
Phone call to remind subject to 
take evening dose on the day 
before each visit 
 
 
 
X 
X 
X 
X 
X 
a Informed Consent Form must be signed and dated before study procedures are performed. Informed consent for the 
optional pharmacogenomics/genomics laboratory research study may be obtained at any visit prior to study exit. 
b An interim safety visit may be performed during the washout period Visit 1a (optional, mid-washout visit), if in the 
Investigator’s opinion a subject’s IOP may be of concern. If subjects are treated with a tropical CAI during the 
washout period, Visit 1a (optional, mid-washout visit) is recommended to be performed. 
c The previous use of prostaglandin analogs should be confirmed by either subject’s medical records or subject 
history. 
d A urine pregnancy test will be conducted for all female subjects of childbearing potential.  
e Refraction will be performed at the screening visit. If more than 10 letters in BCVA are lost compared to the 
screening visit, then refraction should be performed again.  BCVA examination will be completed before IOP 
measurement at 08:00 (±60 min).  
f Biomicroscopy examination must be completed before IOP is measured at 08:00 (±60 min).  Aqueous flare and cell 
evaluation will be performed before fluorescein instillation.  
g IOP measurements will be performed at 08:00, 12:00, and 16:00 (±60 min) at all visits except for Visit 1 
(Screening) and Visit 1a (optional, mid-washout visit).  
h Pachymetry will be performed after IOP measurement at Visit 1 (Screening). 
i Eye photograph will be taken at Visits 4 (Baseline, Visit 4) and 7 (Month 3).  
j If gonioscopy was performed within 3 months (90 days) prior to screening and was documented in the subject’s 
records, no additional screening gonioscopy examination is necessary.  Gonioscopy will be performed after IOP 
measurement at Visit 1 (Screening). 
k If visual field test was performed within 3 months (90 days) prior to screening and was documented in the 
subject’s records, no additional screening visual field test is necessary.  
l Ophthalmoscopy will be performed at Visits 1, 4, and 7 (i.e., Screening, Baseline and Month 3) after the 16:00 IOP 
measurements.  Ophthalmoscopy will be performed with pupil dilation at Screening and Visit 7 (Month 3)/Study 
Exit or Early Termination.  Dilation of the pupil will be performed after the 16:00 IOP measurement. 
m Blood sampling for the pharmacogenomics/genomics laboratory research study may be performed at any visit after 
pharmacogenomics/genomics informed consent obtained, subject is enrolled, and study drug, DE-117 ophthalmic 
solution 0.002%, dosing has begun. 


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4. 
TIME-RELATED TERMS 
4.1. 
Baseline Visit 
The Baseline Visit is Visit 4 (Day 1) when the subject is enrolled for treatment with DE-117 
0.002% ophthalmic solution. 
4.2. 
Study Periods, Treatment Start Date, and Treatment End Date 
This study has two study periods when subjects received treatments provided by the Sponsor: 
Run-in Period and Treatment Period. The start date and end date for each period are defined as 
follows in Table 3. 
 
Table 3: 
Definitions for Period Start and End Dates by Study Period 
Study Period 
Period Start Date 
Period End Date 
Run-in Period 
The date at which a 
subject takes the 
first dose of 
latanoprost 0.005%  
The date at which a subject takes the last dose of 
latanoprost 0.005%. If the date of the last dose is missing, 
the day before the Visit 4 (Day 1) date will considered as 
the end date. 
Treatment Period 
The date at which a 
subject takes the 
first dose of the 
study medication, 
DE-117. 
The date at which a subject takes the last dose of the study 
medication, DE-117.  If the date of the last dose is missing, 
then 
 
The day before the Visit 7 (Month 3) date will be 
considered the end date for subjects who completed 
the study. 
 
The day before the Exit Visit date will be used for 
subjects who prematurely discontinued from the 
study.  If the Exit Visit date of a non-completer is 
not available, then the day before the last available 
visit date will be considered the end date. 
 
Treatment start date and Treatment end date are the start date and the end date of the Treatment 
Period, defined in Table 3.  
4.3. 
Study Day 
The study day describes the relative day of an observation starting with the reference date 
designated as Study Day 1.  In this study, the treatment start date is the reference date.  Thus, the 
study day will be calculated as: 
 For a pre-baseline date, Study Day = Date – Treatment Start Date  
 For a post-baseline date, Study Day = Date – Treatment Start Date + 1 
 


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4.4. 
Analysis Visit and Analysis Window 
Analysis visit is a timing variable to be used for analyses involving visits.  For each analysis visit, 
an analysis window is set up to determine the analysis visit to which a measurement should be 
mapped (Table 4). The analysis visit of a measurement will be determined based on the study 
day of the measurement and specified analysis windows and is not necessarily the same as the 
study visit at which the measurement was collected.  For example, an out-of-window 
measurement collected at the Week 2 study visit will be mapped to the Week 6 analysis visit, if 
the study day of the measurement falls into the analysis window of Week 6. 
The following analysis windows will be applied to minimize the amount of missing data for 
analysis purposes: 
 
Table 4: 
Analysis Visit and Analysis Window 
Analysis Visit 
Name 
(Target Day) 
Protocol Visit 
Window 
Analysis Window 
Ophthalmoscopy 
Iris Color, Eyelash, 
and Eyelid 
Other 
Parameters 
Baseline (Day 1) 
[1, 1] 
[ - , 1] 
[1, 1] 
[1, 1] 
Week 2 (Day 15) 
[12, 18] 
NA* 
NA* 
[2, 28] 
Week 6 (Day 43) 
[38, 48] 
NA* 
NA* 
[29, 61] 
Month 3 (Day 91) 
[84, 98] 
[2,  - ] 
[2,  - ] 
[62, - ] 
*Not collected at this visit. 
 
If there are two or more visits that fall into the same analysis window, then the visit closest to the 
target assessment day will be selected for that visit window.  In the case that two visits are 
equidistant to the target assessment day, i.e., one is before and one is after the target assessment 
day, the later one will be selected for that visit. 
For analyses of IOP involving post-baseline visits, if there are two or more visits that fall into the 
same analysis window of a post-baseline visit, then the visit in which IOP are measured at all the 
scheduled timepoints (8:00, 12:00, and 16:00) will be selected for that analysis visit first, before 
applying the above rule. 
4.5. 
Analysis Timepoint and Analysis Timepoint Window 
Analysis timepoint is a timing variable to be used for analyses involving timepoints. For each 
analysis timepoint, an analysis timepoint window is set up to determine the allowance range 
(Table 5). 
 
 


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Table 5: 
Analysis Timepoint and Analysis Timepoint Window 
Analysis Timepoint 
Protocol Timepoint Window 
Analysis Timepoint Window  
8:00 
[7:00, 9:00] 
[   -      , 9:59] 
12:00 
[11:00, 13:00] 
[10:00, 13:59] 
16:00 
[15:00, 17:00] 
[14:00,    -     ] 
4.6. 
Extent of Exposure 
The extent of exposure to study medication will be assessed by duration of treatment exposure, 
derived as: 
Duration of treatment exposure = Treatment end date – Treatment start date + 1 


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5. 
GENERAL CONSIDERATIONS 
All measures will be summarized descriptively.  Continuous variables will be summarized using 
descriptive statistics such as number of observations (n), mean, standard deviation, standard 
error, median, minimum, and maximum.  Categorical variables will be tabulated using frequency 
(n) and percent (%). 
Unless otherwise specified, the following conventions will be followed in reporting the decimal 
places. 
Reporting Statistics 
Decimal places  
Range (Low Value, High Value) 
Recorded Decimal Places 
Mean, Median  
Recorded value + 1 Decimal Places 
Confidence Interval, Standard Deviation, Standard Error 
Recorded value + 2 Decimal Places 
p-Value 
4 Decimal Places (ex. 0.0021) 
The statistical testing will be conducted at a significance level of 0.05 (two-sided) and the  
95% confidence interval will be shown, unless specified otherwise.  No statistical testing will be 
conducted for safety measures. 
All data manipulations, descriptive summaries, and statistical hypothesis testing will be 
performed using Statistical Analysis System (SAS) Version 9.4 or later. Individual data, 
including relevant derived variables, will be listed. 
Additional analyses not specified in this SAP may be conducted if deemed necessary and will be 
documented in the CSR. 
5.1. 
Adjustments for Covariates 
The efficacy endpoint will be analyzed using a paired t-test; hence no covariate adjustment will 
be necessary. 
5.2. 
Handling of Missing Data 
5.2.1. 
Efficacy Measures 
The primary analysis of IOP will be based on observed cases. As a sensitive analysis of the 
primary efficacy endpoint, missing IOP data at Month 3 will be imputed by last observed post-
baseline IOP. If none of the post-baseline IOP data is available, baseline IOP can be used to 
impute the missing IOP data at Month 3. 
5.2.2. 
Safety Measures 
Descriptive summaries of safety measures will be based on observed data only.  No imputation 
of missing scores will be implemented. 
5.2.3. 
Dates for Medical Events and Medications 
Completely or partially missing onset and resolution dates for AEs, Concomitant Medications 
(CM), and Medical History (MH) will be imputed in a conservative fashion as follows:   


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Incomplete Adverse Event Onset Date 
1. Year imputation  
 If year is missing (or AE onset date is completely missing), then the onset date will 
not be imputed. 
2. Month imputation 
 If year is not missing but month is missing, then:  
 If year = year of first study dose date, then set the month and day to the day and 
month of first study dose 
 Else if year ≠ year of first study dose: set month to January 
3. Day imputation 
 If day is missing (month and year not missing), then: 
 If year = year and month = month of first study dose, then set day to day of first 
study dose 
 Else if year ≠ year and month ≠ month of first study dose, then set day to first day 
of the month in the year 
Incomplete Adverse Event Resolution Date 
 Do not impute if any resolution date is missing 
 If the duration of AE is needed, the following approach may be considered: 
 If year is missing (or AE resolution date is completely missing): do not impute 
 If year is not missing but month and day are missing: impute December 31st for 
missing month and day 
 If year and day are not missing but month is missing: impute December for 
missing month 
 If year and month are not missing but day is missing: impute last day of the month 
for missing day. 
Incomplete CM or MH Onset Date  
1. If year is missing (or CM/MH onset date is completely missing): do not impute 
2. If year is not missing but month and day are missing: impute January 1st for missing 
month and day 
3. If year and day are not missing but month is missing: impute January for missing month 
4. If year and month are not missing but day is missing: impute 01 for missing day 
Incomplete CM or MH Resolution Date 
 Do not impute if any resolution date is missing. 


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5.3. 
Multi-Center Studies 
This is a multi-center study enrolling subjects from approximately 25 US sites.  The number of 
subjects per site might be small.  Therefore, there are no analyses adjusting for sites. 
5.4. 
Multiple Comparisons / Multiplicity 
This trial plans to have only one hypothesis testing, which is for the primary efficacy endpoint.  
Therefore, multiple comparisons do not apply and there is no need to adjust for multiplicity. 
5.5. 
Interim Analysis 
No interim analysis is planned for this study. 
 


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6. 
STUDY POPULATION 
6.1. 
Safety Population 
The Safety Population will include all subjects who signed informed consent and received at 
least one dose of the study medication, DE-117.  The safety analyses will be performed on the 
Safety Population. 
6.2. 
Full Analysis Set 
The Full Analysis Set (FAS) will include all Safety population who had at least one post-baseline 
IOP measurement. The efficacy analyses will be performed using the FAS or a subset of the 
FAS. 
6.3. 
Per-Protocol Set 
The Per-Protocol Set (PPS) is a subset of the FAS, restricted to the subjects who fulfill the 
protocol in the terms of eligibility, interventions, and other assessment.  It will be the analysis 
population for some sensitivity analyses. 
Before database lock, Santen’s study team will review all protocol deviations, identify subjects 
with any protocol deviation that could impact the efficacy outcome, and determine whether to 
exclude the subject from the PPS. 
 


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7. 
SUMMARY OF STUDY POPULATION DATA 
7.1. 
Subject Disposition 
The disposition of all subjects who enrolled for open-label DE-117 treatment will be 
summarized.  The summary will include the number and percentage of subjects in the Safety 
population, FAS, and PPS.  The disposition summary will also include the number and 
percentage of subjects who completed the study drug, subjects who discontinued the study drug 
prematurely but continued with study participation and among which who completed or not 
completed all study visits, as well as the number and percentage of subjects who discontinued 
from the study or discontinued the study drug prior to Month 3 Visit by the primary 
discontinuation reason separately. 
7.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be descriptively summarized for FAS.  
Specifically, for subject demographics, the following variables will be summarized: 
 Age at enrollment (continuous and categorical: < 65 years or ≥ 65 years) 
 Sex (categorical: Male or Female) 
 Ethnicity (categorical: Hispanic/Latino or Not) 
 Race (categorical: American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, or Other) 
For baseline characteristics, the following variables will be summarized for study eye and fellow 
eye, separately: 
 Primary ocular diagnosis (categorical: POAG or OHT) 
 Prior use of IOP-lowering medications (categorical: oral/topical carbonic anhydrase 
inhibitors, alpha agonists, beta-blockers, prostaglandin/prostaglandin analogues, Rho 
kinase inhibitor, Miotics, other IOP medication, or none) 
 Baseline lens status (categorical: phakic or pseudophakic/aphakic) 
 Mean diurnal IOP score and IOP score at each scheduled timepoint (08:00, 12:00, and 
16:00) at Baseline (Day 1). 
 BCVA (logMAR) 
 Central corneal thickness (µm) 
 Glaucomatous optic nerve findings (categorical: none, mild, moderate, or severe) 
 Anterior chamber angle classification (Shaffer scale; categorical: approximately 20 
degrees, approximately 30 degrees, or approximately 40 degrees or more) 
 Iris Color (categorical: Blue/Gray, Blue/Gray with Slightly Brown,  
Blue/Gray – Brown, Green, Green with Slightly Brown, Green – Brown,  
Yellow – Brown, or Brown) 


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 Visual field (parameters: glaucoma Hemifield test, visual field mean deviation by 
device, and visual field pattern standard deviation by device) 
7.3. 
Medical and Surgical History 
For this study, medical and surgical history and adverse events will be coded using  
MedDRA 21.1, 2018.  Each medical event will be classified into a SOC and mapped to a 
Preferred Term (PT). 
The medical and surgical history will be summarized for the Safety population.  Subjects 
reporting any medical and surgical history at baseline will be tabulated by SOC and PT. 
7.4. 
Protocol Deviations 
In this study, protocol deviations are categorized as follows: 
 Informed Consent 
 Inclusion/Exclusion Criteria 
 Concomitant Treatment  
 Investigational Product  
 Procedures/Tests/Assessments 
 Laboratory  
 Time Window 
 Other 
A protocol deviation is considered significant if it may affect the subject’s rights, safety, or  
well-being, and/or the completeness, accuracy, or reliability of the study data.  Santen’s study 
team will review all protocol deviations and determine the list of significant protocol deviations 
prior to database lock.  All enrolled subjects with any significant protocol deviation(s) will be 
tabulated by deviation category.  In addition, two listings will be provided: (1) all significant 
protocol deviations and (2) subjects excluded from the per protocol population. 
7.5. 
Impact of the COVID-19 Pandemic 
The impact of the COVID-19 pandemic is defined as any disruption to the study and subject 
participation, such as changes in study visits, missed visits, subject discontinuations, etc.  All 
Safety Population subjects who experienced any of such impact will be summarized and listed 
along with the description of how their participation was altered. 
7.6. 
Prior and Concomitant Medications 
Non-study medications will be categorized into prior medications and concomitant medications.  
Specifically, prior medication is defined as any non-study medication taken and ended prior to 
the study medication (DE-117) start date.  The latanoprost ophthalmic solution 0.005%, 
administered during the Run-in Period, is qualified as one of the prior medications by the above 
definition. However, it becomes trivial to include the latanoprost in any summaries or listings as 


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all enrolled subjects must complete the Run-in Period before taking the study medication,  
DE-117. Hence, the latanoprost medication will be excluded from the prior medication analyses. 
However, any latanoprost medication used prior to entering the Run-in Period will still be 
included in the prior medication. 
Concomitant medication is defined as any non-study medication taken concurrently while 
receiving study medication (DE-117), i.e., the period of time from first dose to last dose of a 
concomitant medication taken by a subject must overlap with the period of time from first dose 
to last dose of the study medication (DE-117). While latanoprost medication taken during the 
Run-in Period will be excluded from the prior medication analyses, any latanoprost medication 
used as a rescue medication during the Treatment Period will be included in the concomitant 
medication analyses. 
For this study, non-study medications, including prior and concomitant medications, will be 
coded using World Health Organization (WHO) Drug Global, Version September 2018, format 
B3.  Each non-study medication will be classified using the Anatomical-Therapeutic-Chemical 
(ATC) classification system and mapped to a WHO Drug preferred drug name. 
Non-study medications will be summarized for the Safety population. Subjects taking any prior 
medications, will be tabulated by ATC level 3, level 4, and preferred drug name.  A subject will 
be counted at most once for each prior medication, even if the subject took the same prior 
medication on multiple occasions.  Subjects taking any concomitant medications will be 
tabulated similarly.  In addition, prior medications and concomitant medications will also be 
listed, separately. 
7.7. 
Treatment Compliance 
For the purpose of compliance calculation, there will be three study intervals in the Treatment 
Period: 
 Baseline Visit to Week 2 
 Week 2 to Week 6 
 Week 6 to Month 3 
The compliance rate for a subject will be calculated as follows for each study interval: 
Compliance Rate (%) = (Duration – ∑Miss) / Duration × 100 
Where 
Duration: The number of days subject should have administered study medication (i.e., DE-117) 
calculated as: 
Study Interval 
Equation for Duration Calculation 
Baseline Visit to Week 2 
Week 2 Visit date – Date of first DE-117 drug dispensation 
Week 2 to Week 6 
Week 6 Visit date – Week 2 Visit date 
Week 6 to Month 3 
Month 3 Visit date – Week 6 Visit date 
Miss:  The number of missed doses since the last visit. 


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The compliance rate of subjects in the FAS will be summarized by study intervals in the 
Treatment Period. 
7.8. 
Exposure to Study Medication 
The duration of exposure to a study medication, DE-117 ophthalmic solution 0.002%, is 
measured by days on treatment as derived in Section 4.3.  For subjects in the Safety Population, 
the duration of exposure will be summarized using descriptive statistics, and frequency and 
percentage of subjects will be tabulated by duration category (1-30 days, 31-60 days, 61-70 days, 
71-80 days, 81-90 days, or ≥ 91 days). 


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8. 
EFFICACY ANALYSES 
8.1. 
Efficacy-Related Definitions 
8.1.1. 
Study Eye and Fellow Eye 
The study eye of a treated subject will be the eye that received the study medication, the DE-117 
ophthalmic solution 0.002%, and met the eligible criteria as study eye at Visit 4 (Baseline,  
Day 1).  If both eyes meet the eligibility criteria, the eye with the higher mean diurnal IOP at 
Visit 4 (Baseline, Day 1) will be designated as the study eye.  If both eyes meet the eligibility 
criteria and have the same mean diurnal IOP, the right eye will be designated as the study eye.  
The other eye will be the non-study eye, or fellow eye. 
8.1.2. 
Baseline Score 
The baseline score is the observed measurement at Visit 4 (Baseline).  If a baseline score is 
missing, the last observed measurement or derived score prior to the first dose of study 
medication will be used to impute the baseline score. 
8.1.3. 
Change and Percent Change from Baseline 
The change and the percent change from baseline in a measure at a post-baseline visit will be 
derived as: 
 Change = (Score at the Post-Baseline Visit) – (Baseline Score) 
 Percent Change from Baseline = 100 × Change / (Baseline Score) 
8.1.4. 
Response Endpoint and Response Rate 
Six IOP response endpoints (Table 6) will be evaluated at Month 3 (Visit 7) in this study: 
Table 6: 
Response Endpoints 
Response Endpoint 
Response criteria in mean diurnal IOP 
IOP 10% response 
Percent reduction from Baseline ≥ 10% 
IOP 15% response 
Percent reduction from Baseline ≥ 15% 
IOP 20% response 
Percent reduction from Baseline ≥ 20% 
IOP 25% response 
Percent reduction from Baseline ≥ 25% 
IOP 30% response 
Percent reduction from Baseline ≥ 30% 
IOP ≤ 18 mmHg response 
Mean diurnal IOP ≤ 18 mmHg 
For a response endpoint, the response rate at Month 3 (Visit 7) is calculated as the proportion of 
subjects who met the response criterion at Month 3 (Visit 7). 
8.2. 
Analyses of Primary Endpoint and Secondary Endpoints 
Unless specified otherwise, efficacy analyses will be performed on the study eye, based on the 
FAS, and data on fellow eye will not be used. 


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8.2.1. 
Primary Analyses 
The primary efficacy endpoint is the change from Baseline (Day 1) in the mean diurnal 
intraocular pressure at Month 3 (Visit 7).  
For the primary endpoint, the change of mean diurnal IOP will be evaluated in accordance with 
the following null (versus alternative) hypothesis: 
H0: 𝜇𝑗−𝜇𝑖= 0  
versus 
HA: 𝜇𝑗−𝜇𝑖≠0 
where 𝜇𝑖 is the mean value of mean diurnal IOP at Baseline (Day 1) and 𝜇𝑗 is that value at 
Month 3 (Visit 7). 
The primary analysis of the primary efficacy endpoint will be performed based on the observed 
cases of the FAS. Paired t-test will be used to determine whether the change from the Baseline 
(Visit 4) in mean diurnal IOP at Month 3 (Visit 7) is different from zero. The mean value and 
standard deviation of the change from baseline in mean diurnal IOP will be reported along with a 
95% confidence interval and a p-value.  
8.2.2. 
Sensitivity Analyses 
The following sensitivity analyses will be performed to assess the robustness of the results from 
the primary analysis (Table 7). 
Table 7: 
Overview of Primary and Sensitivity Analysis Methods 
Primary or Sensitivity 
Analysis 
Statistical 
Method 
Analysis 
Population 
Handling of Missing 
Data 
Primary 
Paired t-test 
FAS 
Observed cases 
Sensitivity 
Paired t-test 
FAS 
LOCF 
Paired t-test 
PPS 
Observed cases 
Abbreviations: FAS = full analysis set; PPS = per protocol set; LOCF = Last observation carried forward. 
Paired t-tests in primary and sensitive analyses will be implemented using SAS PROC TTEST.  
8.2.3. 
Analyses of Secondary Efficacy Endpoints 
The following secondary endpoints will be analyzed: 
 Percent change from baseline in mean diurnal IOP at Month 3 (Visit 7) 
 Change and percent change from baseline (Visit 4) in mean diurnal IOP at Week 2 
(Visit 5) and Week 6 (Visit 6) 
 Change and percent change from baseline in IOP at each post-baseline timepoint/visit 
 Having a mean diurnal IOP reduction ≥ 10%, ≥ 15%, ≥ 20%, ≥ 25%, or ≥ 30% from 
Baseline (Visit 4) at Month 3 (Visit 7) 
 Having a mean diurnal IOP ≤ 18mmHg at Month 3 (Visit 7) 


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For continuous secondary endpoints (change and percent change from baseline in IOP and in 
mean diurnal IOP) at Week 2 (Visit 5), Week 6 (Visit 6), and Month 3 (Visit 7), descriptive 
statistics will be provided including the number of subjects (n), mean, standard deviation, 
median, minimum and maximum. For binary secondary endpoints, the responder rates will be 
tabulated using frequencies and percentages.    
8.3. 
Subgroup Analyses 
The homogeneity of treatment effects among prospectively defined subgroups will be assessed 
via descriptive statistics of the mean diurnal IOP and its change from baseline by analysis visit 
for the following subgroups: 
 Age (< 65 or ≥ 65 years) 
 Sex (males or females) 
 Race (White, Black or African American, Asian)  
 Primary ocular diagnosis (POAG or OHT) 
 Prior use of IOP-lowering medication (oral/topical carbonic anhydrase inhibitors, 
alpha agonists, beta-blockers, prostaglandin/prostaglandin analogues, ROCK Rho 
kinase inhibitor, Miotics, other IOP medications, or none) 
 Mean diurnal IOP at baseline (< 25 or ≥ 25 mmHg) 
 Baseline lens status (categorical: phakic or pseudophakic/aphakic) 
Other subgroup analyses may be performed as deemed necessary. 


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9. 
SAFETY ANALYSES 
9.1. 
Safety-Related Definitions 
9.1.1. 
Adverse Event 
Under Protocol 011711IN, an AE is defined as any on-study untoward medical occurrence (e.g., 
sign, symptom, disease, syndrome, intercurrent illness) that occurs in a study subject, regardless 
of the suspected cause and regardless of the timing of the study medication administration.  An 
on-study AE can occur any time after the date of informed consent through the last study visit. 
An AE will be considered as treatment-emergent if the AE occurred on or after the treatment 
start date up to 2 days after treatment end date (or the last study visit).  For this study, treatment 
refers to the study treatment of DE-117 ophthalmic solution 0.002%.  Treatment-emergent AEs 
(TEAEs) are a subset of on-study AEs.  All on-study AEs will be collected, but only AEs 
occurring during the Treatment Period (TEAEs) will be tabulated. 
The severity of each AE will be graded by the Clinical Investigator as Mild, Moderate, or 
Severe. AEs will also be rated by the Investigator as to their causality/relationship to the study 
drug. 
Each AE will be classified into a system organ class (SOC) and coded to a preferred term (PT) 
using Medical Dictionary for Regulatory Activities (MedDRA), version 21.1 published in 2018. 
9.1.1.1. 
Ocular Adverse Event 
An AE will be counted as an ocular AE if the Clinical Investigator selected “OD”, “OS”, or 
“OU” under ‘Eye(s) affected’ on the AE eCRF. 
9.1.1.2. 
 
Adverse Drug Reaction 
An AE will be counted as an adverse drug reaction (ADR) if the Clinical Investigator answered 
‘Related’ to the AE eCRF question “Relationship to Study Drug” for AEs that started during the 
Treatment Period. 
9.1.1.3. 
 
Serious Adverse Event 
An AE will be counted as a serious adverse event (SAE) if the Clinical Investigator selected 
“Yes” to the question ‘Is the adverse event serious?’ on the AE eCRF.  Any AE is considered a 
SAE if it fulfills one or more of the following criteria: 
 Death (i.e., the AE caused or led to death) 
 Life threatening (i.e., immediately life-threatening) 
 It required or prolonged inpatient hospitalization. 
 It resulted in a persistent or significant disability/incapacity (i.e., the AE resulted in a 
substantial disruption of the subject’s ability to carry out normal life functions). 
 It resulted in a congenital anomaly/birth defect in the offspring of a study subject who 
was exposed to study therapy prior to conception or during pregnancy. 


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 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. 
9.1.1.4. 
Events of Special Interest 
For this study, events of special interest (ESI) are pregnancy, clinically significant study 
medication administration error, and macular edema/cystoid macular edema. 
9.1.2. 
Safety Measures 
Table 8 lists the safety measures to be evaluated for this study. 
Table 8: 
Safety Assessments 
Safety Measures 
Note 
BCVA 
Best-corrected visual acuity will be measured for each eye at each visit 
under normal room illumination using visual acuity chart (e.g., 
ETDRS chart) and the logMAR scoring will be recorded in the 
subject’s source document.  Increase in logMAR scores means 
worsening in visual acuity. 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy examinations (severity scores for  
12 parameters: anterior chamber cells, anterior chamber flare, lid 
hyperemia, lid edema, conjunctival hyperemia, conjunctival chemosis, 
corneal edema, corneal staining, keratic precipitates, lens, anterior 
synechiae of iris, posterior synechiae of iris) will be performed and 
graded right before the 8:00 IOP measurement at all visits except Visit 
1/1a (Screening or mid washout visit).  Cataract severity will be 
assessed for subjects with phakic lens.  
Ophthalmoscopy 
The ophthalmoscopy (fundus) examination will be performed for each 
eye at Visit 1, Visit 4, and Visit 7 Study Exit/Early Termination.  
Variables from ophthalmoscopy are cup-to-disc ratio, glaucomatous 
optic nerve severity, and assessments of vitreous, retina, macula, and 
choroid.  
Eyelid Sulcus, Eyelid, and 
Iris Color 
The investigator (or his/her designee) will take front view and side 
view photograph of each eye at Visit 4 (Baseline).  The photographs 
must include iris, eye lids and eyelashes of each eye.  The photographs 
taken at Visit 4 (Baseline) will be used to help the Investigator assess 
any changes (“No changes”, “Increased”, or “Decreased”) from 
baseline in eyelid, eyelashes, iris color, and DUES (“Yes”, “No”) at 
Visit 7 Study Exit/Early Termination. 
The safety-related measures collected in this study include AEs, events of special interest (ESIs), 
best-corrected visual acuity, slit-lamp biomicroscopy (severity scores for 12 parameters), 
ophthalmoscopy (cup-to-disc ratio, glaucomatous optic nerve severity score, and assessments of 
retina, macula, choroid, and vitreous), and eyelid sulcus/eyelid/eyelash/iris color. The Safety 
population will be used for all summaries during the Treatment Period. 


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All the safety-related measures will be summarized descriptively. Except AEs, the descriptive 
summary of each ocular safety-related measure and the change from baseline in that measure 
will be performed for study eyes and fellow eyes separately. 
9.2. 
Adverse Events 
AEs, SAEs, ADRs, serious ADRs, and significant AEs (AEs leading to study drug 
discontinuation and AEs leading to death) will be tabulated by type of AEs for all AEs, ocular 
AEs, and non-ocular AEs separately. 
Besides the overall AE summary, AEs, SAEs, ADRs, serious ADRs will be tabulated by SOC 
and preferred term for all AEs, ocular AEs, and non-ocular AEs separately.  A subject who 
experienced multiple AEs within a SOC or preferred term will be counted only once for that 
SOC or preferred term.  Non-serious AEs (including number of events) will also be summarized 
by SOC and preferred term. ESIs will be summarized descriptively. 
AEs, SAEs, ADRs, serious ADRs, ocular AEs, AEs leading to death, AEs leading to study drug 
discontinuation, non-TEAEs, and ESIs, if any, will be listed separately. 
9.2.1. 
Ocular Inflammation 
Subjects who developed AEs during the Treatment Period with one of the following preferred 
terms will be included in the ocular inflammation summary: 
 Anterior chamber cell 
 Anterior chamber flare 
 Anterior chamber inflammation 
 Eye inflammation  
 Iridocyclitis  
 Iritis 
 Uveitis 
Other preferred terms might be added upon review of the AE data before database lock. 
Ocular inflammation leading to study drug discontinuation, requiring steroid treatment, or 
requiring NSAIDs treatment will be summarized by frequency and percentage separately. 
Ocular inflammation start time (in terms of study day) and duration of the AE will be 
summarized at the eye level using mean, standard deviation, median, minimum, and maximum 
by study eye and fellow eye separately.  To allow for the computation of simple descriptive 
statistics, only subjects who develop ocular inflammation during the Treatment Period will be 
used for the ocular inflammation start time summary, and only subjects who develop these AEs 
during the Treatment Period and later resolved will be used in the duration of AE analysis. 
All ocular inflammation AEs will be provided in a listing. 


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9.2.2. 
Macular Edema 
Subjects who developed AEs during the Treatment Period with one of the following preferred 
terms will be included in the macular edema summary: 
 Macular edema 
 Cystoid macular edema 
Macular edema start time (in terms of study day) and duration of the AE will be summarized 
using mean, standard deviation, median, minimum, and maximum by study eye and fellow eye 
separately.  To allow for the computation of simple descriptive statistics, only subjects who 
develop macular edema during the Treatment Period will be used for the macular edema start 
time summary, and only subjects who develop these AEs during the Treatment Period and later 
resolved will be used in the duration of AE analysis. 
Change from baseline in BCVA at the onset of macular edema, when macular edema is resolved, 
and at the last visit will be summarized using mean, standard deviation, median, minimum, and 
maximum by study eye and fellow eye separately.  Subjects with pseudophakic lens or phakic 
lens at baseline who developed macular edema during the Treatment Period will be summarized 
by frequencies and percentages separately. 
The aforementioned summaries will be performed at the eye level.  All macular edema AEs will 
be provided in a listing. 
9.2.3. 
Cosmetic Change(s) 
Subjects who developed AEs during the Treatment Period with one of the following preferred 
terms will be included in the cosmetic change summary: 
 Blepharal pigmentation  
 Eyelash changes 
 Eyelash hyperpigmentation  
 Eyelash thickening  
 Growth of eyelashes  
 Lid sulcus deepened 
 Trichiasis  
 Iris hyperpigmentation 
Other preferred terms might be added upon review of the AE data before database lock. 
Cosmetic change(s) start time (in terms of study day) will be summarized using mean, standard 
deviation, median, minimum, and maximum by study eye and fellow eye separately.  To allow 
for the computation of simple descriptive statistics, only subjects who develop cosmetic 
change(s) during the Treatment Period will be used for the cosmetic change start time summary. 
The aforementioned summaries will be performed at the eye level.  All cosmetic change AEs 
will be provided in a listing. 


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9.3. 
Best-Corrected Visual Acuity 
BCVA (logMAR scores) and changes from baseline will be summarized by analysis visit for 
study eyes and fellow eyes, separately.  In addition, any worsening of ≥ 0.2 LogMAR (2 lines) 
from baseline will be summarized and listed. 
9.4. 
Slit-lamp Biomicroscopy 
For each biomicroscopy parameter rated on a 0-3 scale (0=None, 1=Mild, 2=Moderate, 
3=Severe), rating scores and changes from baseline will be summarized by analysis visit for 
study eyes and fellow eyes, separately.  In addition, any clinically significant worsening 
(increase of ≥ 1 unit in rating scale of anterior chamber cell and of anterior chamber flare and 
increase of ≥ 2 units in other parameters) from baseline in severity will be listed. 
9.5. 
Ophthalmoscopy 
Cup-to-disc ratio will be summarized with n, mean, standard deviation, median, minimum, and 
maximum by analysis visit for study eyes and fellow eyes separately.  In addition, subjects with 
at least 0.2 increase in cup/disc ratio from baseline will be listed. 
Glaucomatous optic nerve findings will be assessed as 0 = none, 1 = mild, 2 = moderate, or  
3 = severe.  Frequency and percentage of rating scores will be summarized by analysis visit for 
study eyes and fellow eyes, separately.  In addition, subjects with any worsening (increase) of  
≥ 2 units from baseline at Month 3 will be listed. 
Retina/Macula/Choroid and vitreous will be assessed as normal or abnormal.  Shift from baseline 
at Month 3 will be summarized on study eyes and fellow eyes separately.  In addition, subjects 
with change from baseline from normal to abnormal in these parameters will be listed. 
9.6. 
Eyelid Sulcus, Eyelid, Eyelash, and Iris Color 
For changes from baseline in eyelid pigmentation, eyelid hair growth, eyelash length, eyelash 
thickness, eyelash pigmentation, eyelash number, and iris color/pigmentation, frequency and 
percentage of subjects with No change, Increased, or Decreased will be summarized by analysis 
visit for study eyes and for fellow eyes.  For changes from baseline in eyelid sulcus, count and 
percentage of changes (Yes) at Month 3 will be summarized for study eyes and for fellow eyes.  
In addition, any changes from baseline in eyelid sulcus at Month 3 will be listed. 


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10. 
EXPLORATORY ANALYSES 
In order to enroll the study targeted population, latanoprost low/non-responders, there is an 
additional Run-in Period in this study. The exploratory analyses, specified below in this section, 
will be conducted to facilitate the description of this population.  
10.1. 
Definitions 
10.1.1. 
Run-in Period Population 
The Run-in Period Population will include all subjects who signed informed consent, met the 
eligibility criteria at the start of a Run-in Period (Visit 2), and received at least one dose of 
latanoprost ophthalmic solution 0.005%.  
10.1.2. 
Time-Related Terms for Exploratory Analyses 
For exploratory analyses, the Run-in Period Baseline is the Visit 2, the start of the Run-in Period, 
when Run-in Period Population subjects takes the first dose of latanoprost ophthalmic solution 
0.005%. Analysis visit of a measurement during the Run-in Period (i.e., Visit 2 and Visit 3) are 
the same as the study visit at which the measurement was collected, specified by the protocol. 
Analysis timepoint and analysis timepoint window are defined in the same manner as in 
Section 4.5.  
10.1.3. 
Endpoint-Related Terms for Exploratory Analyses 
For IOP measurements, the Run-in Period baseline score is the observed measurement at Visit 2. 
The change and the percent change from Run-in Period baseline in IOP at subsequent visits will 
be derived as: 
 Change = (Score at the Visit) – (Run-in Period Baseline Score) 
 Percent Change from Run-in Period Baseline = 100 × Change / (Run-in Period 
Baseline Score) 
Safety-related definitions used in the exploratory analyses are the same as defined in Section 9.1.  
10.2. 
Summary of Run-in Period Population 
10.2.1. 
Subject Disposition 
The disposition of the Run-in Period Population subjects will be summarized for the Run-in 
Period.  The summary will include the number and percentage of subjects who completed 
Washout Period and entered Run-in Period (Visit 2), subjects who reached midpoint of the Run-
in Period and eligible to stay on the study (Visit 3), and subjects who completed Run-in Period 
but did not meet inclusion/exclusion criteria (Visit 4). Screen failure subjects and their failure 
reasons will also be summarized and listed.  
10.2.2. 
Demographics 
Subject demographics will also be summarized for the Run-in Period Population in the same 
manner as described in Section 7.2.  


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10.3. 
Exploratory Efficacy Analyses 
10.3.1. 
Analysis of Efficacy Measurements in the Run-in Period 
The IOP and mean diurnal IOP for both eyes (OD and OS) at Visit 1, 2, 3 and 4, as well as their 
changes and percent changes from the start of the Run-in Period (Visit 2) will be summarized for 
the following three sets of subjects: 
1. Subjects who met the eligible criteria at the Baseline Visit (Visit 4) and enter the 
Treatment Period. 
2. Subjects who completed the Run-in Period but failed to meet the eligible criteria at the 
Baseline Visit (Visit 4). 
3. Subjects in the Run-in Period Population. 
Summaries of IOP and mean diurnal IOP for the first set of subjects will be provided for study 
eye and fellow eye separately, while those for second and third sets will be provided for OD and 
OS separately. 
10.3.2. 
Other Exploratory Analyses  
The following exploratory efficacy endpoints will be analyzed for the FAS subjects: 
 Change and percent change from Run-in Period baseline (Visit 2) in mean diurnal IOP at 
Week -4 (Visit 3), Baseline (Visit 4), Week 2 (Visit 5), Week 6 (Visit 6) and Month 3 
(Visit 7) 
 Change and percent change from Run-in Period baseline (Visit 2) in IOP at each 
timepoint of Week -4 (Visit 3), Baseline (Visit 4), Week 2 (Visit 5), Week 6 (Visit 6) and 
Month 3 (Visit 7) 
For these endpoints, descriptive statistics will be provided including the number of subjects (n), 
mean, standard deviation, median, minimum, and maximum. 
10.4. 
Safety Analyses 
AEs, SAEs, ADRs, serious ADRs, and significant AEs (AEs leading to study drug 
discontinuation and AEs leading to death) will be tabulated by type of AEs for all AEs, ocular 
AEs, and non-ocular AEs separately. The Run-in Period Population will be used for AEs 
summary during the Run-in Period. 
In addition, AEs emerged in the Run-in Period will be tabulated separately by SOC and preferred 
term on the Run-in Period Population. No other safety measurements will be summarized for the 
Run-in Period Population. 
 


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11. 
SUMMARY OF CHANGES TO THE PROTOCOL 
11.1. 
Adding Exploratory Analyses 
The exploratory analyses were added to the SAP to explore the demographics, efficacy and 
safety measures of the study targeted population, latanoprost low/non-response. A new study 
population was proposed along with descriptive summary and analyses in Section 10. In 
addition, efficacy analyses for FAS in the entire study from screening to the end of the study 
were added in Section 10.3.2, for exploratory purpose. 
11.2. 
Change in Handling Missing Data  
PROTOCOL: Missing IOP data at Month 3 will be imputed by last observed post-base IOP. 
The protocol did not specify on how to handle missing data when all post-baseline IOP data are 
missing. 
SAP: Add detail on how to handle missing IOP data at Month 3 when none of post-baseline IOP 
data is available. Specifically, the baseline IOP can be used for imputation in this scenario. 
11.3. 
Change in Safety Population 
PROTOCOL and SAP:  The eligibility criteria at baseline (Visit 4, Day 1) was removed for 
Safety Population. The updated Safety Population includes all subjects who signed informed 
consent and received at least one dose of the study medication, DE-117.   
11.4. 
Change in Sample Size Planning  
PROTOCOL and SAP:  The planned sample size was changed from 150 to 100. Using one 
sample t-test with a significant level of 5%, a sample size of 100 will have 75% power to detect a 
mean diurnal IOP reduction of 1.0 mmHg from baseline with a standard deviation 3.5 mmHg, 
after taking into account of up to 12% dropouts.  


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12. 
APPENDIX