Clinical trial NCT03691662
Conditions: Glaucoma and Ocular Hypertension
Sponsor: Santen Inc.
Start date: 2018-09-27; Completion date: 2019-10-23
Enrollment: 417 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase III, randomized, double-masked, active-controlled, parallel-group, multi-center study. Subjects diagnosed with glaucoma or OHT who meet eligibility criteria at Visit 1 (Screening) will washout of their current topical IOP-lowering medication(s), if any. After completing the required washout period, subjects will return for Visit 2 (Baseline, Day 1). Subjects who meet all eligibility criteria at baseline will be randomized to receive double-masked treatment for 3 months.

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

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

Detailed description:

Arms: arm 1: Topical DE-117 Ophthalmic Solution once daily and Vehicle once daily for 3 months arm 2: Topical Timolol Maleate Ophthalmic Solution 0.5% twice daily for 3 months
Interventions: intervention 1: DE-117 Ophthalmic Solution intervention 2: Timolol Maleate Ophthalmic Solution 0.5%
Intervention descriptions: intervention 1: Topical DE-117 Ophthalmic Solution once daily and Vehicle once daily for 3 months intervention 2: Topical Timolol Maleate Ophthalmic Solution 0.5% twice daily for 3 months

Protocol documents:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:   
A Phase III, Randomized, Double-Masked, Active-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety 
of DE-117 Ophthalmic Solution 0.002% Compared with Timolol 
Maleate Ophthalmic Solution 0.5% in Subjects with Glaucoma or 
Ocular Hypertension - Spectrum 4 Study 
 
 
NCT Number:  
NCT03691662 
 
Date of the document: 
13 JULY 2018  
 
 
 


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DE-117 Protocol 
Study 011710IN 
Amendment 1 
 
TITLE:  A Phase III, Randomized, Double-Masked, Active-Controlled, Parallel-Group, 
Multicenter Study Assessing the Efficacy and Safety of DE-117 Ophthalmic Solution 
0.002% Compared with Timolol Maleate Ophthalmic Solution 0.5% in Subjects with 
Glaucoma or Ocular Hypertension - Spectrum 4 Study 
SPONSOR: 
SANTEN Inc. 
6401 Hollis St, Suite 125 
Emeryville, CA 94608 USA 
STUDY DRUG:  
DE-117 Ophthalmic Solution 0.002% 
Timolol Maleate Ophthalmic Solution 0.5% 
I have read the 011710IN 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 
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: A Phase III, Randomized, Double-Masked, Active-Controlled, Parallel-Group, 
Multicenter Study Assessing the Efficacy and Safety of DE-117 Ophthalmic Solution 0.002% 
Compared with Timolol Maleate Ophthalmic Solution 0.5% in Subjects with Glaucoma or 
Ocular Hypertension - Spectrum 4 Study 
Protocol Number: 011710IN 
Number of Subjects (planned): Approximately 400 adult subjects (200 in each treatment arm) 
with Open-Angle Glaucoma (OAG) or Ocular Hypertension (OHT) and up to 30 pediatric 
subjects (15 in each treatment arm) with pediatric glaucoma or OHT will be randomized in this 
study 
Number of Sites (planned): Approximately 35 Sites  
Study Period: Approximately 10 months 
Phase of Development: Phase III 
Primary objective:  
To determine whether DE-117 Ophthalmic Solution 0.002% given once daily is non-inferior to 
Timolol Maleate Ophthalmic Solution 0.5% given twice daily in reducing the intraocular 
pressure (IOP) in subjects with glaucoma or OHT after 3 months of treatment 
Secondary objectives:  
To determine whether DE-117 Ophthalmic Solution 0.002% is non-inferior to Timolol Maleate 
Ophthalmic Solution 0.5% in reducing mean diurnal IOP in subjects with glaucoma or OHT 
after 3 months of treatment 
To determine whether DE-117 Ophthalmic Solution 0.002% is superior to that of Timolol 
Maleate Ophthalmic Solution 0.5% in reducing mean diurnal IOP in subjects with glaucoma or 


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OHT after 1 week of treatment 
Safety objective:  
To determine the safety of DE-117 Ophthalmic Solution 0.002% as compared to Timolol 
Maleate Ophthalmic Solution 0.5% in subjects with glaucoma or OHT 
Duration of Treatment: 3 months 
Methodology:   
This is a Phase III, randomized, double-masked, active-controlled, parallel-group, multi-center 
study. Subjects diagnosed with glaucoma or OHT who meet eligibility criteria at Visit 1 
(Screening) will washout of their current topical IOP-lowering medication(s), if any. After 
completing the required washout period, subjects will return for Visit 2 (Baseline, Day 1). 
Subjects who meet all eligibility criteria at baseline will be randomized to receive treatment for 
3 months. 
Approximately 400 adult subjects and up to 30 pediatric subjects with glaucoma or OHT who 
meet all eligibility criteria will be randomized in a 1:1 ratio to receive either: 
 DE-117 Ophthalmic Solution 0.002% QD (20:00) and Vehicle QD (08:00), or 
 Timolol Maleate Ophthalmic Solution 0.5% BID (20:00 & 08:00). 
Study Design 
 
This study will consist of a Screening Period of up to 35 days including a washout period of up 
to 28 days (+ 7 days window) and a 3-month Double-Masked Treatment Period. 
At the Screening visit (Visit 1), subjects will be screened against the inclusion and exclusion 
criteria. Eligible subjects will be instructed to discontinue use of all IOP-lowering medications, 


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if any, during a washout period as follows (up to +7 days as a window is allowed): 
 Miotics: 7 days 
 Oral/topical Carbonic Anhydrase Inhibitors (CAIs): 7 days 
 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandin Analogs (PGA): 28 days 
 Rho kinase inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will be 
used. 
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 1 week before the randomization at Visit 2 
(Baseline, Day 1). An interim safety visit during the washout period (mid-washout visit; Visit 
1a) may be performed during the washout period if, in the Investigator’s opinion, a subject’s 
IOP may be of concern during the washout period. If subjects are treated with a topical CAI 
during the washout period, mid-washout visit (Visit 1a) is recommended to be performed. 
Final eligibility for randomization will be determined at Visit 2 (Baseline) after all necessary 
washout from prior IOP-lowering medications have been completed. Subjects who have not 
used any IOP-lowering medication for the last 28 days, including treatment-naive subjects, must 
have ≥ 1 day between their screening visit and Visit 2 (Baseline).  
At Visit 2, baseline IOP will be measured for both eyes at 08:00 (±60 min), 10:00 (±60 min) and 
16:00 (±60 min). The study eye will be the eye that qualifies per eligibility criteria at Visit 2. If 
both eyes meet the eligibility criteria, the eye with the higher mean diurnal IOP at Visit 2 will be 
designated as the study eye. If both eyes meet the eligibility criteria and have the same mean 
diurnal IOP, the right eye will be designated as the study eye. Both eyes should be treated with 
the study medication for the duration of the study, even if only one eye is eligible per IOP 
inclusion criteria. For pediatric subjects, if only one eye has a diagnosis of glaucoma or 
OHT, the fellow eye doesn’t have to be treated by the study medications for the duration 
of the study. 
Double-Masked Treatment Period (3 months):  
Approximately 400 eligible adult subjects and up to 30 pediatric subjects will be randomized to 
receive either DE-117 0.002% QD in the evening and vehicle QD in the morning or Timolol 
Maleate 0.5% BID in a 1:1 ratio. Subjects will be treated for 3 months with scheduled visits at 
Visits 2, 3, 4 and 5 (Baseline, Week 1, Week 6 and Month 3). 
At Visit 2 (Baseline), subjects will receive their first dose of study medication (study eye drops) 
as per their assigned/randomized study treatment at 20:00 (±60 min). The next day, subjects will 


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subsequently dose with their assigned study medication at 08:00 (±60 min), and 20:00 (±60 
min). At each scheduled follow-up visit, subjects will receive their morning dose of study 
medication/eye drops following the 08:00 IOP measurement at the investigative site (the 
doctor’s office). 
Timolol Maleate Ophthalmic Solution 0.5% was chosen as the active control because it has 
previously been proven to be effective for the reduction of elevated IOP in patients with 
glaucoma or OHT and is approved for these indications. 
IOP will be measured at 08:00, 10:00 and 16:00 (±60 min). At these scheduled visits, best-
corrected visual acuity (BCVA) and slit-lamp biomicroscopy will be performed just prior to the 
08:00 IOP measurement. Ophthalmoscopy (fundus examination) will be performed after the 
16:00 IOP measurement. Vital signs (resting blood pressure and pulse rate) will be collected in 
sitting position anytime at visit 1, and approximately 08:00 for Visits 2, and 5 before the 
morning dose. 
Pharmacogenomics/Genomics: 
Subjects who consent to the optional pharmacogenomics/genomics laboratory study will 
provide a blood sample for future testing. The purpose of this exploratory research is to identify 
possible genetic markers associated with the study medication(s) and/or ocular conditions. 
Masking: 
This is a double-masked study. The subjects, Investigators, Examiners and Santen personnel 
involved in the conduct of the study will be masked to the study treatment. An authorized 
unmasked study staff member who is not the Investigator or Examiner at the investigative site 
will dispense and collect study medication(s) and will query about dosing compliance. Subjects 
will be instructed not to show the eye drop bottles or discuss the eye drop to either the 
Investigator or the Examiner or other study subjects. The active control treatment (Timolol 
Maleate) containers will be over-labeled and packaged in the same secondary package (e.g., 
cardboard carton) as the investigational treatment (DE-117). All subjects will receive a bottle 
labeled “morning” for the morning dose and a bottle labeled “evening” for the evening dose. 
However, the DE-117/Vehicle arm will receive the vehicle (i.e., “morning” bottle) at the 
morning dose, while the Timolol Maleate arm receives the active treatment (i.e., “morning” 
bottle) at the morning dose. Each eligible subject will be assigned to receive a numbered study 
medication kit as assigned by Central randomization via Interactive Response Technology 
(Medidata BALANCE) at Visit 2 (Baseline) and at Visit 4 (Week 6). 
Inclusion Criteria for ADULT subjects: 
At Visit 1 (Screening), the subjects 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 a female of childbearing potential (i.e., not post-menopausal [within 12 
months since the last menses] or not surgically sterile [less than 6 months from date of 


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surgery]), she must have a negative urine pregnancy test and must use at least one of the 
following acceptable contraceptive methods during the study (as well as for 4 weeks 
following last dose in study). 
 Abstinence 
 Hormonal contraceptive method (including oral or transdermal contraceptives, 
injectable progesterone, progestin subdermal implants, progesterone-releasing 
intrauterine devices [IUDs]) initiated at least 28 days prior 
 Placement of a copper-containing IUD 
 Condom with spermicidal foam/gel/film/cream/suppository 
 Vasectomized male partner (surgery at least 6 months prior) 
Male subjects capable of fathering children should use/ 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 OAG (including Pigmentary Glaucoma or Pseudoexfoliative 
Glaucoma) or OHT in both eyes, or one eye with OAG 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. 
In addition to continuing to meet inclusion criterion 5 (BCVA), the subject must meet the 
following criteria at Visit 2 (Baseline, Day 1): 
8. Completed the required wait/washout period. 
9. At all time points of IOP measurements (08:00, 10:00 and 16:00) at Visit 2 (Baseline, 
Day 1), have IOP of ≥ 22 mmHg in at least one eye (the same eye), and ≤ 34 mmHg in 
both eyes. 
Exclusion Criteria for ADULT subjects: 
At Visit 1 (Screening) and Visit 2 (Baseline, Day 1), subjects with any of the following ocular 
conditions in either eye or with any of the following non-ocular conditions or characteristics are 
not eligible to participate in the study: 
General 
1. Females who are pregnant, nursing or planning a pregnancy.  
2. Subjects with known or suspected drug or alcohol abuse. 
3. 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). 


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Medications / Therapies 
5. Intended or current use of the following prohibited medications/therapies during the 
study duration: 
 All ocular medications other than sodium chloride/potassium chloride ophthalmic 
solution, cataract treatment agents (e.g., glutathione, pirenoxine), Vitamin B12 
formulation (e.g., cyanocobalamine), over-the-counter dry eye artificial tears/drops, 
and study medications. 
 All systemic medications for ocular hypotensive (e.g., oral or intravenous CAI, oral 
glycerol). 
 Any ocular, periocular, inhaled, nasal or systemic corticosteroids including for joint 
injection, etc. 
 Lacrimal/punctal occlusion via plug (s) or cautery. 
6. Subjects who cannot safely discontinue use of ocular hypotensive medications during the 
wait/washout period. 
7. 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 be on a stable 
dose use for at least 30 days prior to Visit 1 (Screening) and during the study duration. 
8. Use of contact lenses within 2-3 weeks prior to Visit 2 (Baseline, Day 1) until end of 
treatment in either eye (2 weeks for soft contact lens wearers, and 3 weeks for rigid 
contact lens wearers). 
9. Any ocular surgery or ocular laser treatment within 180 days prior to Visit 1 (Screening) 
and throughout the study in either eye. 
10. 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. 
11. History of keratorefractive surgery (e.g., RK, PRK, LASIK) in either eye.  
12. Allergy, hypersensitivity or contraindications to EP2 receptor agonists, beta-blockers, 
benzalkonium chloride (BAK) or any other components of the study medications, or 
other study related procedures/medications. This also includes subjects with a history or 
presence of contraindications to beta-blocker therapy, such as chronic obstructive 
pulmonary disease (e.g., chronic bronchitis, emphysema), bronchial asthma, second or 
third degree atrioventricular block, uncontrolled congestive heart failure. 
Diseases 
13. Presence of advanced glaucoma (e.g., visual field mean deviation worse than -12 dB) in 
either eye. 
14. Presence of any corneal abnormality or other conditions interfering with or preventing 
reliable Goldmann applanation tonometry (e.g., Fuch’s dystrophy or significant corneal 


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surface abnormality) in either eye. 
15. Presence of any active severe external ocular disease, inflammation, or infection of the 
eye and/or eyelids in either eye. 
16. Presence or history of macular edema or known risk factors for macular edema in either 
eye. 
17. History of severe ocular trauma in either eye. 
18. History of iritis and/or uveitis in either eye. 
19. History of retinal detachment, proliferative diabetic retinopathy, or any retinal disease 
that may be progressive during the time course of the study in either eye. 
20. Presence or history of any disease or condition that in the opinion of the study 
Investigator may put the subject at significant risk, may confound study results, or may 
interfere significantly with the subject’s participation in the study (e.g., recurrent corneal 
erosion syndrome, uncontrolled cardiovascular disease etc.). 
21. Any decision by the Investigator or Medical Monitor to terminate a subject in screening 
or declare any subject ineligible for any sound medical reason. 
 
Inclusion Criteria Specific for PEDIATRIC subjects: 
At Visit 1 (Screening), the pediatric subjects must meet all of the following inclusion criteria: 
1. Parent/legal guardian signed written informed consent on the Institutional Review 
Board (IRB)/Ethics Committee (EC) approved Informed Consent Form (ICF) and 
patient assent has been given as applicable.  
2. The patient and parent/legal guardian should agree to comply with study restrictions, 
treatment plan, procedures and keep scheduled visits. 
3. Be ≥ 1 year and less than 18 years old on the date of signing the ICF. 
4. If a subject is a female of childbearing potential, she must have a negative urine 
pregnancy test and must use at least one of the following acceptable contraceptive 
methods during the study (as well as for 4 weeks following last dose in study). 
 Abstinence 
 Hormonal contraceptive method (including oral or transdermal contraceptives, 
injectable progesterone, progestin subdermal implants, progesterone-releasing 
intrauterine devices [IUDs]) initiated at least 28 days prior 
 Placement of a copper-containing IUD 
 Condom with spermicidal foam/gel/film/cream/suppository 
 Vasectomized male partner (surgery at least 6 months prior)  
Male subjects capable of fathering children should use/ practice an acceptable 
contraceptive method, such as abstinence, condom or vasectomy (surgery at least 6 


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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). 
5. Must have a diagnosis of pediatric glaucoma or OHT in one or both eyes, including 
primary (congenital and juvenile open angle glaucoma) and secondary glaucoma. For 
a child with pediatric glaucoma due to secondary causes, the Investigator or study site 
should discuss the case with the Medical Monitor prior to subject enrollment. 
6. Must have elevated IOP to such a level that investigator deems pharmacologic 
intervention with IOP-lowering medication to be clinically necessary in at least one 
eye.  
7. Must have a sufficiently clear cornea that allows for a complete ophthalmic 
examination. 
8. Anterior chamber angle grade ≥ 2 (Shaffer scale) in each eye, based on gonioscopy 
performed at Visit 1 (Screening), or historical gonioscopy performed within 12 
months prior. 
In addition to continuing to meet inclusion criteria 6 (elevated IOP) and 7 (clear cornea), the 
subject must meet the following criterion at Visit 2 (Baseline, Day 1): 
9. Completed the required wait/washout period. 
Exclusion Criteria Specific for PEDIATRIC subjects: 
At Visit 1 (Screening) and Visit 2 (Baseline, Day 1), subjects with any of the following 
ocular conditions in either eye or with any of the following non-ocular conditions or 
characteristics are not eligible to participate in the study. Exception: criteria 8, 9 and 10 only 
apply to the eye being considered for study treatment. E.g. if only the non-treated eye has a 
history of LASIK, the other eye may still qualify for participation and treatment in the study 
if the subject meets all other criteria. 
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. Intended or current use of the following prohibited medications/therapies during the 
study duration: 
 All ocular medications other than sodium chloride/potassium chloride ophthalmic 


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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.  
6. Subjects who cannot safely discontinue use of ocular hypotensive medications during 
the wait/washout period. 
7. 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 be on a stable 
dose use for at least 30 days prior to Visit 1 (Screening) and during the study duration. 
8. Use of contact lenses within 2-3 weeks prior to Visit 2 (Baseline, Day 1) until end of 
treatment (2 weeks for soft contact lens wearers, and 3 weeks for rigid contact lens 
wearers). 
9. Any ocular surgery (including goniotomy or glaucoma surgery) or ocular laser 
treatment within 180 days prior to Visit 1 (Screening) and throughout the study. 
10. History of keratorefractive surgery (e.g. RK, PRK, LASIK).  
11. Allergy, hypersensitivity or contraindications to EP2 receptor agonists, beta-blockers, 
benzalkonium chloride (BAK) or any other components of the study medications, or 
other study related procedures/medications. This also includes subjects with a history 
or presence of contraindications to beta-blocker therapy, such as chronic obstructive 
pulmonary disease (e.g. chronic bronchitis, emphysema), bronchial asthma, second or 
third degree atrioventricular block, uncontrolled congestive heart failure. 
Diseases 
12. Presence of advanced glaucoma in either eye. 
13. Presence of any corneal abnormality or other conditions interfering with or preventing 
reliable tonometric measurement (e.g. Fuch’s dystrophy or significant corneal surface 
abnormality) in either eye. 
14. Presence of any active severe external ocular disease, inflammation, or infection of 
the eye and/or eyelids in either eye. 
15. Presence or history of macular edema or known risk factors for macular edema in 
either eye. 
16. Aphakia or pseudophakia 


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17. Single sighted subject 
18. History of severe ocular trauma in either eye. 
19. History of iritis and/or uveitis in either eye. 
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 (such as contraindication to the 
use of Timolol Maleate Ophthalmic Solution 0.5%),  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:  
Subjects will be assigned in a 1:1 ratio to the DE-117/Vehicle arm and Timolol Maleate arms as 
follows: 
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
Vehicle: 
The vehicle is identical to the investigational product but does not contain the active ingredient 
in DE-117.
Comparator: 
Timolol Maleate Ophthalmic Solution 0.5% contains the active ingredient, timolol 5 mg/mL and 
the preservative BAK 0.01%. Other ingredients include monobasic and dibasic sodium 
phosphate and purified water. The pH is adjusted to 6.5 to 7.5 with sodium hydroxide. 
Each subject will be instructed to instill one drop of study medication from bottle labeled 
“evening” in each eye at 20:00 and one drop of study medication from bottle labeled “morning” 
in each eye at 08:00 starting the evening of Visit 2 (Baseline, Day 1) through the morning 


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before Visit 5 (Month 3). 
Route of Administration of Investigational Product: Topical ocular 
Duration of the Study: The study duration includes up to 5 week Screening Period, and a  
3-month Double-Masked Treatment Period. 
Criteria for Evaluation: 
Efficacy: 
Efficacy will be assessed by evaluating IOP at scheduled time points (08:00, 10:00 and 16:00) at 
all scheduled visits with the exception of the Screening visit.  
Safety: 
Safety will be assessed by adverse events (AEs), BCVA, slit-lamp biomicroscopy, 
ophthalmoscopy, iris color/eyelash/eyelid examination, resting blood pressure and pulse rate.  
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 
The primary efficacy endpoint is the IOP in the study eye measured at the specified time points: 
08:00, 10:00 and 16:00 at Week 1, Week 6 and Month 3 (Visits 3, 4 and 5).  
Key Secondary Efficacy Endpoints 
 Mean diurnal IOP in the study eye at Month 3 (Visit 5) 
 Mean diurnal IOP in the study eye at Week 1 (Visit 3) 
Other Secondary Efficacy Endpoints 
 Change and percent change from baseline in IOP at each timepoint/post-baseline 
visit 
 Change and percent change from baseline in mean diurnal IOP at each post-baseline 
visit 
 Having a  mean diurnal IOP reduction ≥ 20%, ≥ 25%, or ≥ 30% from Baseline  
(Visit 2) at each post-baseline visit 
 Having a mean diurnal IOP ≤ 18 mmHg at each post-baseline visit 
Safety Endpoints 
Safety will be evaluated by the following parameters: 
 Incidence of ocular and systemic AEs 


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 Blood pressure and pulse rate  
 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: 
The sample size calculation was based on a two-sided Type I error rate of 5% and a non-
inferiority margin of 1.5 mmHg. Assuming a between-treatment difference of 0 mmHg, a 
standard deviation (SD) of 4.0 mmHg, and a correlation coefficient of 0.6 among repeated 
measures, approximately 400 adult subjects in total (200 subjects per treatment arm) will 
provide 90% power to demonstrate non-inferiority of DE-117 Ophthalmic Solution 0.002% to 
Timolol Maleate Ophthalmic Solution 0.5%. 
A mixed-effects model for repeated measures (MMRM) will be fitted and 95% confidence 
interval for least square mean difference between the DE-117/Vehicle arm and the Timolol 
Maleate arm at each scheduled time point of each post-baseline visit up to Month 3 will be 
estimated. Non-inferiority is achieved if the upper limit of the two-sided 95% confidence 
interval for the difference in the mean IOP (0.002% DE-117 - Timolol Maleate) is ≤ 1.5 mmHg 
at all nine time points and ≤ 1.0 mmHg in majority (5 or more) of the 9 time points. 
Separate statistical analysis for pediatric subjects may be performed depending on the number of 
pediatric subjects enrolled in this study. 
 
 


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Schedule of Events and Procedures for ADULT Subjects 
 
Washout Period 
Double-Masked Treatment Period 
Visit 1 
Screening 
Washout Period 
(up to 4 weeks) 
Optional Visit 
1a 
Visit 2  
Eligibility/Baseline 
(Day 1) 
Visit 3 
Week 1 
(Day 8±2) 
Visit 4 
Week 6 
(Day 43 ±3) 
Visit 5 
Month 3 
(Day 91±7) 
Exit or Early 
Termination n 
Informed Consent(s) including 
the optional consent for 
pharmacogenomics/ genomics 
laboratory research study a 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
Demographics and 
Medical History, including prior 
PGA b 
X 
 
 
 
 
 
Concomitant Medications/ 
Therapies 
X 
X 
X 
X 
X 
X 
Dosing Compliance 
 
 
 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
Pregnancy Test c 
X 
 
X 
 
 
X 
Vital Signs (blood 
pressure/pulse rate) d 
X 
 
X (08:00) 
 
 
X (08:00) 
Refraction e 
X 
 
 
 
 
 
BCVAe 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
Biomicroscopy f 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
IOP g 
X 
X 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
Pachymetry h 
X 
 
 
 
 
 
Instill study medication after 
IOP measurement 
 
 
 
X (08:00) 
X (08:00) 
X (08:00) 
Iris color, eyelash, eyelid i 
 
 
X (photo) 
 
 
X (photo) 
Gonioscopy j 
X 
 
 
 
 
 
Visual Field k 
X 
 
 
 
 
 
Ophthalmoscopy l 
X (pupil 
dilation) 
 
X (16:00) 
 
 
X (16:00, 
pupil dilation) 
Blood Sampling for 
Pharmacogenomics/genomics m 
 
 
 
X 
Dispense Study Medication 
 
 
X 
 
X 
 
Collect Study Medication 
 
 
 
 
X 
X 
Phone call to remind subject to 
take evening dose on the day 
before each visit 
 
 
 
X 
X 
X 
 
a. 
Informed Consent Form must be signed and dated before study procedures are performed. Informed consent for the optional 
pharmacogenomics/genomics laboratory research study may be obtained at any visit prior to study exit. 
b. 
Prostaglandin naive subjects are defined as subjects who are not known to have used prostaglandin as their glaucoma 
treatment. The previous use of prostaglandin should be confirmed by either subject’s medical records or subject history. 
c. 
A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
d. 
Vital signs (resting blood pressure and pulse rate) will be collected in sitting position anytime at Visit 1 (Screening), and 
approximately 08:00 for Visit 2 (Baseline), and Visit 5 before the morning dose.  
e. 
Refraction will be performed at the screening visit. If more than 10 letters in BCVA are lost compared to the screening visit, 
then refraction should be performed again. BCVA examination will be completed before IOP measurement at 08:00.  
f. 
Biomicroscopy examination must be completed before IOP is measured at 08:00. Aqueous flare and cell evaluation will be 
performed before fluorescein instillation.  
g. 
IOP measurements will be performed at 08:00, 10:00 and 16:00 (±60 min) at all visits except for Visit 1 and the optional 
Visit 1a (screening and mid-washout).  
h. 
Pachymetry will be performed after IOP measurement at Visit 1 (Screening). 
i. 
Eye photograph will be taken at Visits 2 (Baseline) and 5 (Month 3).  


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j. 
If gonioscopy was performed within 3 months (90 days) prior to screening and was documented in the subject’s records, no 
additional screening gonioscopy examination is necessary. Gonioscopy will be performed after IOP measurement at Visit 1 
(Screening). 
k. 
If visual field test was performed within 3 months (90 days) prior to screening and was documented in the subject’s records, 
no additional screening visual field test is necessary.  
l. 
Ophthalmoscopy will be performed at Visits 1, 2 and 5 (i.e. Screening, Baseline and Month 3) after the 16:00 IOP 
measurements. Ophthalmoscopy will be performed with pupil dilation at Visit 1 and Visit 5/exit or early termination. 
Dilation of the pupil will be performed after the 16:00 IOP measurement. 
m. Blood sampling for the pharmacogenomics/genomics laboratory research study may be performed at any visit after 
pharmacogenomics/genomics informed consent obtained, subject randomized and study drug dosing has begun. 
n. 
Optional at unscheduled visit, required for early terminated subjects.  
 
 


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Schedule of Events and Procedures Specially for PEDIATRIC Subjects 
 
Washout Period 
Double-Masked Treatment Period 
Visit 1 
 Screening 
Washout Period 
(up to 4 weeks) 
Optional Visit 1a 
Visit 2 
Eligibility/Baseli
ne 
(Day 1) 
Visit 3 
Week 1 
(Day 8±2) 
Visit 4 
Week 6 
(Day 43 ±3) 
Visit 5 
Month 3 
(Day 91±7)  
Exit or Early 
Termination n 
Informed Consent(s) including the 
optional consent for 
pharmacogenomics/ genomics 
laboratory research study a 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
Demographics and 
Medical History, including prior 
PGA b 
X 
 
 
 
 
 
Concomitant Medications/ 
Therapies 
X 
X 
X 
X 
X 
X 
Dosing Compliance 
 
 
 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
Pregnancy Test c 
X 
 
X 
 
 
X 
Vital Signs (blood pressure/pulse 
rate) d 
X 
 
X (08:00) 
 
 
X (08:00) 
Refraction e 
X 
 
 
 
 
 
BCVAe 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
Biomicroscopy f 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
IOP g 
X 
X 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
Pachymetry h 
X 
 
 
 
 
 
Instill study medication after IOP 
measurement 
 
 
 
X (08:00) 
X (08:00) 
X (08:00) 
Iris color, eyelash, eyelid i 
 
 
X (photo) 
 
 
X (photo) 
Gonioscopy j 
X 
 
 
 
 
 
Visual Field k 
X 
 
 
 
 
 
Ophthalmoscopy l 
X (pupil 
dilation) 
 
X (16:00) 
 
 
X (16:00 pupil 
dilation) 
Blood Sampling for 
Pharmacogenomics/genomics m 
 
 
 
X 
Dispense Study Medication 
 
 
X 
 
X 
 
Collect Study Medication 
 
 
 
 
X 
X 
Phone call to remind subject to 
take evening dose on the day 
before each visit 
 
 
 
X 
X 
X 
 
a. 
Informed Consent Form and the Assent Form must be signed and dated before study procedures are performed. Informed 
consent for the optional pharmacogenomics/genomics laboratory research study may be obtained at any visit prior to study 
exit. 
b. 
Prostaglandin-naive subjects are defined as subjects who are not known to have used prostaglandin as their glaucoma 
treatment. The previous use of prostaglandin should be confirmed by either subject’s medical records or subject history. 
c. 
A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
d. 
Vital signs (resting blood pressure and pulse rate) will be collected in anytime at Visit 1 (Screening), and approximately 
08:00 for Visit 2 (Baseline), and Visit 5 before the morning dose.  
e. 
Refraction will be performed at the screening visit if the pediatric subject is able to cooperate. Autorefraction is also 
acceptable. If more than 10 letters in BCVA are lost compared to the screening visit level, then refraction should be 
performed again if the pediatric subject is able to cooperate. BCVA examination will be completed before IOP measurement 
at 08:00. BCVA will be performed for the pediatric subjects who are able to cooperate using an age-appropriate eye chart 
and method (e.g. ETDRS chart, LEA symbols chart with logMAR notation, Tumbling E’s with logMAR notation, Landolt's 
broken rings with LogMAR notation, fix and follow) under normal room illumination. Same eye chart should be used for a 
given subject throughout the study.  


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f. 
Biomicroscopy examination must be completed before IOP is measured at 08:00. Aqueous flare and cell evaluation will be 
performed before instillation of fluorescein.  
g. 
IOP measurements will be performed at 08:00, 10:00 and 16:00 (±60 min) at all visits except for Visit 1 and the optional 
Visit 1a (screening and mid-washout). IOP will be measured with age-appropriate tonometers (e.g. Goldmann applanation 
tonometer, a Perkins tonometer, or a tonopen, or iCare tonometer etc.) to the extent the subject is able to cooperate.  
h. 
Pachymetry will be performed after IOP measurement at Visit 1 (Screening) if the subject is able to cooperate. Subject must 
have sufficiently clear cornea that allows for a complete ophthalmic exam to be enrolled if pachymetry is not able to be 
obtained. 
i. 
Eye photograph will be taken at Visits 2 (Baseline), and 5 (Month 3) if the subject is able to cooperate.  
j. 
Gonioscopy will be performed at Visit 1 (Screening) if the subject is able to cooperate. If unable to cooperate, historical 
gonioscopy performed within 12 months prior to screening and documented in the subject’s records is acceptable. 
Gonioscopy performed at Visit 1 (Screening) should occur after IOP measurement. 
k. 
Visual field test will be performed if the subject is able to cooperate. If visual field test was performed within 3 months (90 
days) prior to screening and was documented in the subject’s records, no additional screening visual field test is necessary.  
l. 
Ophthalmoscopy will be performed if the subject is able to cooperate. Ophthalmoscopy will be performed at Visits 1, 2, and 
5 (i.e. Screening, Baseline and Month 3) after the 16:00 IOP measurements. Ophthalmoscopy will be performed with pupil 
dilation at Visit 1 and visit 5/exit or early termination. Dilation of the pupil will be performed after the 16:00 IOP 
measurement. 
m. Blood sampling for the pharmacogenomics/genomics laboratory research study may be performed at any visit after the 
pharmacogenomics/genomics informed consent is obtained, subject is randomized and study drug dosing has begun. 
n. 
Optional at unscheduled visit, required for early terminated subjects.  
 
Guidance for the visual acuity and IOP measurements in pediatric subjects are shown in  
Section 21.4. 
 
 


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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 ...............20 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................25 
5. 
INTRODUCTION ......................................................................................................28 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................30 
6.1. 
Primary Objective .......................................................................................................30 
6.2. 
Secondary Objectives .................................................................................................30 
6.3. 
Safety Objective ..........................................................................................................30 
7. 
INVESTIGATIONAL PLAN .....................................................................................31 
7.1. 
Overall Study Design ..................................................................................................31 
7.2. 
Number of Subjects ....................................................................................................33 
7.3. 
Treatment Assignment ................................................................................................33 
7.4. 
Schedule of Events and Procedures ............................................................................34 
7.4.1. 
Visit 1 (Screening) ......................................................................................................38 
7.4.2. 
Visit 1a (Optional, Washout Period) ..........................................................................39 
7.4.3. 
Visit 2 (Baseline, Day 1) ............................................................................................40 
7.4.4. 
Visit 3 (Week 1, Day 8 ±2) .........................................................................................42 
7.4.5. 
Visit 4 (Week 6, Day 43 ±3) .......................................................................................42 
7.4.6. 
Visit 5 (Month 3, Day 91 ±7) Study Exit/Early Termination .....................................43 
7.5. 
Study Termination ......................................................................................................45 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................46 
8.1. 
Subject Inclusion Criteria for ADULT Subjects ........................................................46 
8.2. 
Subject Exclusion Criteria for ADULT Subjects .......................................................47 
8.3. 
Subject Inclusion Criteria for PEDIATRIC Subjects .................................................49 
8.4. 
Subject Exclusion Criteria for PEDIATRIC Subjects ................................................50 
8.5. 
Subject Withdrawal Criteria .......................................................................................52 
9. 
TREATMENT OF SUBJECTS ..................................................................................53 
9.1. 
Description of Study Medication ................................................................................53 


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9.2. 
Concomitant Medications or Therapies ......................................................................53 
9.2.1. 
Prohibited Medications or Therapies ..........................................................................53 
9.3. 
Treatment Compliance ................................................................................................54 
9.4. 
Randomization and Masking ......................................................................................55 
10. 
STUDY MEDICATION MATERIALS AND MANAGEMENT .............................57 
10.1. 
Study Medication ........................................................................................................57 
10.1.1. 
Investigational Product ...............................................................................................57 
10.1.2. 
Vehicle ........................................................................................................................57 
10.1.3. 
Active Control ............................................................................................................57 
10.2. 
Study Medication Packaging and Labeling ................................................................57 
10.3. 
Study Medication Storage ...........................................................................................58 
10.4. 
Study Medication Preparation ....................................................................................58 
10.5. 
Study Medication Administration...............................................................................58 
10.6. 
Study Medication Accountability ...............................................................................58 
10.7. 
Study Medication Handling and Disposal ..................................................................59 
10.8. 
Study Supplies ............................................................................................................59 
11. 
ASSESSMENT OF EFFICACY ................................................................................60 
11.1. 
Efficacy Parameter ......................................................................................................60 
12. 
ASSESSMENT OF SAFETY .....................................................................................61 
12.1. 
Adverse Events and Serious Adverse Events .............................................................61 
12.1.1. 
Definition of Adverse Events .....................................................................................61 
12.1.1.1. 
Assessment of Adverse Events ...................................................................................61 
12.1.1.2. 
Reporting Adverse Events ..........................................................................................62 
12.1.2. 
Serious Adverse Events ..............................................................................................63 
12.1.2.1. 
Assessment of Serious Adverse Events ......................................................................63 
12.1.2.2. 
Reporting Serious Adverse Events .............................................................................64 
12.1.2.3. 
Expedited Reporting of Serious Adverse Events ........................................................64 
12.1.3. 
Events of Special Interest ...........................................................................................64 
12.1.4. 
Follow-up of Adverse Events .....................................................................................65 
12.1.5. 
Manual Back-Up Reporting Procedures .....................................................................65 
12.2. 
Safety Parameters .......................................................................................................66 
12.2.1. 
Ocular Assessments ....................................................................................................66 
12.2.2. 
Non-ocular Assessments .............................................................................................66 


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13. 
OTHER ASSESSMENTS ..........................................................................................67 
13.1. 
Demographic, Baseline Characteristics and Other Assessments ................................67 
14. 
STATISTICAL METHODS .......................................................................................68 
14.1. 
Interim Analysis ..........................................................................................................68 
14.2. 
Final Analysis .............................................................................................................68 
14.3. 
General Considerations ...............................................................................................68 
14.3.1. 
Sample Size ................................................................................................................68 
14.3.2. 
Statistical Hypotheses and Level of Significance .......................................................68 
14.4. 
Study Populations .......................................................................................................69 
14.4.1. 
Safety Population ........................................................................................................69 
14.4.2. 
Full Analysis Set .........................................................................................................69 
14.4.3. 
Per-Protocol Set ..........................................................................................................70 
14.5. 
Handling of Missing Values .......................................................................................70 
14.6. 
Demographic and Baseline Characteristics ................................................................70 
14.7. 
Efficacy Analyses .......................................................................................................70 
14.7.1. 
Analysis of Primary Efficacy Endpoint ......................................................................70 
14.7.2. 
Analysis of Secondary Efficacy Endpoints ................................................................71 
14.7.2.1. 
Key Secondary Efficacy Endpoints ............................................................................71 
14.7.2.2. 
Other Secondary Efficacy Endpoints ..........................................................................71 
14.8. 
Safety Analyses ..........................................................................................................71 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................73 
15.1. 
Study Monitoring ........................................................................................................73 
15.2. 
Audits and Inspections ................................................................................................74 
15.3. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................74 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................75 
16.1. 
Quality Control ...........................................................................................................75 
16.2. 
Quality Assurance .......................................................................................................75 
17. 
ETHICS ......................................................................................................................76 
17.1. 
Ethics Review .............................................................................................................76 
17.2. 
Ethical Conduct of the Study ......................................................................................76 
17.3. 
Written Informed Consent ..........................................................................................76 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................78 
18.1. 
Inspection of Records .................................................................................................78 


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18.2. 
Retention of Records ..................................................................................................78 
18.2.1. 
Source Documents ......................................................................................................78 
18.2.2. 
Source Data .................................................................................................................79 
18.2.3. 
Data Collection ...........................................................................................................79 
19. 
PUBLICATION POLICY ..........................................................................................80 
20. 
REFERENCES ...........................................................................................................81 
20.1. 
Literature .....................................................................................................................81 
20.2. 
Study Data ..................................................................................................................82 
21. 
APPENDICES ............................................................................................................84 
21.1. 
Appendix A - Obligations of Investigators .................................................................84 
21.2. 
Appendix B - Elements of Informed Consent ............................................................86 
21.3. 
Appendix C - Procedures for Assessments .................................................................88 
21.3.1. 
Demographics, Medication/Therapy and Medical History ........................................88 
21.3.2. 
Pregnancy Test ............................................................................................................88 
21.3.3. 
Vital signs (Blood pressure/Pulse rate) .......................................................................88 
21.3.4. 
Iris color, Eyelash, Eyelid ...........................................................................................89 
21.3.4.1. 
Iris Color .....................................................................................................................89 
21.3.4.2. 
Eyelash ........................................................................................................................89 
21.3.4.3. 
Eyelid ..........................................................................................................................89 
21.3.5. 
Refraction ...................................................................................................................90 
21.3.6. 
Best-Corrected Visual Acuity .....................................................................................90 
21.3.6.1. 
ETDRS Visual Acuity Scoring ...................................................................................90 
21.3.7. 
Slit-lamp Biomicroscopy ............................................................................................91 
21.3.8. 
Intraocular Pressure ....................................................................................................93 
21.3.8.1. 
Goldmann Applanation Tonometer Calibration .........................................................95 
21.3.9. 
Pachymetry (Central Corneal Thickness) ...................................................................95 
21.3.10. 
Gonioscopy .................................................................................................................95 
21.3.11. 
Visual Field .................................................................................................................95 
21.3.12. 
Ophthalmoscopy (Fundus) Examination ....................................................................96 
21.3.13. 
Blood Sample for Pharmacogenomics/genomics Study .............................................96 
21.4. 
Appendix D - Guidance for Visual Acuity and Intraocular Pressure 
Measurement for Pediatric Subjects ...........................................................................97 
21.5. 
Appendix E - Timolol Maleate Ophthalmic Solution 0.5% Package Insert ...............99 


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21.6. 
Appendix F - Summary of Changes .........................................................................103 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................25 
Table 3: 
Schedule of Events and Procedures for ADULT subjects ..........................................34 
Table 4: 
Schedule of Events and Procedures for PEDIATRIC subjects ..................................36 
Table 5: 
LogMAR Scoring Grid for ETDRS Eye Chart...........................................................90 
Table 6: 
Eye Charts/Vision Tests in Pediatric Subjects ............................................................97 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................31 
Figure 2: 
DE-117 Structure ........................................................................................................53 
 
 
 
 


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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 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AGIS 
Advanced Glaucoma Intervention Study 
ARB 
Angiotensin II Receptor Blockers 
ATC 
Anatomical Therapeutic Chemical 
BAK 
Benzalkonium Chloride 
BCVA 
Best-Corrected Visual Acuity 
BID 
Twice a Day 
CAI 
Carbonic Anhydrase inhibitor 
CV 
Curriculum Vitae 
D 
Diopter 
dB 
Decibel 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMGT 
Early Manifest Glaucoma Trial 
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 Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 


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Table 2: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Definition 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IUDs 
Intrauterine Devices 
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 
MMRM 
Mixed-effects Model for Repeated Measures 
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 
PMM 
Pattern Mixture Model 
POAG 
Primary Open-Angle Glaucoma 
PPS 
Per-Protocol Set 
PRK 
Refractive Keratectomy 


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Table 2: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist Term 
Definition 
PT 
Preferred Term 
QD 
Once a day 
RK 
Radial Keratotomy 
SAE 
Serious Adverse Event 
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 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. 
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 
receptor agonists are thought to mediate the IOP-lowering effect by relaxing the ciliary muscle 


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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 a randomized, double-masked, active-controlled, parallel group, multi-
center, Phase III study. The total duration of treatment is 3 months. The objective is to 
investigate the efficacy and safety of DE-117 Ophthalmic Solution 0.002% compared with 
Timolol Maleate Ophthalmic Solution 0.5% in subjects with glaucoma or OHT.  


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
To determine whether DE-117 Ophthalmic Solution 0.002% given once daily is non-inferior to 
Timolol Maleate Ophthalmic Solution 0.5% given twice daily in reducing the IOP in subjects 
with glaucoma or OHT after 3 months of treatment 
6.2. 
Secondary Objectives 
To determine whether DE-117 Ophthalmic Solution 0.002% is non-inferior to Timolol Maleate 
Ophthalmic Solution 0.5% in reducing mean diurnal IOP in subjects with glaucoma or OHT after 
3 months of treatment 
To determine whether DE-117 Ophthalmic Solution 0.002% is superior to that of Timolol 
Maleate Ophthalmic Solution 0.5% in reducing mean diurnal IOP in subjects with glaucoma or 
OHT after 1 week of treatment 
6.3. 
Safety Objective 
To determine the safety of DE-117 Ophthalmic Solution 0.002% as compared to Timolol 
Maleate Ophthalmic Solution 0.5% in subjects with glaucoma or OHT. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase III, randomized, double-masked, active-controlled, parallel-group and multi-
center study investigating the efficacy and safety of DE-117 Ophthalmic Solution 0.002% in 
subjects with glaucoma or OHT. 
See the study design diagram in Figure 1. This study will consist of a Screening Period of up to 
35 days including a washout period of up to 28 days (+ 7 days window) and a 3-month Double-
Masked Treatment Period.  
Approximately 400 adult subjects and up to 30 pediatric subjects s with glaucoma or OHT who 
meet all eligibility criteria will be randomized in a 1:1 ratio to receive either: 
 DE-117 Ophthalmic Solution 0.002% QD (20:00) and Vehicle QD (08:00), or 
 Timolol Maleate Ophthalmic Solution 0.5% BID (20:00 & 08:00). 
In the Double-Masked Treatment Period, Timolol Maleate Ophthalmic Solution 0.5% will be 
used as active control. 
Figure 1: 
Study Design 
 
At the Screening visit (Visit 1), subjects will be screened against the inclusion and exclusion 
criteria. Eligible subjects will be instructed to discontinue use of all IOP-lowering medications, if 
any, during a washout period as follows (up to +7 days as a window is allowed):  
 Miotics: 7 days 
 Oral/topical Carbonic Anhydrase Inhibitors (CAIs): 7 days 


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 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandin Analogs (PGA): 28 days 
 Rho kinase inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will be 
used. 
During the required washout period, subjects who discontinue their current treatment may, if the 
Investigator deems it necessary, be treated with a short-acting IOP lowering agent, topical CAI, 
e.g., brinzolamide or dorzolamide eye drops, one drop twice daily. Topical CAI treatment must 
be stopped 1 week before the randomization at Visit 2 (Baseline, Day 1). An interim safety visit 
during the washout period (mid-washout visit; Visit 1a) may be performed during the washout 
period if, in the Investigator’s opinion, a subject’s IOP may be of concern during the washout 
period. If subjects are treated with a topical CAI during the washout period, mid-washout visit 
(Visit 1a) is recommended to be performed. 
Final eligibility for randomization will be determined at Visit 2 (Baseline) after all necessary 
washouts from prior IOP-lowering medications have been completed. Subjects who have not 
used any IOP-lowering medication for the last 28 days, including treatment-naive subjects, must 
have ≥ 1 day between their screening visit and Visit 2 (Baseline).  
At Visit 2, baseline IOP will be measured for both eyes at 08:00 (±60 min), 10:00 (±60 min) and 
16:00 (±60 min). The study eye will be the eye that qualifies per eligibility criteria at Visit 2. If 
both eyes meet the eligibility criteria, the eye with the higher mean diurnal IOP at Visit 2 will be 
designated as the study eye. If both eyes meet the eligibility criteria and have the same mean 
diurnal IOP, the right eye will be designated as the study eye. Both eyes should be treated with 
the study medication for the duration of the study, even if only one eye is eligible per IOP 
inclusion criteria. For pediatric subjects, if only one eye has a diagnosis of glaucoma or OHT, 
the fellow eye doesn’t have to be treated by the study medications for the duration of the 
study. 
Double-Masked Treatment Period (3 months): 
Approximately 400 eligible adult subjects and up to 30 pediatric subjects will be randomized to 
receive either DE-117 0.002% QD in the evening and vehicle QD in the morning or Timolol 
Maleate 0.5% BID in a 1:1 ratio. Subjects will be treated for 3 months with scheduled visits at 
Visits 2, 3, 4 and 5 (Baseline, Week 1, Week 6 and Month 3). 
At Visit 2 (Baseline), subjects will receive their first dose of study medication (study eye drops) 
as per their assigned/randomized study treatment at 20:00 (±60 min). The next day, subjects will 
subsequently dose with their assigned study medication at 08:00 (±60 min), and 20:00 (±60 min). 
At each scheduled follow-up visit, subjects will receive their morning dose of study 
medication/eye drops following the 08:00 IOP measurement at the investigative site (the doctor’s 
office). 


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Timolol Maleate Ophthalmic Solution 0.5% was chosen as the active control because it has 
previously been proven to be effective for the reduction of elevated IOP in patients with 
glaucoma or OHT and is approved for these indications. 
IOP will be measured at 08:00, 10:00 and 16:00 (±60 min). At these scheduled visits, BCVA and 
slit-lamp biomicroscopy will be performed just prior to the 08:00 IOP measurement. 
Ophthalmoscopy (fundus examination) will be performed after the 16:00 IOP measurement. 
Vital signs (resting blood pressure and pulse rate) will be collected in sitting position anytime at 
Visit 1, and approximately 08:00 for Visits 2, and 5 before the morning dose. 
Pharmacogenomics/genomics: 
Subjects who consent to the optional pharmacogenomics/genomics laboratory study will provide 
a blood sample for future testing. 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 400 adult subjects and up to 30 pediatric subjects are planned to be enrolled in 
this study. 
7.3. 
Treatment Assignment 
Subjects are randomized to one of two following treatment arms in a 1:1 ratio during the Double-
Masked Treatment Period: 
 DE-117 Ophthalmic Solution 0.002% QD (20:00) and Vehicle QD (08:00) 
 Timolol Maleate Ophthalmic Solution 0.5% BID (20:00 & 08:00) 
 
 


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7.4. 
Schedule of Events and Procedures 
Table 3: 
Schedule of Events and Procedures for ADULT subjects 
 
Washout Period 
Double-Masked Treatment Period 
Visit 1 
Screening 
Washout Period 
(up to 4 weeks) 
Optional Visit 
1a 
Visit 2 
Eligibility/Basel
ine 
(Day 1) 
Visit 3 
Week 1 
(Day 8±2) 
Visit 4 
Week 6 
(Day 43 ±3) 
Visit 5 
Month 3 
(Day 91±7) 
Exit or Early 
Termination n 
Informed Consent(s) including 
the optional consent for 
pharmacogenomics/ genomics 
laboratory research study a 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
Demographics and 
Medical History, including prior 
PGA b 
X 
 
 
 
 
 
Concomitant Medications/ 
Therapies 
X 
X 
X 
X 
X 
X 
Dosing Compliance 
 
 
 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
Pregnancy Test c 
X 
 
X 
 
 
X 
Vital Signs (blood 
pressure/pulse rate) d 
X 
 
X (08:00) 
 
 
X (08:00) 
Refraction e 
X 
 
 
 
 
 
BCVAe 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
Biomicroscopy f 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
IOP g 
X 
X 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
Pachymetry h 
X 
 
 
 
 
 
Instill study medication after 
IOP measurement 
 
 
 
X (08:00) 
X (08:00) 
X (08:00) 
Iris color, eyelash, eyelid i 
 
 
X (photo) 
 
 
X (photo) 
Gonioscopy j 
X 
 
 
 
 
 
Visual Field k 
X 
 
 
 
 
 
Ophthalmoscopy l 
X (pupil 
dilation) 
 
X (16:00) 
 
 
X (16:00, 
pupil dilation) 
Blood Sampling for 
Pharmacogenomics/genomics m 
 
 
 
X 
Dispense Study Medication 
 
 
X 
 
X 
 
Collect Study Medication 
 
 
 
 
X 
X 
Phone call to remind subject to 
take evening dose on the day 
before each visit 
 
 
 
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. 
Prostaglandin naive subjects are defined as subjects who are not known to have used prostaglandin as their glaucoma 
treatment. The previous use of prostaglandin should be confirmed by either subject’s medical records or subject history. 
c. 
A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
d. 
Vital signs (resting blood pressure and pulse rate) will be collected in sitting position anytime at Visit 1 (Screening), and 
approximately 08:00 for Visit 2 (Baseline), and Visit 5 before the morning dose.  
e. 
Refraction will be performed at the screening visit. If more than 10 letters in BCVA are lost compared to the screening visit, 
then refraction should be performed again. BCVA examination will be completed before IOP measurement at 08:00.  
f. 
Biomicroscopy examination must be completed before IOP is measured at 08:00. Aqueous flare and cell evaluation will be 
performed before fluorescein instillation.  
g. 
IOP measurements will be performed at 08:00, 10:00 and 16:00 (±60 min) at all visits except for Visit 1 and the optional 
Visit 1a (screening and mid-washout).  
h. 
Pachymetry will be performed after IOP measurement at Visit 1 (Screening). 
i. 
Eye photograph will be taken at Visits 2 (Baseline) and 5 (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, 2 and 5 (i.e. Screening, Baseline and Month 3) after the 16:00 IOP 
measurements. Ophthalmoscopy will be performed with pupil dilation at Visit 1 and Visit 5/exit or early 
termination..Dilation of the pupil will be performed after the 16:00 IOP measurement. 
m. Blood sampling for the pharmacogenomics/genomics laboratory research study may be performed at any visit after 
pharmacogenomics/genomics informed consent obtained, subject randomized and study drug dosing has begun. 
n. 
Optional at unscheduled visit, required for early terminated subjects.  
 
 
 
 


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Table 4: 
Schedule of Events and Procedures for PEDIATRIC subjects  
 
Washout Period 
Double-Masked Treatment Period 
Visit 1 
 Screening 
Washout Period 
(up to 4 weeks) 
Optional Visit 1a 
Visit 2 
Eligibility/Baseli
ne 
(Day 1) 
Visit 3 
Week 1 
(Day 8±2) 
Visit 4 
Week 6 
(Day 43 ±3) 
Visit 5 
Month 3 
(Day 91±7)  
Exit or Early 
Termination n 
Informed Consent(s) including the 
optional consent for 
pharmacogenomics/ genomics 
laboratory research study a 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
X 
 
 
 
Demographics and 
Medical History, including prior 
PGA b 
X 
 
 
 
 
 
Concomitant Medications/ 
Therapies 
X 
X 
X 
X 
X 
X 
Dosing Compliance 
 
 
 
X 
X 
X 
AEs 
 
X 
X 
X 
X 
X 
Pregnancy Test c 
X 
 
X 
 
 
X 
Vital Signs (blood pressure/pulse 
rate) d 
X 
 
X (08:00) 
 
 
X (08:00) 
Refraction e 
X 
 
 
 
 
 
BCVAe 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
Biomicroscopy f 
X 
X 
X (08:00) 
X (08:00) 
X (08:00) 
X (08:00) 
IOP g 
X 
X 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
08:00 
10:00 
16:00 
Pachymetry h 
X 
 
 
 
 
 
Instill study medication after IOP 
measurement 
 
 
 
X (08:00) 
X (08:00) 
X (08:00) 
Iris color, eyelash, eyelid i 
 
 
X (photo) 
 
 
X (photo) 
Gonioscopy j 
X 
 
 
 
 
 
Visual Field k 
X 
 
 
 
 
 
Ophthalmoscopy l 
X (pupil 
dilation) 
 
X (16:00) 
 
 
X (16:00 pupil 
dilation) 
Blood Sampling for 
Pharmacogenomics/genomics m 
 
 
 
X 
Dispense Study Medication 
 
 
X 
 
X 
 
Collect Study Medication 
 
 
 
 
X 
X 
Phone call to remind subject to 
take evening dose on the day 
before each visit 
 
 
 
X 
X 
X 
a. 
Informed Consent Form and the Assent Form must be signed and dated before study procedures are performed. Informed 
consent for the optional pharmacogenomics/genomics laboratory research study may be obtained at any visit prior to study 
exit. 
b. 
Prostaglandin-naive subjects are defined as subjects who are not known to have used prostaglandin as their glaucoma 
treatment. The previous use of prostaglandin should be confirmed by either subject’s medical records or subject history. 
c. 
A urine pregnancy test will be conducted for all female subjects of childbearing potential. 
d. 
Vital signs (resting blood pressure and pulse rate) will be collected in anytime at Visit 1 (Screening), and approximately 
08:00 for Visit 2 (Baseline), and Visit 5 before the morning dose.  
e. 
Refraction will be performed at the screening visit if the pediatric subject is able to cooperate. Autorefraction is also 
acceptable. If more than 10 letters in BCVA are lost compared to the screening visit level, then refraction should be 
performed again if the pediatric subject is able to cooperate. BCVA examination will be completed before IOP measurement 
at 08:00. BCVA will be performed for the pediatric subjects who are able to cooperate using an age-appropriate eye chart 
and method (e.g. ETDRS chart, LEA symbols chart with logMAR notation, Tumbling E’s with logMAR notation, Landolt’s 
broken rings with LogMAR notation, fix and follow) under normal room illumination. Same eye chart should be used for a 
given subject throughout the study. 
f. 
Biomicroscopy examination must be completed before IOP is measured at 08:00. Aqueous flare and cell evaluation will be 
performed before instillation of fluorescein.  


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g. 
IOP measurements will be performed at 08:00, 10:00 and 16:00 (±60 min) at all visits except for Visit 1 and the optional 
Visit 1a (screening and mid-washout). IOP will be measured with age-appropriate tonometers (e.g. Goldmann applanation 
tonometer, a Perkins tonometer, or a tonopen, or iCare tonometer etc.) to the extent the subject is able to cooperate.  
h. 
Pachymetry will be performed after IOP measurement at Visit 1 (Screening) if the subject is able to cooperate. Subject must 
have sufficiently clear cornea that allows for a complete ophthalmic exam to be enrolled if pachymetry is not able to be 
obtained. 
i. 
Eye photograph will be taken at Visits 2 (Baseline), and 5 (Month 3) if the subject is able to cooperate.  
j. 
Gonioscopy will be performed at Visit 1 (Screening) if the subject is able to cooperate. If unable to cooperate, historical 
gonioscopy performed within 12 months prior to screening and documented in the subject’s records is acceptable. 
Gonioscopy performed at Visit 1 (Screening) should occur after IOP measurement. 
k. 
Visual field test will be performed if the subject is able to cooperate. If visual field test was performed within 3 months (90 
days) prior to screening and was documented in the subject’s records, no additional screening visual field test is necessary.  
l. 
Ophthalmoscopy will be performed if the subject is able to cooperate. Ophthalmoscopy will be performed at Visits 1, 2, and 
5 (i.e. Screening, Baseline and Month 3) after the 16:00 IOP measurements. Ophthalmoscopy will be performed with pupil 
dilation at Visit 1 and Visit 5/exit or early termination. Dilation of the pupil will be performed after the 16:00 IOP 
measurement. 
m. Blood sampling for the pharmacogenomics/genomics laboratory research study may be performed at any visit after the 
pharmacogenomics/genomics informed consent is obtained, subject is randomized and study drug dosing has begun. 
n. 
Optional at unscheduled visit, required for early terminated subjects.  
 
Guidance for the visual acuity and IOP measurements in pediatric subjects are shown in  
Section 21.4. 
 
 


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7.4.1. 
Visit 1 (Screening) 
 Explain the purpose and conduct of the study to the subject and obtain written 
individual informed consent. Informed consent for the optional 
pharmacogenomics/genomics laboratory research study may be obtained at any visit 
prior to blood sampling. Ensure the subject understands that if he/she does not wish to 
provide a blood sample for the pharmacogenomics/genomics laboratory research 
study that their decision will have no influence on their participation in the main 
study. 
For pediatric subjects, written informed consent must be provided by the 
parent/legal guardian, and assent should be provided by the pediatric subjects. 
The evaluation of whether or not a child can give assent should not solely be 
based on chronological age, but should also depend on factors such as 
developmental stage, intellectual capacity and disease experience/understanding. 
 Prepare the list of screening/registration of subjects. 
 Obtain demographics. 
 Obtain medications, procedures/therapies and medical history including all lifetime 
ocular medical history to the extent possible, non-ocular medical history within 5 
years, diagnosis, ocular surgical history, current ocular and systemic conditions. 
 Obtain urine and perform urine pregnancy test, if the subject is a female of child-
bearing potential. 
 As per Schedule of Events and Procedures Table 3 (for adult subjects) or Table 4 
(for pediatric subjects), perform the following procedures or assessments (all 
ophthalmic procedures to be performed in both eyes): 
 Vital signs (blood pressure/pulse rate)  
 Refraction  
 BCVA (before IOP measurement) 
 Biomicroscopy (before IOP measurement) 
 IOP 
 Pachymetry (after IOP measurement)  
 Ophthalmoscopy with pupil dilation (after IOP measurement) 
 Gonioscopy  
 Visual field  
 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 medications if any according to the following 
schedule (up to +7 days as a window is allowed): 
 Miotics: 7 days 


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 Oral/topical Carbonic Anhydrase Inhibitors (CAIs): 7 days 
 Alpha agonists: 14 days 
 Alpha/beta agonists: 14 days 
 Alpha antagonists (α1 blocker): 28 days 
 Beta antagonists (β blocker, including αβ blockers): 28 days 
 Prostaglandin Analogs (PGA): 28 days 
 Rho kinase inhibitor: 28 days 
 Combination drugs: The longest washout period of the individual component will 
be used. 
 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 the randomization at Visit 2 (Baseline, Day 1). 
 An interim safety visit, mid-washout visit (Visit 1a), may be performed during the 
washout period if, in the Investigator’s opinion, a subject’s IOP causes any safety 
concerns during the washout period. If subjects are to be treated with topical CAI in 
the week before Visit 2 (Baseline, Day 1), mid washout visit (Visit 1a) is 
recommended to be performed. 
 The eligibility visit (Visit 2) will be scheduled at the end of the washout period for 
those subjects on prior IOP-lowering medications. 
 Subjects who have not used an IOP-lowering medication for the last 28 days, 
including treatment-naive subjects, will need a wait period of ≥ 1 day before their 
Visit 2 (Baseline, Day 1). 
 If a subject does not require washout from an IOP-lowering medication, but they 
use contact lenses in either eye for adult subjects or in the eye being considered 
for study treatment for pediatric subjects, 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 (Baseline, Day 1). 
 Schedule the eligible subject to return for Visit 2 (Baseline, Day 1) after the required 
wait/washout period. 
 A subject who does not meet eligibility criteria or will not otherwise continue in the 
study is considered a screen failure. 
7.4.2. 
Visit 1a (Optional, Washout Period) 
 Visit 1a is an interim safety visit (referred to as mid-washout visit) that may be 
performed during the washout period if, in the Investigator’s opinion, a subject’s IOP 
causes any safety concern during washout period. 
 Update concomitant medications and procedures/therapies. 


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 Query the subject regarding AEs. 
 As per Schedule of Events and Procedures Table 3 (for adult subjects) or Table 4 
(for pediatric subjects), 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 (Baseline, Day 1) 
 Update concomitant medications and procedures/therapies. 
 Confirm the subject has complied with the required wait/washout period for ocular 
hypotensive medication(s), or contact lenses use, if required. 
 Query the subject regarding AEs. 
 Perform vital signs (blood pressure/pulse rate) measurements at approximately 08:00. 
 As per Schedule of Events and Procedures Table 3 (for adult subjects) or Table 4 
(for pediatric subjects), perform the following procedures or assessments 
immediately before the 08:00 IOP measurement (all ophthalmic procedures to be 
performed in both eyes): 
 BCVA (before the 08:00 IOP measurement) 
 If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Biomicroscopy (before the 08:00 IOP measurement) 
 Perform IOP measurement at 08:00 (±60 min). 
 If subject meets the 08:00 IOP eligibility requirements, schedule additional IOP 
measurements at 10:00. 
 Perform IOP measurement at 10:00 (±60 min). 
 If subject meets the 08:00 and 10:00 IOP eligibility requirements, schedule additional 
IOP measurements at 16:00 
 Perform IOP measurement at 16:00 (±60 min). 
 Perform ophthalmoscopy in both eyes immediately after the 16:00 IOP measurement. 
 As per Schedule of Events and Procedures Table 3 (for adult subjects) or Table 4 
(for pediatric subjects), perform the following procedures or assessments at any 
time during this visit. 
 Iris color, eyelash, eyelid assessment, 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: 


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 Obtain urine and perform urine pregnancy test, if the subject is a female of child-
bearing potential. 
 Perform final review of eligibility criteria after the 16:00 IOP measurement. The 
subject will then be randomized, via Interactive Response Technology (Medidata 
BALANCE). 
 A subject who does not meet eligibility criteria or will not otherwise continue in the 
study is considered a screen failure. 
 After the subject has been randomized to a treatment arm, and assigned a treatment 
kit by BALANCE, an authorized unmasked study staff member, other than the 
Investigator or Examiner, must: 
 Dispense the assigned kit to the subject which will contain the following;  
 Two (2) bottles of study drug labeled “morning” 
 Two (2) bottles of study drug labeled “evening” 
 Give the subject verbal and written instructions for proper instillation of the study 
medication, the dosing regimen, and study medication storage.  
 Instruct the subject not to show or discuss their study medication with other study 
staff including the Investigator or Examiner, or other study subjects. 
 Instruct the subject to instill the study medicine daily, starting from this evening 
(“evening” dose) (20:00).  
 Schedule the subject to return on Day 8 ±2 for Visit 3 (Week 1). 
 Inform the subjects they will be reminded of the evening instillation of the study 
medication by phone call a few days before Visit 3. 
 Remind the subjects that the morning dose of Visit 3 will be done at the clinic. 
 Remind the subject to bring all used and unused study medication at Visit 3. 


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7.4.4. 
Visit 3 (Week 1, Day 8 ±2) 
 Update concomitant medications and procedures/therapies. 
 An authorized unmasked study staff member, other than the Investigator or Examiner 
should query the subject regarding dosing compliance and ensure subject has 
sufficient study medication to complete dosing through Visit 4. 
 Query the subject regarding AEs. 
 As per Schedule of Events and Procedures Table 3 (for adult subjects) or Table 4 
(for pediatric subjects), perform the following procedures or assessments 
immediately before the 08:00 IOP measurement (all ophthalmic procedures to be 
performed in both eyes): 
 BCVA (before the 08:00 IOP measurement) 
 If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Biomicroscopy (before the 08:00 IOP measurement) 
 Perform IOP measurement at 08:00 (±60 min). 
 Instill study medication/eye drop after the 08:00 IOP measurement in both eyes (for 
pediatric subjects, the investigator may elect to dose only one eye). An authorized 
unmasked study staff should make sure the instillation is performed. 
 Perform IOP measurement at 10:00, and 16:00 (±60 min). 
 If the subject provided written consent to provide a blood sample for a future 
pharmacogenomics/genomics laboratory research study, collect the sample at this 
visit or subsequent visit prior to exit from the study. 
 Note: If a blood sample cannot be collected at this visit, it may be collected at any 
one of the following Visits, for example, Visits 4, 5 or unscheduled or early 
termination visit, the subject has provided written consent prior to collection of 
the sample. 
 Schedule the subject to return on Day 43±3 for Visit 4 (Week 6). 
 Remind the subject to continue dosing according to the written instructions. 
 Inform the subjects they will be reminded of the evening instillation of the study 
medication by phone call a few days before Visit 4. 
 Remind the subjects that the morning dose of Visit 4 will be done at the clinic. 
 Remind the subject to bring all used and unused study medication at Visit 4. 
7.4.5. 
Visit 4 (Week 6, Day 43 ±3) 
 Update concomitant medications and procedures/therapies. 
 An authorized unmasked study staff member, other than the Investigator or Examiner 
should query the subject regarding dosing compliance. 


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 Query the subject regarding AEs. 
 As per Schedule of Events and Procedures Table 3 (for adult subjects) or Table 4 
(for pediatric subjects), perform the following procedures or assessments 
immediately before the 08:00 IOP measurement (all ophthalmic procedures to be 
performed in both eyes): 
 BCVA (before the 08:00 IOP measurement) 
 If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Biomicroscopy (before the 08:00 IOP measurement) 
 Perform IOP measurement at 08:00 (±60 min). 
 Instill study medication/eye drop after the 08:00 IOP measurement in both eyes (for 
pediatric subjects, the investigator may elect to dose only one eye, the study eye). 
An authorized unmasked study staff should make sure the instillation is performed. 
 Perform IOP measurement at 10:00, and 16:00 (±60 min). 
 An authorized unmasked study staff member, other than the Investigator or Examiner, 
must: 
 Collect all used and unused bottles of study medication. 
 Dispense the assigned kit (from BALANCE) to the subject which will contain the 
following;  
 Two (2) bottles of study drug labeled “morning” 
 Two (2) bottles of study drug labeled “evening” 
 Instruct the subject not to show or discuss their study medication with other study 
staff including the Investigator or Examiner, or other study subjects. 
 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. 
 Schedule the subject to return on Day 91±7 for Visit 5 (Month 3). 
 Remind the subject to continue dosing according to the written instructions. 
 Inform the subjects they will be reminded of the evening instillation of the study 
medication by phone call a few days before Visit 5. 
 Remind the subjects that the morning dose of Visit 5 will be done at the clinic. 
 Remind the subject to bring all used and unused study medication at Visit 5. 
7.4.6. 
Visit 5 (Month 3, Day 91 ±7) Study Exit/Early Termination 
 Update concomitant medications and procedures/therapies. 


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 An authorized unmasked study staff member, other than the Investigator or Examiner 
should query the subject regarding dosing compliance. 
 Query the subject regarding AEs. 
 Perform vital signs (blood pressure/pulse rate) measurements at approximately 08:00. 
 As per Schedule of Events and Procedures Table 3 (for adult subjects) or Table 4 
(for pediatric subjects), perform the following procedures or assessments 
immediately before the 08:00 IOP measurement (all ophthalmic procedures to be 
performed in both eyes): 
 BCVA (before the 08:00 IOP measurement) 

If more than 10 letters in BCVA were lost compared to the screening visit, 
then refraction should be performed again. 
 Biomicroscopy (before the 08:00 IOP measurement) 
 Perform IOP measurement at 08:00 (±60 min). 
 Instill study medication/eye drop after the 08:00 IOP measurement in both eyes (for 
pediatric subjects, the investigator may elect to dose only one eye, the study eye). 
An authorized unmasked study staff should make sure the instillation is performed. 
 Perform IOP measurement at 10:00, and 16:00 (±60 min). 
 Perform pupil dilation in both eyes after the 16:00 IOP measurement. 
 Perform ophthalmoscopy with pupil dilation in both eyes immediately after the 16:00 
IOP measurement. 
 As per Schedule of Events and Procedures Table 3 (for adult subjects) or Table 4 
(for pediatric subjects), perform the following procedures or assessments at any 
time during this visit. 
 Assess any changes from baseline in Iris color, Eyelash, Eyelid and take front 
view and side view photographs of each eye. The following six (6) photos are 
required at this visit as follows: 


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 Obtain urine and perform urine pregnancy test, if the subject is a female of child-
bearing potential. 
 An authorized unmasked study staff member, other than the Investigator or Examiner, 
must: 
 Collect all used and unused bottles of study medication. 
 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 the study drug administration is discontinued prior to Visit 5, the subject 
should be encouraged to still participate in follow-up study visits until Visit 5 on 
an observational basis. 
 If the study drug administration is discontinued prior to Visit 5, then to the 
extent possible, all procedures for Study Exit/Early Termination as per Table 3 
(for adult subjects) or Table 4 (for pediatric subjects) will be performed on the 
day of early termination. Subjects who are discontinued from the study early 
will not be replaced.  
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. 
8.1. 
Subject Inclusion Criteria for ADULT Subjects 
Inclusion Criteria Specific for ADULT Subjects: 
At Visit 1 (Screening), the subjects 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 a female of childbearing potential (i.e., not post-menopausal [within 12 
months since the last menses] or not surgically sterile [less than 6 months from date of 
surgery]), she must have a negative urine pregnancy test and must use at least one of the 
following acceptable contraceptive methods during the study (as well as for 4 weeks 
following last dose in study). 
 Abstinence 
 Hormonal contraceptive method (including oral or transdermal contraceptives, 
injectable progesterone, progestin subdermal implants, progesterone-releasing 
intrauterine devices [IUDs]) initiated at least 28 days prior 
 Placement of a copper-containing IUD 
 Condom with spermicidal foam/gel/film/cream/suppository 
 Vasectomized male partner (surgery at least 6 months prior) 
Male subjects capable of fathering children should use/ 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 OAG (including Pigmentary Glaucoma or Pseudoexfoliative 
Glaucoma) or OHT in both eyes, or one eye with OAG 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. 
In addition to continuing to meet inclusion criterion 5 (BCVA), the subject must meet the 
following criteria at Visit 2 (Baseline, Day 1): 
8. Completed the required wait/washout period. 


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9. At all time points of IOP measurements (08:00, 10:00 and 16:00) at Visit 2 (Baseline, 
Day 1), have IOP of ≥ 22 mmHg in at least one eye (the same eye), and ≤ 34 mmHg in 
both eyes. 
8.2. 
Subject Exclusion Criteria for ADULT Subjects 
Exclusion Criteria Specific for ADULT Subjects: 
At Visit 1 (Screening) and Visit 2 (Baseline, Day 1), subjects with any of the following ocular 
conditions in either eye or with any of the following non-ocular conditions or characteristics are 
not eligible to participate in the study: 
General 
1. Females who are pregnant, nursing or planning a pregnancy.  
2. Subjects with known or suspected drug or alcohol abuse. 
3. 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. Intended or current use of the following prohibited medications/therapies during the 
study duration: 
All ocular medications other than sodium chloride/potassium chloride ophthalmic 
solution, cataract treatment agents (e.g., glutathione, pirenoxine), Vitamin B12 
formulation (e.g., cyanocobalamine), over-the-counter dry eye artificial tears/drops, 
and study medications. 
All systemic medications for ocular hypotensive (e.g., oral or intravenous CAI, oral 
glycerol). 
Any ocular, periocular, inhaled, nasal or systemic corticosteroids including joint 
injection, etc. 
Lacrimal/punctal occlusion via plug (s) or cautery.  
6. Subjects who cannot safely discontinue use of ocular hypotensive medications during the 
wait/washout period. 
7. 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 be on a stable dose 
use for at least 30 days prior to Visit 1 (Screening) and during the study duration. 


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8. Use of contact lenses within 2-3 weeks prior to Visit 2 (Baseline, Day 1) until end of 
treatment in either eye (2 weeks for soft contact lens wearers, and 3 weeks for rigid 
contact lens wearers). 
9. Any ocular surgery or ocular laser treatment within 180 days prior to Visit 1 (Screening) 
and throughout the study in either eye. 
10. 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. 
11. History of keratorefractive surgery (e.g., RK, PRK, LASIK) in either eye.  
12. Allergy, hypersensitivity or contraindications to EP2 receptor agonists, beta-blockers, 
benzalkonium chloride (BAK) or any other components of the study medications, or 
other study related procedures/medications. This also includes subjects with a history or 
presence of contraindications to beta-blocker therapy, such as chronic obstructive 
pulmonary disease (e.g., chronic bronchitis, emphysema), bronchial asthma, second or 
third degree atrioventricular block, uncontrolled congestive heart failure. 
Diseases 
13. Presence of advanced glaucoma (e.g., visual field mean deviation worse than -12 dB) in 
either eye. 
14. 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. 
15. Presence of any active severe external ocular disease, inflammation, or infection of the 
eye and/or eyelids in either eye. 
16. Presence or history of macular edema or known risk factors for macular edema in either 
eye. 
17. History of severe ocular trauma in either eye. 
18. History of iritis and/or uveitis in either eye. 
19. History of retinal detachment, proliferative diabetic retinopathy, or any retinal disease 
that may be progressive during the time course of the study in either eye. 
20. Presence or history of any disease or condition that in the opinion of the study 
Investigator may put the subject at significant risk, may confound study results, or may 
interfere significantly with the subject’s participation in the study (e.g., recurrent corneal 
erosion syndrome, uncontrolled cardiovascular disease etc.). 
21. Any decision by the Investigator or Medical Monitor to terminate a subject in screening 
or declare any subject ineligible for any sound medical reason. 
 


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8.3. 
Subject Inclusion Criteria for PEDIATRIC Subjects 
Inclusion Criteria Specific for PEDIATRIC Subjects: 
At Visit 1 (Screening), the pediatric subjects must meet all of the following inclusion criteria: 
1. Parent/legal guardian signed written informed consent on the Institutional Review 
Board (IRB)/Ethics Committee (EC) approved Informed Consent Form (ICF) and 
patient assent has been given as applicable.  
2. The patient and parent/legal guardian should agree to comply with study restrictions, 
treatment plan, procedures and keep scheduled visits. 
3. Be ≥1 year and less than 18 years old on the date of signing the ICF. 
4. If a subject is a female of childbearing potential she must have a negative urine 
pregnancy test and must use at least one of the following acceptable contraceptive 
methods during the study (as well as for 4 weeks following last dose in study). 
 Abstinence 
 Hormonal contraceptive method (including oral or transdermal contraceptives, 
injectable progesterone, progestin subdermal implants, progesterone-releasing 
intrauterine devices [IUDs]) initiated at least 28 days prior 
 Placement of a copper-containing IUD 
 Condom with spermicidal foam/gel/film/cream/suppository 
 Vasectomized male partner (surgery at least 6 months prior)  
Male subjects capable of fathering children should use/ 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). 
5. Must have a diagnosis of pediatric glaucoma or OHT in one or both eyes, including 
primary (congenital and juvenile open angle glaucoma) and secondary glaucoma. For a 
child with pediatric glaucoma due to secondary causes, the Investigator or study site 
should discuss the case with the Medical Monitor prior to subject enrollment. 
6. Must have elevated IOP to such a level that investigator deems pharmacologic 
intervention with IOP-lowering medication to be clinically necessary in at least one 
eye. 
7. Must have a sufficiently clear cornea that allows for a complete ophthalmic 
examination. 
8. Anterior chamber angle grade ≥ 2 (Shaffer scale) in each eye, based on gonioscopy 
performed at Visit 1 (Screening), or historical gonioscopy performed within 12 months 
prior. 
In addition to continuing to meet inclusion criteria 6 (elevated IOP) and 7 (clear cornea), the 


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subject must meet the following criterion at Visit 2 (Baseline, Day 1): 
9. Completed the required wait/washout period. 
8.4. 
Subject Exclusion Criteria for PEDIATRIC Subjects 
Exclusion Criteria Specific for PEDIATRIC Subjects: 
At Visit 1 (Screening) and Visit 2 (Baseline, Day 1), subjects with any of the following ocular 
conditions in either eye or with any of the following non-ocular conditions or characteristics 
are not eligible to participate in the study. Exception: criteria 8, 9 and 10 only apply to the eye 
being considered for study treatment. E.g. if only the non-treated eye has a history of LASIK, 
the other eye may still qualify for participation and treatment in the study if the subject meets 
all other criteria. 
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. Intended or current use of the following prohibited medications/therapies during the 
study duration: 
All ocular medications other than sodium chloride/potassium chloride ophthalmic 
solution, cataract treatment agents (e.g., glutathione, pirenoxine), Vitamin B12 
formulation (e.g., cyanocobalamine), over-the-counter dry eye artificial tears/drops, 
and study medications. 
All systemic medications for ocular hypotensive (e.g., oral or intravenous CAI, oral 
glycerol). 
Any ocular, periocular, inhaled, nasal or systemic corticosteroids including joint 
injection, etc. 
Lacrimal/punctal occlusion via plug (s) or cautery.  
6. Subjects who cannot safely discontinue use of ocular hypotensive medications during 
the wait/washout period. 
7. 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 


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channel blockers, angiotensin-converting enzyme [ACE] inhibitors, and angiotensin II 
receptor blockers [ARB]). Subjects using the above medications must be on a stable 
dose use for at least 30 days prior to Visit 1 (Screening) and during the study duration. 
8. Use of contact lenses within 2-3 weeks prior to Visit 2 (Baseline, Day 1) until end of 
treatment (2 weeks for soft contact lens wearers, and 3 weeks for rigid contact lens 
wearers). 
9. Any ocular surgery (including goniotomy or glaucoma surgery) or ocular laser 
treatment within 180 days prior to Visit 1 (Screening) and throughout the study. 
10. History of keratorefractive surgery (e.g. RK, PRK, LASIK).  
11. Allergy, hypersensitivity or contraindications to EP2 receptor agonists, beta-blockers, 
benzalkonium chloride (BAK) or any other components of the study medications, or 
other study related procedures/medications. This also includes subjects with a history 
or presence of contraindications to beta-blocker therapy, such as chronic obstructive 
pulmonary disease (e.g. chronic bronchitis, emphysema), bronchial asthma, second or 
third degree atrioventricular block, uncontrolled congestive heart failure. 
Diseases 
12. Presence of advanced glaucoma in either eye. 
13. Presence of any corneal abnormality or other conditions interfering with or preventing 
reliable tonometric measurements (e.g., Fuch’s dystrophy or significant corneal surface 
abnormality) in either eye. 
14. Presence of any active severe external ocular disease, inflammation, or infection of the 
eye and/or eyelids in either eye. 
15. Presence or history of macular edema or known risk factors for macular edema in 
either eye. 
16. Aphakia or pseudophakia 
17. Single sighted subject  
18. History of severe ocular trauma in either eye. 
19. History of iritis and/or uveitis in either eye. 
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 (such as contraindication to the use 
of Timolol Maleate Ophthalmic Solution 0.5%), 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. 


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8.5. 
Subject Withdrawal Criteria 
An early termination occurs when a subject who provides written informed consent ceases 
participation in the study, regardless of circumstances, before the completion of the study. 
Subjects may be voluntarily discontinued from study medication or withdrawn from the study at 
any time for any reason. In addition, the Principal Investigator or Medical Monitor may 
discontinue the study drug administration or terminate a subject’s study participation due to any 
of the following reasons: 
 AE (e.g., not compatible with study continuation) 
 Non-compliance with study drug 
 Lack of efficacy (e.g., IOP exceeds 34 mmHg in either eye after randomization) 
 Progressive disease 
 Protocol deviation (e.g., not fulfilling eligibility criteria) 
 Pregnancy 
 Voluntary withdrawal by subject at any time for any reason 
 Lost to follow-up (e.g., no contact is possible) 
 Death 
 Other 
If the study drug administration is discontinued prior to Visit 5, they should be encouraged to 
still participate in all follow-up study visits until Visit 5 on an observational basis. 
If the study drug administration is discontinued prior to Visit 5, then to the extent possible, all 
procedures for Early Termination will be performed on the day of early drug discontinuation as 
per Table 3 (for adult subjects) or Table 4 (for pediatric subjects). Subjects who are discontinued 
from the study early will not be replaced. 


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9.
TREATMENT OF SUBJECTS 
9.1.
Description of Study Medication 
DE-117 Ophthalmic Solution 0.002% is an aqueous solution containing DE-117.
Figure 2: 
DE-117 Structure 
 
Investigational Product: 
 DE-117 Ophthalmic Solution 0.002% contains 0.02 mg/mL DE-117 
Active Control: 
 Timolol Maleate Ophthalmic Solution 0.5% contains the active ingredient, timolol  
5 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 other than the study medication during the study duration will be 
considered as a concomitant treatment. The information of concomitant treatment must be 
recorded in the subject’s source documents and on the eCRF.  
 Concomitant medication: name of medication, route of administration, treated eye(s) 
(if applicable), dose, frequency, indication, start date and stop date. 
 Concomitant therapy: name of therapy, treated eye(s) (if applicable), indication, start 
date and stop date. 
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 
formulation (e.g., cyanocobalamine), over-the-counter dry eye artificial tears/drops, 
and study medications during the study duration. 


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 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 (Baseline, Day 1) until end of 
treatment in either eye for adult subjects or in the eye being considered for study 
treatment for pediatric subjects (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 for adult subjects or in the eye 
being considered for study treatment for pediatric subjects. 
 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 
 Twice daily at 08:00 and 20:00 [±60min] through Visit 2 to 5  
 Subjects will be reminded of the evening instillation of the study drug on the day 
before Visit 3 through Visit 5/Early Termination respectively. 


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 Subjects will be reminded that the morning instillation of the study drug at each visit 
through Visit 3 to 5 will be done at the clinic.  
 For adult subjects, since subjects must have a diagnosis of OAG 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. 
For pediatric subjects, if only one eye has a diagnose of glaucoma or OHT, the 
fellow eye doesn’t have to be treated by the study medications for the duration of 
the study.  
 Subjects will be queried regarding compliance with the protocol’s dosing regimen at 
Visit 3 through Visit 5/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 
through Visit 5/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 
A stratified permuted-block randomization will be employed to randomize eligible subjects in a 
1:1 ratio to either DE-117/Vehicle arm or Timolol Maleate arm. Two strata will be constructed 
based on age (adult: ≥ 18 years; pediatric: < 18 years).  
The randomization schedule will be generated and implemented using central randomization via 
Interactive Response Technology (Medidata BALANCE). Each randomized subject will receive 
numbered study medication kits as assigned by BALANCE. 
This is a double-masked study. The subjects, Investigators, Examiners and Santen personnel 
involved in the conduct of the study will be masked to the study treatment. An authorized 
unmasked study staff member who is not the Investigator or Examiner at the investigative site 
will dispense and collect study medication(s) and will query about dosing compliance. Subjects 
will be instructed not to show the eye drop bottles or discuss the eye drop to either the 
Investigator or the Examiner or other study subjects. The active control treatment (Timolol 
Maleate) containers will be over-labeled and packaged in the same secondary package (e.g., 
cardboard carton) as the investigational treatment (DE-117). All subjects will receive a bottle 
labeled “morning” for the morning dose and a bottle labeled “evening” for the evening dose. 
However, the DE-117/Vehicle arm will receive the vehicle (i.e., “morning” bottle) at the 
morning dose, while the Timolol Maleate arm receives the active treatment (i.e., “morning” 
bottle) at the morning dose. 
In case of a medical emergency, the Principal Investigator may reveal the treatment information 
by unmasking through Medidata BALANCE to know which treatment the subject has received. 


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The Principal Investigator (or his/her designee) should contact Santen, or Santen’s designee, 
before taking this measure, if there is sufficient time. Santen, or Santen’s designee, must be 
informed of all instances where the code is broken and of the reasons for such instances. 
Additionally, the AE or SAE for which study treatment was unmasked should be reported to 
Santen Pharmacovigilance. 


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10.
STUDY MEDICATION MATERIALS AND MANAGEMENT 
10.1.
Study Medication 
10.1.1.
Investigational Product 
DE-117 Ophthalmic Solution contains 0.002% or 0.02 mg/mL 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.
Vehicle 
The vehicle is identical to the investigational product but does not contain the active ingredient 
in DE-117.
10.1.3.
Active Control 
The active control used in this clinical study, Timolol Maleate Ophthalmic Solution 0.5%, is 
supplied as a sterile, isotonic, buffered aqueous solution. 
Timolol Maleate Ophthalmic Solution 0.5% contains the active ingredient, timolol 5 mg/mL and 
the preservative BAK 0.01%. Other ingredients include monobasic and dibasic sodium 
phosphate and purified water. The pH is adjusted to 6.5 to 7.5 with sodium hydroxide. See 
Section 21.5. 
10.2.
Study Medication Packaging and Labeling 
DE-117 Ophthalmic Solution 0.002% and DE-117 vehicle ophthalmic solution will be supplied 
as 
Timolol Maleate Ophthalmic Solution 0.5% will be supplied as a 5 mL solution in a 5 mL white 
low density polyethylene bottle. 
Each eye drop bottle will be placed in a unit carton. Four 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. 
Kits dispensed at Visit 2 and Visit 4 (double-masked portion) will contain two (2) “morning” eye 
drop bottles and two (2) “evening” eye drop bottles of study medication.  


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An authorized unmasked study staff member, other than the Investigator or Examiner, will 
dispense and collect study medications. When collecting the study medications, the kit 
containing all the used and unused eye drop bottles will be sealed. 
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) 
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 
During the Double-Masked Treatment Period subjects will instill one drop of study medication 
in each eye at approximately 20:00 (±60min) and 08:00 (±60min) daily for 3 months.  
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 


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ensure that any used and unused supplies are available to Santen (or designee) for accountability 
purposes throughout the study. 
10.7. 
Study Medication Handling and Disposal 
The used study medication kits will be stored at room temperature and the unused study 
medication kits will be refrigerated until final study medication accountability has been 
completed by Santen (or designee). Following final study medication accountability and 
reconciliation by Santen (or designee), all used and unused study medication will be returned to 
the assigned central drug depot. 
10.8. 
Study Supplies 
Commercial urine pregnancy test kits 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, 10:00 and 16:00) will be 
evaluated at each post-baseline visit. Besides observed IOP measurements, change and percent 
change from baseline in IOP at each scheduled time point as well as the change and percent 
change from baseline in mean diurnal IOP will also be derived and evaluated. 


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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, DE-117 vehicle and Timolol. Regardless of relationship to 
the study medication, an AE can be a clinically relevant unintended sign (including an abnormal 
laboratory finding), symptom, or disease.  
Any significant change in a subject’s condition from the time that written informed consent is 
obtained, regardless of causality, is to be considered an AE. A clinically significant worsening in 
severity, intensity, or frequency of a pre-existing condition may indicate an AE. 
An elective surgical procedure scheduled or planned prior to study entry that does not require 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 an SAE. 
The lack of efficacy of the study medication for the condition being investigated is not 
considered an AE unless a clinically significant change is assessed by the Investigator. 
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 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 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 precipitate, lens, anterior synechiae of iris and 
posterior synechiae of iris 
 Ophthalmoscopy variables: glaucomatous optic nerve 
 Iris color/eyelash/eyelid 
12.2.2. 
Non-ocular Assessments 
Non-Ocular assessments include: 
 Blood pressure and pulse rate 


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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 
An unmasked final analysis will be performed after all subjects completed Month 3. The analysis 
will evaluate the efficacy and safety of DE-117 Ophthalmic Solution 0.002% once daily 
compared with Timolol Maleate Ophthalmic Solution 0.5% twice daily. 
14.3. 
General Considerations 
Descriptive statistics, unless otherwise noted, will include the number of subjects (N), mean, 
standard deviation (SD), median, minimum, and maximum for continuous variables and N and 
percent for categorical variables. 
The study eye will be defined as the eye that qualifies per inclusion criteria at Baseline (Visit 2). 
For example, IOP must be ≥ 22 mmHg at all IOP measurement time-points (08:00, 10:00 and 
16:00). See Section 8.1 and Section 8.2 for all inclusion/exclusion criteria. If both eyes qualify, 
the eye with the higher mean diurnal IOP at Baseline (Visit 2) 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. 
Statistical analyses for pediatric subjects may be performed separately depending on the number 
of pediatric subjects enrolled in this study. 
More details on the statistical methods will be described in SAP which will be finalized prior to 
unmasking the data. 
14.3.1. 
Sample Size 
The sample size calculation was based on a two-sided Type I error rate of 5% and a non-
inferiority margin of 1.5 mmHg. Assuming a between-treatment difference of 0 mmHg, SD of 
4.0 mmHg and a correlation coefficient of 0.6 among repeated measures, approximately 400 
adult subjects in total (200 subjects per treatment arm) will provide 90% power to demonstrate 
non-inferiority of DE-117 Ophthalmic Solution 0.002% to Timolol Maleate Ophthalmic Solution 
0.5%. 
14.3.2. 
Statistical Hypotheses and Level of Significance 
The primary efficacy endpoint is the IOP in the study eye measured at the specified time points: 
08:00, 10:00 and 16:00 at Week 1, Week 6 and Month 3 visits. 


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For the primary endpoint, a Mixed Effect Model for Repeated Measurement (MMRM) will be 
used to test the following hypotheses: 
H0: µT – µC > Δ versus HA: µT – µC ≤ Δ  
where µT and µC denote the mean values of the primary endpoint in DE-117/Vehicle arm and 
Timolol Maleate arm, respectively, and Δ denotes the non-inferiority margin of 1.5 mmHg.  
Treatment difference between the DE-117/Vehicle arm and Timolol Maleate arm at each 
specified time point of each post-baseline visit up to Month 3 will be reported along with 95% 
confidence intervals. Non-inferiority is established if the upper limit of the two-sided 95% 
confidence interval for the difference in the mean IOP (0.002% DE-117 - Timolol Maleate) is  
≤ 1.5 mmHg at all nine time points and ≤ 1.0 mmHg in majority (5 or more) of the time points.  
If the upper limit of the 95% confidence interval for the difference is ≤ 0 at all nine time points, 
superiority of DE-117 to Timolol will be claimed.  
If non-inferiority in the primary endpoint is achieved, then the following two key secondary 
endpoints will be tested sequentially according to hierarchical fixed sequence procedure:  
1. Mean diurnal IOP in the study eye at Month 3 
The corresponding hypothesis is: 
H0S1: µTs1 – µCs1  > Δ versus HAS1: µTs1– µCs1 ≤  Δ 
where µTs1 and µCs1 denote the mean diurnal IOP at Month 3 in DE-117/Vehicle arm and Timolol 
Maleate arm, respectively; and Δ denotes the non-inferiority margin of 1.5 mmHg.   
If the hypothesis is rejected at 0.05 significance level, then the following key secondary endpoint 
will be tested: 
2. Mean diurnal IOP in the study eye at Week 1 
The corresponding hypothesis is: 
H0S2: µTs2  = µCs2  versus HAS2: µTs2 ≠ µCs2 
Where µTs2 and µCs2 denote the mean diurnal IOP at Week 1 in DE-117/Vehicle arm and Timolol 
Maleate arm, respectively.  
14.4. 
Study Populations 
14.4.1. 
Safety Population 
The Safety Population will include all randomized subjects who received at least one dose of the 
study medication. The safety analysis will be performed on the Safety Population by actual 
treatment received. 
14.4.2. 
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized subjects who received at least one dose 
of study medication and provided at least one post-baseline IOP measurement. The efficacy 
analysis will be performed on the FAS or a subset of the FAS by planned treatment. 


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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 SAP. 
14.5. 
Handling of Missing Values 
The primary analysis of continuous IOP endpoints will be performed using the MMRM analysis 
on observed cases. As sensitivity analyses, a last-observation-carried-forward (LOCF) approach 
and a Pattern Mixture Models (PMM) approach may be applied to evaluate the impact of missing 
data on the primary analysis results. For the binary IOP endpoints, the missing data at Month 3 
will be imputed using an LOCF approach. 
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. 
Unless specified otherwise, descriptive summaries will be based on observed cases.  
More 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 by treatment. 
Concurrent diseases will be coded using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA). Subjects with any concurrent diseases will be tabulated by primary 
System Organ Class (SOC) and Preferred Term (PT) specified in the MedDRA. 
Subjects using any prior medications that has been used for glaucoma or OHT within 28 days 
before Screening (Visit 1) will be tabulated by Anatomical Therapeutic Chemical (ATC) levels 
and PT specified in the latest version of World Health Organization Drug Dictionary Enhanced 
(Organization, 2011). 
14.7. 
Efficacy Analyses  
Unless specified otherwise, for subjects who discontinue from the study medication per protocol 
before the Study Exit, the IOP data collected after the study medication discontinuation with any 
use of non-study IOP lowering medication or surgery will be censored from all efficacy analyses. 
14.7.1. 
Analysis of Primary Efficacy Endpoint  
The primary efficacy endpoint is the IOP in the study eye measured at the specified time points: 
08:00, 10:00 and 16:00 at Week 1, Week 6 and Month 3 (Visits 3, 4 and 5). 
A MMRM will be carried out on observed cases up to Month 3. At each scheduled time point of 
each visit, least square mean IOP of each treatment arm and 95% confidence interval for the 
difference in least square means between DE-117/Vehicle and Timolol Maleate will be 
estimated. Non-inferiority is established if the upper limit of the 95% confidence interval for the 


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difference is ≤ 1.5 mmHg for all nine time points and ≤ 1.0 mmHg for at least 5 out of the 9 time 
points.  
The primary analysis will be based on the FAS. The same analysis will be repeated on the PPS 
population as a sensitivity analysis. More details on the model specifications will be provided in 
the SAP. 
14.7.2. 
Analysis of Secondary Efficacy Endpoints 
14.7.2.1. Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are 
 Mean diurnal IOP in the study eye at Month 3 (Visit 5), and 
 Mean diurnal IOP in the study eye at Week 1 (Visit 3) 
A MMRM will be carried out on observed cases up to Month 3. The least square mean diurnal 
IOP of each treatment arm and 95% confidence interval for the difference in least square means 
between DE-117/Vehicle and Timolol Maleate at Week 1 and Month 3 will be estimated, 
respectively. If non-inferiority in the primary endpoint is achieved, then the two key secondary 
endpoints will be tested sequentially at the 0.05 significance level (2-sided) to control the overall 
Type I error rate associated with the two comparisons. 
The primary analysis will be based on the FAS. The same analysis will be repeated on the PPS 
population as a sensitivity analysis. More details on the model specifications and multiplicity 
adjustment will be provided in the SAP. 
14.7.2.2. Other Secondary Efficacy Endpoints 
Other secondary endpoints to be assessed include: 
 Change and percent change from baseline in IOP at each timepoint/post-baseline visit 
 Change and percent change from baseline in mean diurnal IOP at each post-baseline  
visit 
 Having a mean diurnal IOP reduction ≥ 20%, ≥ 25%, or ≥ 30% from Baseline  
(Visit 2) at each post-baseline visit 
 Having a mean diurnal IOP ≤ 18mmHg at each post-baseline visit 
The Continuous secondary endpoints will be analyzed using MMRM on observed cases. More 
details on the model specifications will be provided in the SAP. 
The binary secondary endpoints will be analyzed using the Pearson’s chi-square test for a 2×2 
contingency table. The Fisher’s Exact test may be conducted as a sensitivity analysis. 
Subgroup analyses may be performed for secondary endpoints using descriptive statistics. 
14.8. 
Safety Analyses 
All safety outcome measures will be summarized descriptively for the Safety Population. The 
safety outcome measures include AEs, blood pressure and pulse rate, BCVA, slit-lamp 
biomicroscopy findings, ophthalmoscopy, iris color, eyelash, and eyelid. 


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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 treatment and maximum 
severity. In addition, SAEs and discontinuations due to AEs will be summarized. 
Safety parameters listed in Section 12.2.1 and Section 12.2.2 will be summarized using 
descriptive statistics by actual treatment received. Changes from baseline in these safety 
parameters will also be summarized by treatment. 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Principal Investigator will allow representatives of Santen’s monitoring team (or designee), 
the governing 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 study, assent form and other study related material, 
as appropriate, must be approved in writing by an IRB or IEC as appropriate. If an IRB or IEC 
does not approve the collection of blood samples for optional future pharmacogenomic 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 pharmacogenomic 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. 
For the pediatric subjects, written informed consent must be signed in accordance with 
local regulatory and legal requirements by the patient or parent/legal guardian, and giving 
of assent by the patient if appropriate, must be documented prior to initiation of any study-
related procedures. Subjects and their parents/legal guardians must be provided with 
adequate time to think over their possible participation in the study, to ask questions from 
the investigator and/or to discuss the study participation with their family or primary care 


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physician. No measures whatsoever described in the study protocol shall be undertaken, 
nor any current medication discontinued without such consent indicating that the patient 
and/or the parent/legal guardian have been given both verbal and written information 
about the study and the study treatment. The evaluation of whether or not a child can give 
assent should not solely be based on chronological age, but should also depend on factors 
such as developmental stage, intellectual capacities and disease experience/understanding.  


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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 
 If unmasking at the site occurred, proper documentation and notifications were made 


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18.2.2. 
Source Data 
Source data is defined as all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data should be accurate, legible, 
contemporaneous, original, attributable, complete and consistent. Source data is documented in 
source documents which may be both electronic and on paper. 
The Investigator(s) should be aware about the location of the source data and consistent in 
recording them. The intended location should be clearly defined prior to subject enrollment. One 
way of achieving this is to generate a source data location list. The source data location list will 
be prepared by the site and will be signed and dated by the Principal Investigator. The list will be 
filed in the Investigator’s trial master file. 
18.2.3. 
Data Collection 
The Principal Investigator must maintain detailed records on all subjects who provide informed 
consent. Data for screened and randomized subjects will be entered into eCRFs. eCRFs should 
be completed within 3 business days of each subject visit as much as possible. Review of the 
eCRFs will be completed remotely by Santen (or designee). At designated intervals, a study 
monitor will perform Source Data Verification on site. During those visits, Santen (or designee) 
will monitor the subject data recorded in the eCRF against source documents at the study site. 
Santen (or designee) will review and evaluate eCRF data and use standard system edits, and may 
use centralized monitoring evaluations, to detect errors in data collection. At the end of the study, 
a copy of the completed eCRFs will be sent to the site to be maintained as study records. 


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19. 
PUBLICATION POLICY 
The existence of this clinical study is confidential, and it should not be discussed with persons 
outside of the study. Additionally, the information in this document and regarding this study 
contains trade secrets and commercially sensitive information that is confidential and may not be 
disclosed unless such disclosure is required by federal or state law or regulations. Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who 
have a need to know, but all such persons must be instructed not to further disseminate this 
information to others. These restrictions of disclosure will apply equally to all future information 
supplied that is indicated as confidential. Information pertaining to this study will be published 
on www.clinicaltrials.gov. 
The data generated by this clinical study are the property of Santen and should not be disclosed 
without the prior written permission of Santen. These data may be used by Santen now and in the 
future for presentation or publication at Santen’s discretion or for submission to governmental 
regulatory agencies. Santen reserves the right of prior review of any publication or presentation 
of data from this study. 
In signing this protocol, the Principal Investigator agrees to the release of the data from this 
study, and acknowledges the above publication policy. 


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20. 
REFERENCES 
20.1. 
Literature 
1. 
AGIS_Investigators. (2000).  The Advanced Glaucoma Intervention Study (AGIS): 7. 
The Relationship Between Control of Intraocular Pressure and Visual Field Deterioration. 
American Journal of Ophthalmology. 130(4):429-40. 
 
2. 
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. 
 
8. 
MedDRA.  Medical Dictionary for Regulatory Activities. 14.1. 
 
9. 
Organization, W. H. (2011).  World Health Organization Drug Dictionary Enhanced. 
 


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10. 
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. 
 
11. 
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. 
 
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 
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 


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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 
The following descriptions are for adult and pediatric subjects, however specific guidance 
for pediatric subjects is shown in Section 21.4.  
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 glaucoma or OHT within 28 days 
before the date of Visit 1, or any concomitant medication, must be recorded in the subject’s 
source documents. 
 Name of medication, route of administration, treated eye(s) (if applicable), dose, 
frequency, indication, start date and stop date 
Following details of prior procedure/therapy that has been received for glaucoma or OHT within 
28 days before the date of Visit 1, 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 2 (Baseline), and recorded in the subject’s source 
documents. 
21.3.2. 
Pregnancy Test 
A urine pregnancy test will be conducted using a commercially available test kit at Visit 1 
(Screening), Visit 2 (Baseline), and Visit 5 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. 
Vital signs (Blood pressure/Pulse rate) 
Systolic blood pressure, diastolic blood pressure, and pulse rate will be measured at Visit 1 
(Screening), Visit 2 (Baseline) and Visit 5 Study Exit/Early Termination. Vital signs (resting 
blood pressure and pulse rate) will be collected anytime at Visit 1 (Screening), and 
approximately 08:00 for Visit 2 (Baseline), and Visit 5 before the morning dose.  


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Vital signs will be collected in a sitting position after keeping quiet for more than 5 minutes.  
21.3.4.
Iris color, Eyelash, Eyelid  
Please take photographs of the iris, eyelids and eyelashes of each eye at Visit 2 (Baseline), and 
Visit 5 Study Exit/Early Termination. Six (6) photos are required at each visit as follows:   
The photographs taken at Visit 2 (Baseline) will be used to help the Investigator assess iris color 
(e.g., brown, yellow-brown, green-brown, green with slightly brown, green, blue/gray-brown, 
blue/gray with slightly brown, blue/gray) and any changes from baseline (decreased/no 
change/increased) in iris color, eyelashes and eyelids at Visit 5 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. 
21.3.4.1. Iris Color 
The Investigator will assess the iris color and any change (e.g., pigmentation) at Visit 5 
Exit/Early Termination using the photographs obtained at Visit 2 (Baseline). 
21.3.4.2. Eyelash 
The Investigator will assess eyelash change at Visit 5 Study Exit/Early Termination (e.g., length, 
thickness, pigmentation and number) using the photographs obtained at Visit 2 (Baseline). 
21.3.4.3. Eyelid 
The Investigator will assess eyelid change at Visit 5 Study Exit/Early Termination (e.g., 
pigmentation, hair growth and deepening of the upper eyelid sulcus) using the photographs 
obtained at Visit 2 (Baseline). For any changes from baseline in deepening of the upper eyelid 
sulcus (DUES), the response will be YES or NO. 


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21.3.5. 
Refraction 
Refraction will be performed for each eye at Visit 1 (Screening). At Visits 2 to 5, if more than 10 
letters in BCVA were lost compared to the screening visit, then refraction should be performed. 
21.3.6. 
Best-Corrected Visual Acuity 
BCVA (Best-Corrected Visual Acuity) will be measured for each eye prior to the 08:00 IOP 
measurement at all visits except Visit 1/1a (Screening or mid washout visit) under normal room 
illumination using visual acuity chart (ETDRS chart) and the logMAR scoring will be recorded 
in the subject’s source document. For Visit 1/1a, the corrected visual acuity should be performed 
prior to IOP measurement. If ETDRS chart is used, the following procedure should be followed. 
21.3.6.1. 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 5: 
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 


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Table 5: 
LogMAR Scoring Grid for ETDRS Eye Chart (Continued) 
 
Total Number of Letters Missed 
Snellen 
Base 
LogMAR 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
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 
21.3.7. 
Slit-lamp Biomicroscopy 
As described below, slit-lamp biomicroscopy examinations will be performed and graded 
immediately prior to the 08:00 IOP measurement at all visits except Visit 1/1a (Screening or mid 
washout visit). For Visit 1/1a, the biomicroscopy examinations should be performed prior to IOP 
measurement. If Investigator evaluates for possible torn posterior lens capsule by biomicroscopy 
under dilation in subjects with pseudophakic eye(s) based on his/her decision at visit 1 
(screening), please dilate pupil and evaluate after all other ocular procedures have been 
completed. 
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) 


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The lid, conjunctiva, cornea, lens, and iris will be observed and graded on a 4-point scale (0-3 
scale).  
Lid Hyperemia 
None 
(0) = Normal 
Mild 
(1) = Redness of most or all the lid(s) margin OR skin 
Moderate (2) = Redness of most or all the lid(s) margin AND skin 
Severe 
(3) =  Marked diffuse redness of both lid(s) margin AND skin  
Lid Edema 
None 
(0) = Normal 
Mild 
(1) = Localized to a small region of the lid(s) 
Moderate (2) = Diffuse, most or all the lid(s) but not  prominent/protruding 
Severe 
(3) = Diffuse, most or all the lid(s) AND prominent/protruding 
Conjunctival (Palpebral and Bulbar) Hyperemia 
None 
(0) = Normal 
Mild 
(1) = Slight localized injection 
Moderate (2) = Pink color, confined to palpebral OR bulbar conjunctiva 
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 


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Severe 
(3) = Diffuse, dense punctate staining which may be confluent staining 
Keratic Precipitate 
None 
(0) = Normal 
Mild 
(1) = Slight pigmentation or keratic precipitate 
Moderate (2) = Moderate pigmentation or keratic precipitate  
Severe 
(3) = Dense pigmentation or keratic precipitate 
Lens 
The lens will be noted as phakic, aphakic, or pseudophakic. Phakic lens will be graded as 
described below: 
None 
(0) = No lens discoloration nor opacification 
Mild 
(1) = Yellow lens discoloration or small lens opacity (axial or peripheral) 
Moderate (2) = Amber lens discoloration or medium lens opacity (axial or peripheral) 
Severe 
(3) = Brunescent lens discoloration or complete lens opacification (no red reflex) 
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 
21.3.8. 
Intraocular Pressure 
IOP will be performed at each visit. At visit 1/1a, IOP can be measured at any time. For Visit 2 
to Visit 5 Study Exit/Early Termination, IOP measurements will be scheduled for 08:00 
(±60min), 10:00 (±60min) and 16:00 (±60min). 
IOP will be measured using calibrated manual Goldmann applanation tonometer. Measurement 
will be performed preferably by the same Investigator (operator) and the same authorized study 
staff (recorder) throughout the study. Investigator (operator) who performs the IOP measurement 
must have at least 2 years of experience in IOP measurement. 


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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. 
Tight-fitting neckwear is loosened. The subject is asked to look straight ahead at a 
distant object or fixation target. If it is necessary to hold the eyelids open, the 
Investigator holds the eyelids against the orbit rim, taking care not to apply any 
pressure to the globe. The subject is cautioned not to hold his breath. 
 The Investigator looks through the slit-lamp and gently brings the tip of the prism into 
contact with the center of the cornea. The mires are well-focused, centered 
horizontally, and positioned vertically so that they are of equal circumference above 
and below the horizontal dividing line. If the mires are narrower than approximately 
1/10 their diameter, additional fluorescein is instilled. 
 The Investigator adjusts the measuring drum until the inner borders of the two mires 
just touch each other or, if pulsation is present, until the mires separate a given 
distance during systole and overlap the same distance during diastole. 
 The Investigator removes the tip from the cornea, and the authorized study staff 
(recorder) records the reading on the dial, rounded to the next highest integer. For 
example, if the measurement indicated is between 16 and 17, then 17 is recorded as 
the measurement in the subject’s source document. 
 The Investigator may be recorder instead of the authorized study staff, if he/she is 
not assigned. 
 If corneal astigmatism is greater than 3.0 D, the prism is rotated so that the red line 
corresponds to the orientation of the longer axis of the elliptical applanated area. 
The above procedure is then repeated for the same eye, and that second measurement is also 
recorded in the subject’s source document. 
 If the two measurements differ by less than 3 mmHg, then the average of the two 
measurements becomes the recorded IOP. For example, if the two measurements are 
22 and 23, then 22.5 is the final recorded IOP. 


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 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. 
21.3.8.1. Goldmann Applanation Tonometer Calibration 
Every tonometer being used in the study must be calibrated for accuracy before the first subject 
undergoes screening (mandatory), and then check calibration monthly until the last subject has 
exited the study. For checking calibration, follow the manufacturer’s instructions. If the variation 
is within ±2 mmHg, the tonometer is considered adequately calibrated. However, if the variation 
exceeds this amount, the tonometer should be sent for repair and a different, adequately 
calibrated instrument should be used for IOP measurement. The date of each calibration, along 
with the name and signature (or initials) of the person who performed the calibration, will be 
documented. The tonometer calibration record will be retained as a part of the study record. 
21.3.9. 
Pachymetry (Central Corneal Thickness) 
The central corneal thickness (µm) of each eye using any pachymeter including optical 
pachymeter, ultrasound pachymeter, OCT (optical coherence tomography) etc. will be measured 
and recorded after IOP measurement at Visit 1 (Screening). Pachymetry should be performed 
after IOP measurement. The same pachymeter should be used during the course of the study. 
21.3.10. 
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 
21.3.11. 
Visual Field 
Visual field examinations will be performed using a static or dynamic perimeter (Humphrey or 
Octopus) without pupil dilation at Visit 1 (Screening), if it has not been performed within 3 
months (90 days) or the previous visual field test(s) indicates low subject reliability (e.g., due to 
fixation losses, false positive errors, or false negative errors). Glaucomatous visual field loss will 
be evaluated by the Investigator as presence or absence (mean deviation, pattern SD, glaucoma 
hemifield test, and type of glaucomatous visual field loss). 


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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. 
21.3.12. 
Ophthalmoscopy (Fundus) Examination 
The ophthalmoscopy (fundus) examination will be performed for each eye at Visit 1, Visit 2, and 
Visit 5 Study Exit/Early Termination, and graded as described below. The examination will be 
performed with pupil dilated at Visit 1 and Visit 5/Study Exit. Please dilate pupil and perform 
after all other ocular procedures have been completed. Cup to disc ratio and abnormality in 
retina, macula, choroid, and vitreous will also be evaluated. 
Glaucomatous Optic Nerve Findings 
The optic nerve will be evaluated using a 4-point scale (0-3 scale). 
None 
(0) = No damage 
Mild 
(1) = Optic nerve damage, secondary to glaucoma including any rim loss 
(sloping or thinning) 
Moderate (2) = Optic nerve damage, including cupping to disc margin at one or more 
points 
Severe 
(3) = Optic nerve damage, nearly total cupping, only nasal rim or less present 
21.3.13. 
Blood Sample for Pharmacogenomics/genomics Study 
At 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 IC. 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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21.4.
Appendix D - Guidance for Visual Acuity and Intraocular Pressure 
Measurement for Pediatric Subjects  
Distance Visual Acuity Assessment for Pediatric Subjects (Pediatric Ophthalmology and 
Strabismus, 2017-2018 Basic and Clinical Science Course, AAO) 
Visual acuity assessment requires different eye charts or approaches depending on the age and 
cooperativeness of the child. The cognitively highest test type that the child is capable of 
performing should be used. The following age-appropriate eye charts or methods used for visual 
acuity testing serve as a guide only.  
 

The same type of eye chart or vision test and lighting conditions (e.g., room 
illumination) should be used throughout the course of the study.  

A child who has corrective glasses should be tested wearing them. The used 
refraction should also be recorded.  

In subjects who could not be tested using the manufacturer’s recommended test 
distance, the actual test distance should be recorded in the eCRF. 


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Intraocular Pressure Measurement for Pediatric Subjects 
IOP is the primary endpoint of the study. Every effort should be made to perform IOP 
measurement to have the diurnal curve. IOP will be measured with age-appropriate tonometers 
(e.g. Goldmann applanation tonometer, a Perkins tonometer, a tonopen, iCare tonometer etc.) to 
the extent the subject is able to cooperate. The same tonometer to measure IOP should be used at 
all visits for a given subject. Investigator or IOP examiner should follow the standard procedures 
used in their office to measure IOP.  
For pediatric subjects who are old enough and can sit at the slit lamp for applanation and are able 
to cooperate with the IOP measurement, Goldmann applanation tonometer is preferred. 
Otherwise, handheld tonometers, for example, Perkins applanation tonometer, iCare tonometer 
or tonopen tonometer are also acceptable. Follow the manufacturing guidance on the use of each 
handheld tonometer. For pediatric subjects who resist anesthetic eye drops, iCare tonometer can 
be tried.   
 
 
 


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21.5. 
Appendix E - Timolol Maleate Ophthalmic Solution 0.5% Package 
Insert 
 


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21.6. 
Appendix F - Summary of Changes 
 
V1.0 to V1.1 
 Text regarding the use of general anesthesia and/or conscious sedation descriptions 
was removed from: 
 Schedule of Events and Procedures for PEDIATRIC Subjects - Synopsis and 
Section 7.4  
 Pediatric Subject Exclusion Criterion #21 - Synopsis and Section 8.4 (Subject 
Exclusion Criteria Specific for PEDIATRIC subjects)   
 Section 21.4 Intraocular Pressure Measurement for Pediatric Subjects 
 To be consistent with the instruction for subject exclusion, the descriptions of "in 
either eye" were removed from Pediatric Subject Exclusion Criteria #8, 9 and 10 - 
Synopsis and Section 8.4. 
 To require recording of non-ocular procedures/therapies (as well as ocular 
procedures/therapies) in the subject’s source documents, the descriptions of “ocular 
procedures/therapies” were updated to “procedures/therapies” in:  
 Section 7.4 Schedule of Events and Procedures  
 Section 21.3.1 Demographics, Medication/Therapy and Medical History 
 
 



SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:   
A Phase III, Randomized, Double-Masked, Active-Controlled, 
Parallel-Group, Multicenter Study Assessing the Efficacy and Safety 
of DE-117 Ophthalmic Solution 0.002% Compared with Timolol 
Maleate Ophthalmic Solution 0.5% in Subjects with Glaucoma or 
Ocular Hypertension - Spectrum 4 Study 
 
 
NCT Number:  
NCT03691662 
 
Date of the document: 
15 Nov 2019  
 
 
 


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STATISTICAL ANALYSIS PLAN 
DE-117 SPECTRUM 4 
 
 
 
Protocol Title: 
A Phase III, Randomized, Double-Masked, Active-Controlled, Parallel-Group,  
Multi-Center Study Assessing the Efficacy and Safety of DE-117 Ophthalmic 
Solution 0.002% Compared with Timolol Maleate Ophthalmic Solution 0.5% in 
Subjects with Glaucoma or Ocular Hypertension - Spectrum 4 Study 
 
 
Product: 
DE-117  
 
 
Protocol Number:  
011710IN 
 
 
Sponsor: 
Santen Inc. 
 
6401 Hollis Street, Suite 125 
Emeryville, CA 94608 
USA. 
 
 
Date:  
November 15, 2019 
 
 
Status:  
Version 1.0 
 
CONFIDENTIAL 
 
The information in this document is considered privileged and confidential by Santen Inc. and 
may not be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by Federal and State Laws.  Persons to 
whom this information is disclosed must be informed that this information is privileged and 
confidential and that it should not be further disclosed. 
 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
1. 
INTRODUCTION ........................................................................................................9 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................10 
2.1. 
Objectives ...................................................................................................................10 
2.1.1. 
Primary Objectives .....................................................................................................10 
2.1.2. 
Secondary Objectives .................................................................................................10 
2.1.3. 
Safety Objective ..........................................................................................................10 
2.2. 
Endpoints ....................................................................................................................10 
2.2.1. 
Primary Efficacy Endpoint .........................................................................................10 
2.2.2. 
Key Secondary Efficacy Endpoints ............................................................................10 
2.2.3. 
Other Secondary Efficacy Endpoints ..........................................................................10 
2.2.4. 
Safety Endpoints .........................................................................................................11 
3. 
STUDY DESIGN .......................................................................................................12 
3.1. 
General Study Design .................................................................................................12 
3.2. 
Randomization and Masking ......................................................................................12 
3.3. 
Sample Size Planning .................................................................................................13 
3.4. 
Visits and Assessments ...............................................................................................13 
4. 
DEFINTIONS .............................................................................................................16 
4.1. 
Time-Related Terms ...................................................................................................16 
4.1.1. 
Baseline Visit ..............................................................................................................16 
4.1.2. 
Treatment Start Date ...................................................................................................16 
4.1.3. 
Treatment End Date ....................................................................................................16 
4.1.4. 
Study Day ...................................................................................................................16 
4.1.5. 
Out-of-Window Measurements, Analysis Visit, and Analysis Window ....................16 
4.1.6. 
Extent of Exposure .....................................................................................................17 
4.2. 
Endpoint-Related Definitions .....................................................................................17 
4.2.1. 
Study Eye and Fellow Eye ..........................................................................................17 
4.2.2. 
Baseline Score ............................................................................................................17 
4.2.3. 
Change and Percent Change from Baseline ................................................................18 


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4.3. 
Efficacy-Related Definitions ......................................................................................18 
4.3.1. 
Response Endpoint and Response Rate ......................................................................18 
4.4. 
Safety-Related Definitions ..........................................................................................18 
4.4.1. 
Adverse Event .............................................................................................................18 
4.4.1.1. 
Serious Adverse Event ................................................................................................19 
4.4.1.2. 
Ocular Adverse Event .................................................................................................19 
4.4.1.3. 
Suspected Adverse Reaction .......................................................................................19 
4.4.1.4. 
Events of Special Interest ...........................................................................................19 
4.4.2. 
Other Safety Measures ................................................................................................19 
4.5. 
Other Definitions ........................................................................................................20 
4.5.1. 
Prior and Concomitant Medications ...........................................................................20 
4.5.2. 
Concurrent Medical Conditions ..................................................................................20 
5. 
STUDY POPULATION .............................................................................................21 
5.1. 
Intent-to-Treat Population ..........................................................................................21 
5.2. 
Safety Population ........................................................................................................21 
5.3. 
Full Analysis Set .........................................................................................................21 
5.4. 
Per-Protocol Set ..........................................................................................................21 
6. 
GENERAL CONSIDERATIONS ..............................................................................22 
6.1. 
Adjustments for Covariates ........................................................................................22 
6.2. 
Handling of Missing Data ...........................................................................................22 
6.2.1. 
Efficacy Measures ......................................................................................................22 
6.2.2. 
Safety Measures ..........................................................................................................22 
6.2.3. 
Dates for Medical Events and Medications ................................................................22 
6.3. 
Multi-Center Studies ...................................................................................................23 
6.4. 
Multiple Comparisons / Multiplicity ..........................................................................23 
6.5. 
Interim Analysis ..........................................................................................................24 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................25 
7.1. 
Subject Disposition .....................................................................................................25 
7.2. 
Demographics and Baseline Characteristics ...............................................................25 
7.3. 
Medical and Surgical History .....................................................................................26 
7.4. 
Protocol Deviations ....................................................................................................26 
7.5. 
Prior and Concomitant Medications ...........................................................................26 
7.6. 
Treatment Compliance ................................................................................................27 


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7.7. 
Exposure to Study Medication ....................................................................................27 
8. 
EFFICACY ANALYSES ...........................................................................................28 
8.1. 
Analyses of Primary Endpoint and Key Secondary Endpoints ..................................28 
8.1.1. 
Primary Analyses ........................................................................................................28 
8.1.1.1. 
Primary Endpoint ........................................................................................................28 
8.1.1.2. 
Key Secondary Endpoints ...........................................................................................29 
8.1.2. 
Sensitivity Analyses ....................................................................................................30 
8.2. 
Analyses of Other Secondary Efficacy Endpoints ......................................................31 
8.3. 
Subgroup Analyses .....................................................................................................32 
9. 
SAFETY ANALYSES ...............................................................................................33 
9.1. 
Adverse Events ...........................................................................................................33 
9.1.1. 
Ocular Inflammation ...................................................................................................33 
9.1.2. 
Macular Edema ...........................................................................................................34 
9.1.3. 
Cosmetic Change(s) ....................................................................................................34 
9.2. 
Best-Corrected Visual Acuity .....................................................................................35 
9.3. 
Slit-lamp Biomicroscopy ............................................................................................35 
9.4. 
Ophthalmoscopy .........................................................................................................35 
9.5. 
Eyelid Sulcus, Eyelid, Eyelash, and Iris Color ...........................................................35 
9.6. 
Vital Signs ..................................................................................................................35 
10. 
ADDITIONS AND CHANGES TO THE PROTOCOL-SPECIFIED 
ANALYSES ...............................................................................................................36 
10.1. 
Full Analysis Set Definition .......................................................................................36 
10.2. 
Key Secondary Endpoint ............................................................................................36 
10.3. 
Sensitivity Analysis of the Primary and Secondary Efficacy Endpoints ....................36 
11. 
REFERENCES ...........................................................................................................37 
12. 
APPENDICES ............................................................................................................38 
 
 
 


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LIST OF TABLES 
Table 1: 
Assessment Schedule for ADULT Subjects ...............................................................14 
Table 2: 
Analysis Visit and Analysis Window .........................................................................17 
Table 3: 
Response Endpoints ....................................................................................................18 
Table 4: 
Safety Assessments .....................................................................................................19 
Table 5: 
Handling of Missing Date for Medical Events and Medications ...............................23 
Table 6: 
Overview of Primary and Sensitivity Analysis Methods ...........................................31 
 
LIST OF FIGURES 
Figure 1: 
Study Design Diagram ................................................................................................12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Abbreviations 
Abbreviation 
Explanation 
AE 
Adverse Event 
ATC 
Anatomical-Therapeutic-Chemical 
BCVA 
Best-Corrected Visual Acuity 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
ESI 
Event of Special Interest 
ET 
Early Termination 
FAS 
Full Analysis Set 
IOP 
Intraocular Pressure 
LOCF 
Last-observation-carried-forward 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MAR 
Missing at Random  
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM  
Mixed-effects Model for Repeated Measures 
mmHg 
Millimeter of Mercury 
MI 
Multiple Imputation  
OHT 
Ocular Hypertension 
OD 
Oculus Dexter (right eye) 
OS 
Oculus Sinister (left eye) 
OU 
Oculus Uterque (both eyes) 
MCMC 
Markov Chain Monte Carlo 
PMM 
Pattern Mixture Models 
POAG 
Primary Open-Angle Glaucoma 
PPS 
Per-Protocol Set 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 


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Abbreviations (Continued) 
Abbreviation 
Explanation 
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 4 study within the scope of Santen’s Protocol 
011710IN, “A Phase III, Randomized, Double-Masked, Active-Controlled, Parallel-Group, 
Multicenter Study Assessing the Efficacy and Safety of DE-117 Ophthalmic Solution  
0.002% Compared with Timolol Maleate Ophthalmic Solution 0.5% in Subjects with Glaucoma 
or Ocular Hypertension.”  It applies to the study protocol Amendment 1 (version 1.1), dated  
13 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 determine whether DE-117 Ophthalmic Solution 0.002% given once daily is non-inferior to 
Timolol Maleate Ophthalmic Solution 0.5% given twice daily in reducing the intraocular 
pressure (IOP) in subjects with glaucoma or OHT (Ocular Hypertension) after 3 months of 
treatment. 
2.1.2. 
Secondary Objectives 
 To determine whether DE-117 Ophthalmic Solution 0.002% is non-inferior to 
Timolol Maleate Ophthalmic Solution 0.5% in reducing mean diurnal IOP in subjects 
with glaucoma or OHT after 3 months of treatment. 
 To determine whether DE-117 Ophthalmic Solution 0.002% is superior to that of 
Timolol Maleate Ophthalmic Solution 0.5% in reducing mean diurnal IOP in subjects 
with glaucoma or OHT after 1 week of treatment. 
2.1.3. 
Safety Objective 
The safety objective of this study is to determine the safety of DE-117 ophthalmic solution 
0.002% as compared to Timolol Maleate Ophthalmic Solution 0.5% in the study population. 
2.2. 
Endpoints 
2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is:  
IOP in the study eye at each scheduled timepoint (08:00, 10:00, and 16:00) at Week 1 (Visit 3), 
Week 6 (Visit 4), and Month 3 (Visit 5). 
2.2.2. 
Key Secondary Efficacy Endpoints 
1. Mean diurnal IOP in the study eye at Month 3 (Visit 5). 
2. IOP at each scheduled timepoint (08:00, 10:00, and 16:00) at Week 1 (Visit 3),  
Week 6 (Visit 4), and Month 3 (Visit 5) in the study eyes with mean diurnal  
IOP < 25 mmHg at the Baseline Visit. 
3. Mean diurnal IOP in the study eye at Week 1 (Visit 3). 
2.2.3. 
Other Secondary Efficacy Endpoints 
The following secondary endpoints will be assessed: 
 Change and percent change from baseline in IOP at each scheduled timepoint of each 
post-baseline visit 


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 Change and percent change from baseline in mean diurnal IOP at each post-baseline 
visit 
 Having a mean diurnal IOP reduction ≥ 20%, ≥ 25%, or ≥ 30% from Baseline at each 
post-baseline visit 
 Having a mean diurnal IOP ≤ 18 mmHg at each post-baseline visit 
2.2.4. 
Safety Endpoints 
The safety of DE-117 will be evaluated by: 
 Incidence of ocular and non-ocular adverse events (AEs) 
 Events of special interest (ESIs, which were defined to be macular edema, medication 
administration errors, and pregnancy) 
 Vital signs: blood pressure and pulse rate 
 Best-corrected visual acuity (BCVA) 
 Slit-lamp biomicroscopy; severity scores for the following 12 parameters: lid 
hyperemia, lid edema, conjunctival hyperemia, conjunctival chemosis, corneal 
staining, corneal edema, keratic precipitate, anterior chamber cells, anterior chamber 
flare, anterior synechiae of iris, posterior synechiae of iris, and cataract 
 Ophthalmoscopy (cup-to-disc ratio, glaucomatous optic nerve severity score, and 
assessments of retina, macula, choroid, and vitreous) 
 Assessments for deepening of the upper eyelid sulcus (DUES) and other changes in 
eyelid, eyelash, and iris 


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3. 
STUDY DESIGN 
3.1. 
General Study Design 
This is a Phase III, randomized, double-masked, active-controlled, parallel-group, multi-center 
study.  Subjects diagnosed with glaucoma or OHT who meet eligibility criteria at Visit 1 
(Screening) will discontinue their current topical IOP-lowering medication(s), if any.  After 
completing the required washout period, subjects will return for Visit 2 (Baseline, Day 1).  
Subjects who meet all eligibility criteria at baseline will be randomized to receive  
double-masked treatment for 3 months (Figure 1). 
Approximately 400 eligible adults and up to 30 eligible pediatric subjects with glaucoma or OHT 
were planned to be randomized.  At the time of finalizing this SAP, enrollment for this study had 
completed and no pediatric subjects were randomized in this study.  Thus, only analyses 
regarding adult subjects are presented in this SAP. 
 
Figure 1: 
Study Design Diagram 
 
3.2. 
Randomization and Masking 
A blocked randomization stratified by age (< 18 and <18 years old) will be employed to 
randomize eligible subjects in a 1:1 ratio to receive either DE-117 or Timolol.  The 
randomization schedule will be generated and implemented by an independent CRO, Medidata 
Solutions, Inc. (New York City, NY). 
This is a double-masked study.  The subjects, Investigators, Examiners, and Santen personnel 
involved in the conduct of the study will be masked to the study treatment.  An authorized 
unmasked study staff member who is not the Investigator or Examiner at the investigative site 


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will dispense and collect study medication(s) and will query about dosing compliance.  In case of 
a medical emergency, when the unmasking of a subject’s treatment assignment code becomes 
necessary for the welfare of that subject, the Clinical Investigator may reveal the treatment 
information by unmasking which treatment the subject has received through the study’s 
interactive web response system (Medidata RTSM). 
3.3. 
Sample Size Planning 
The sample size calculation was based on a two-sided Type I error rate of 5% and a  
non-inferiority margin of 1.5 mmHg.  Assuming a treatment difference of 0 mmHg between the 
DE-117 arm and the Timolol arm, a standard deviation (SD) of 4.0 mmHg, and a correlation 
coefficient of 0.6 among repeated measures, approximately 400 adult subjects in total  
(200 subjects per treatment arm) will provide 90% power to demonstrate non-inferiority of 
DE-117 Ophthalmic Solution 0.002% to Timolol Maleate Ophthalmic Solution 0.5% in  
IOP-lowering effect. 
The standard deviation of 4.0 mmHg was determined from previous DE-117 studies conducted 
in the United States: 33-002 and 33-003. 
3.4. 
Visits and Assessments 
There are 5 scheduled visits for each subject.  Assessments at each visit and the time/visit 
window for each post-baseline assessment are specified in the Assessment Schedule for  
Adult (Table 1).  If the study drug administration is discontinued prior to Visit 5, the subject 
should be encouraged to still participate in follow-up study visits until Visit 5 on an 
observational basis.  For subjects whose study participation is terminated prior to  
Visit 5 (Month 3), to the extent possible, all assessments scheduled for Visit 5 (Month 3) will be 
performed at the Exit Visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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


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


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4. 
DEFINTIONS 
4.1. 
Time-Related Terms 
4.1.1. 
Baseline Visit 
The Baseline Visit is Visit 2 (Day 1) when the subject is randomized. 
4.1.2. 
Treatment Start Date 
Treatment start date is the date at which a randomized subject takes the first dose of the study 
medication. 
4.1.3. 
Treatment End Date 
Treatment end date is the date at which a randomized subject takes the last dose of the study 
medication.  If the date of the last dose is missing, then 
 The day before the Visit 5 (Month 3) date will be considered the treatment end date 
for subjects who completed the study. 
 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 
treatment end date. 
4.1.4. 
Study Day  
The study day describes the relative day of an observation starting with the reference date 
designated as Study Day 1.  In this study, the treatment start date is the reference date.  Thus, the 
study day will be calculated as: 
 
For days prior to the treatment start date, Study Day = Date – Treatment Start Date  
 
For days on/after the treatment start date, Study Day = Date – Treatment Start Date + 1 
4.1.5. 
Out-of-Window Measurements, Analysis Visit, and Analysis Window 
Analysis visit is a timing variable to be used for analyses involving visits.  For each analysis visit, 
an analysis window is set up to determine the analysis visit to which a measurement should be 
mapped (Table 2). 
The analysis visit of a measurement will be determined based on the study day of the 
measurement and specified analysis windows and is not necessarily the same as the study visit at 
which the measurement was collected.  For example, an out-of-window measurement collected 
at the Week 1 study visit will be mapped to the Week 6 analysis visit, if the study day of the 
measurement falls into the analysis window of Week 6. 


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Table 2: 
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] 
Week 1 (Day 8) 
[6, 10] 
NA* 
[2, 22] 
Week 6 (Day 43) 
[40, 46] 
NA* 
[23, 61] 
Month 3 (Day 91) 
[84, 98] 
[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, 10:00, and 16:00) will be selected for that analysis visit first, before 
applying the above rule. 
4.1.6. 
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 
4.2. 
Endpoint-Related Definitions 
4.2.1. 
Study Eye and Fellow Eye 
The study eye will be the eye that qualifies per eligibility criteria at Visit 2.  If both eyes meet the 
eligibility criteria, the eye with the higher mean diurnal IOP at Visit 2 will be designated as the 
study eye.  If both eyes meet the eligibility criteria and have the same mean diurnal IOP, the right 
eye will be designated as the study eye.  The other eye will be the non-study eye, or fellow eye. 
4.2.2. 
Baseline Score 
The baseline score is the observed measurement at Visit 2 (Baseline).  If a baseline score is 
missing, the last observed measurement or derived score prior to the first dose of study 
medication will be used to impute the baseline score. 


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4.2.3. 
Change and Percent Change from Baseline 
The change and the percent change from baseline in a measure at a post-baseline visit will be 
derived as: 
 Change = (Score at the Post-Baseline Visit) – (Baseline Score). 
 Percent Change from Baseline = 100 × Change / (Baseline Score). 
4.3. 
Efficacy-Related Definitions 
4.3.1. 
Response Endpoint and Response Rate 
Four IOP response endpoints (Table 3) will be evaluated at each post-Baseline visit  
(Week 1, Week 6, or Month 3) in this study: 
Table 3: 
Response Endpoints 
Response Endpoint 
Response criteria in mean diurnal IOP 
IOP 20% response 
Percent reduction from Baseline ≥ 20% 
IOP 25% response 
Percent reduction from Baseline ≥ 25% 
IOP 30% response 
Percent reduction from Baseline ≥ 30% 
IOP ≤ 18 mmHg response 
Mean diurnal IOP ≤ 18 mmHg 
For a response endpoint, the response rate at a post-Baseline visit is calculated as the proportion 
of subjects who met the response criterion at the post-baseline visit. 
4.4. 
Safety-Related Definitions 
4.4.1. 
Adverse Event 
Under Protocol 011710IN, an AE is defined as any untoward medical occurrence that occurs in a 
study subject, regardless of the causal relationship with the study treatment.  An on-study AE can 
occur any time after the date of informed consent through the last study visit.  An AE will be 
considered as treatment-emergent if the onset date of the AE occurred on or after the treatment 
start date till up to 2 days (twice the scheduled dosing interval) after treatment end date.  
Treatment-emergent AEs (TEAEs) are a subset of on-study AEs.  Both on-study and TEAEs will 
be collected, but only TEAEs will be tabulated. 
The severity of each AE will be graded by the Clinical Investigator as Mild, Moderate, or 
Severe. AEs will also be rated by the Investigator as to their causality/relationship to the study 
drug. 
Each AE will be classified into a system organ class (SOC) and coded to a preferred term (PT) 
using Medical Dictionary for Regulatory Activities (MedDRA), version 21.1 published in 2018. 


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4.4.1.1. 
Serious Adverse Event 
An AE will be counted as a serious adverse event (SAE) if the Clinical Investigator selected 
“Yes” to the question ‘Is the adverse event serious?’ on the AE eCRF.  Any AE is considered a 
SAE if it fulfills one or more of the following criteria: 
 Death (i.e., the AE caused or led to death) 
 Life threatening (i.e., immediately life-threatening) 
 It required or prolonged inpatient hospitalization. 
 It resulted in a persistent or significant disability/incapacity (i.e., the AE resulted in a 
substantial disruption of the subject’s ability to carry out normal life functions). 
 It resulted in a congenital anomaly/birth defect in the offspring of a study subject who 
was exposed to study therapy prior to conception or during pregnancy. 
 It is a medically significant event(s), which may include “sight-threatening events,” 
that may not meet any of the above serious criteria but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the outcomes listed above. 
4.4.1.2. 
Ocular Adverse Event 
An AE will be counted as an ocular AE if the Clinical Investigator selected “OD”, “OS”, or 
“OU” under ‘Eye(s) affected’ on the AE eCRF. 
4.4.1.3. 
Suspected Adverse Reaction 
An AE will be counted as a suspected adverse reaction (SAR) if the Clinical Investigator 
answered ‘Related’ to the AE eCRF question “Relationship to Study Drug”. 
4.4.1.4. 
Events of Special Interest 
Events of special interest (ESI) are pregnancy, clinically significant study medication 
administration error, and macular edema/cystoid macular edema. 
4.4.2. 
Other Safety Measures 
Table 4 lists the safety measures to be evaluated for this study. 
Table 4: 
Safety Assessments 
Safety Measures 
Note 
BCVA 
Best-corrected visual acuity will be measured for each eye at 
each visit under normal room illumination using visual acuity 
chart  
(e.g., ETDRS chart) and the logMAR scoring will be recorded 
in the subject’s source document.  Increase in logMAR scores 
means worsening in visual acuity. 


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Table 4: 
Safety Assessments (Continued) 
Safety Measures 
Note 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy examinations (severity scores for  
12 parameters: lid hyperemia, lid edema, conjunctival 
hyperemia, conjunctival chemosis, corneal staining, corneal 
edema, keratic precipitate, anterior chamber cells, anterior 
chamber flare, anterior synechiae of iris, posterior synechiae of 
iris, and cataract) will be performed and graded 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 2, and Visit 5 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 2 (Baseline).  The 
photographs must include iris, eye lids and eyelashes of each 
eye.  The photographs taken at Visit 2 (Baseline) will be used 
to help the Investigator assess any changes (“No changes”, 
“Increased”, or “Decreased”) from baseline in eyelid, 
eyelashes, and iris color at each follow-up visit, and assess for 
DUES (“Yes”, “No”) at Visit 5 Study Exit/Early Termination. 
Vital Signs  
Resting blood pressure and pulse rate will be collected at  
Visit 1, Visit 2, and Visit 5. 
4.5. 
Other Definitions 
4.5.1. 
Prior and Concomitant Medications 
Non-study medications will be categorized into prior medications and concomitant medications.  
Specifically, prior medication is defined as any non-study medication taken and ended prior to 
the study medication start date.  Concomitant medication is defined as any non-study medication 
taken concurrently while receiving study medication, i.e., the treatment period (period of time 
from first dose to last dose) of a concomitant medication taken by a subject must overlap with 
the treatment period (period of time from first dose to last dose) of the study medication. 
All prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Global, Version September 2018, format B3.  Each prior or concomitant 
medication will be classified using the Anatomical-Therapeutic-Chemical (ATC) classification 
system and mapped to a WHO Drug preferred drug name. 
4.5.2. 
Concurrent Medical Conditions 
Concurrent medical conditions are those ongoing conditions or diseases that are present at the 
signing of informed consent. 


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5. 
STUDY POPULATION 
5.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population will include all randomized subjects. 
5.2. 
Safety Population 
The Safety Population will include all randomized subjects who received at least one dose of the 
study medication.  Safety analyses will be performed using the Safety Population and 
summarizing by actual treatment received. 
5.3. 
Full Analysis Set 
The Full Analysis Set (FAS) will include all randomized subjects who received at least one dose 
of study medication and provided Baseline IOP data (at any timepoint) and at least one  
post-baseline IOP measurement (at any timepoint).  Efficacy analyses will be performed using 
the FAS and summarized by treatment as randomized. 
5.4. 
Per-Protocol Set 
The Per-Protocol Set (PPS) is a subset of the FAS.  It will be the analysis population for 
sensitivity analyses and will be summarized using treatment as randomized.  Any subject 
affected by a significant protocol deviation that might affect the primary efficacy analysis will be 
excluded from the PPS.  The PPS will be identified before the unmasking of treatment 
assignments. 
Before the unmasking of treatment assignment, Santen’s study team will review all protocol 
deviations, identify subjects with any protocol deviation that could impact the efficacy outcome, 
and determine whether or not to exclude the subject from the PPS. 


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6. 
GENERAL CONSIDERATIONS 
All measures will be summarized by treatment (planned or actual received) descriptively.  
Continuous variables will be summarized using descriptive statistics such as number of 
observations (n), mean, standard deviation, median, minimum, and maximum.  Categorical 
variables will be tabulated using frequency (n) and percent (%). 
The statistical testing will be conducted at a significance level of 0.05 (two-sided) and the  
95% confidence interval will be shown, unless specified otherwise.  No statistical testing will be 
conducted for safety measures. 
All data manipulations, descriptive summaries, and statistical hypothesis testing will be 
performed using Statistical Analysis System (SAS) Version 9.4 or later. 
6.1. 
Adjustments for Covariates 
In general, the inferential analysis of each IOP endpoint will adjust for the baseline IOP.  
Detailed information on covariate adjustment is provided in Section 8.1. 
6.2. 
Handling of Missing Data 
6.2.1. 
Efficacy Measures 
For subjects with the use of any non-study IOP-lowering therapy to lower IOP, unless otherwise 
specified, the IOP data collected after the non-study IOP-lowering therapy will be censored 
(treated as missing) in efficacy analyses. 
For each IOP endpoint, no imputation is needed for the analysis on observed cases using the 
mixed-effects model for repeated measures (MMRM).  Sensitivity analysis will be performed 
using a Pattern-Mixture Model (PMM) approach. 
In the PMM approach, Multiple Imputation (MI) with mixed missing data mechanisms will be 
used to investigate the appropriateness of the missing at random (MAR) assumption for missing 
values resulting from censoring due to the use of IOP-lowering rescue therapy, or resulting from 
study discontinuation due to lack of efficacy or AE. 
6.2.2. 
Safety Measures 
Descriptive summaries of safety measures will be based on observed data only.  No imputation 
of missing scores will be implemented. 
6.2.3. 
Dates for Medical Events and Medications 
Completely or partially missing onset and resolution dates of medical history (MH), AE, and 
concomitant medications (CM) will be imputed as follows (Table 5): 
 
 


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Table 5: 
Handling of Missing Date for Medical Events and Medications 
Date 
Type of Missing Date 
Handling of Missing Date 
Event onset date  
(e.g., YYYY-MM-DD) 
Completely missing 
No imputation will be applied: 
For AE, the event will be considered 
treatment emergent. 
For CM, the event will be considered 
concomitant. 
For MH, the event will be considered to 
occur prior to Inform Consent date. 
Only YYYY is available 
Use the first date of YYYY to impute the 
missing month and day of the onset date. 
YYYY and MM are 
available, but DD is missing 
Use the first date of MM to impute the 
missing day of the onset date. 
Event resolution date 
(e.g., YYYY-MM-DD) 
Completely missing 
No imputation will be applied.  The event 
will be considered ongoing (i.e., not 
resolved) at the last visit date.  
Only YYYY is available 
Use the last date of YYYY to impute the 
missing month and day of the resolution 
date.  
YYYY and MM are 
available, but DD is missing 
Use the last date of MM to impute the 
missing day of the resolution date. 
6.3. 
Multi-Center Studies 
This is a multi-center study enrolling subjects from 33 US sites.  The number of subjects per site 
might be small.  Therefore, there are no analyses adjusting for sites. 
6.4. 
Multiple Comparisons / Multiplicity 
To control the overall Type I error rate across the seven hypothesis tests involving the primary 
endpoint and the key secondary endpoints (listed below) at the 0.05 level (two-sided), a fixed 
sequence procedure will be implemented.  The hypothesis tests will be assessed sequentially as 
follows: 
1. Non-inferiority of 0.002% DE-117 to 0.5% Timolol Maleate for the primary endpoint, 
IOP at each scheduled timepoint (08:00, 10:00, and 16:00) at Week 1, Week 6, and 
Month 3. 
2. Non-inferiority of 0.002% DE-117 to 0.5% Timolol Maleate for the first key secondary 
endpoint, mean diurnal IOP at Month 3. 
3. Non-inferiority of 0.002% DE-117 to 0.5% Timolol Maleate for the second key 
secondary endpoint, IOP at each scheduled timepoint (08:00, 10:00, and 16:00) at  
Week 1, Week 6, and Month 3 in the study eyes with mean diurnal IOP < 25 mmHg at 
the Baseline Visit. 


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4. Superiority of 0.002% DE-117 to 0.5% Timolol Maleate for the third key secondary 
endpoint, mean diurnal IOP at Week 1. 
5. Superiority of 0.002% DE-117 to 0.5% Timolol Maleate for the first key secondary 
endpoint, mean diurnal IOP at Month 3. 
6. Superiority of 0.002% DE-117 to 0.5% Timolol Maleate for the second key secondary 
endpoint, IOP at each scheduled timepoint (08:00, 10:00, and 16:00) at Week 1,  
Week 6, and Month 3 in the study eyes with mean diurnal IOP < 25 mmHg at the 
Baseline Visit. 
7. Superiority of 0.002% DE-117 to 0.5% Timolol Maleate for the primary endpoint, IOP at 
each scheduled timepoint (08:00, 10:00, and 16:00) at Week 1, Week 6, and Month 3. 
The second hypothesis testing 2) will be tested only if the first hypothesis 1) is rejected.  The 
third hypothesis testing 3) will be tested only if the second hypothesis 2) is rejected, and so on. 
6.5. 
Interim Analysis 
No interim analysis is planned for this study. 


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7. 
SUMMARY OF STUDY POPULATION DATA 
7.1. 
Subject Disposition 
The disposition of ITT population (i.e., all randomized subjects) will be summarized by 
treatment and overall.  The summary will include the number and percentage of ITT subjects in 
the Safety population, FAS, and PPS.  The disposition summary will also include the number and 
percentage of subjects who completed the study drug, subjects who discontinued the study drug 
prematurely but continued with study participation 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 from the study drug prior to Month 3 Visit by the primary 
discontinuation reason. 
7.2. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be descriptively summarized for the FAS 
by planned treatment.  Specifically, for subject demographics, the following variables will be 
summarized: 
 Age at randomization (continuous and categorical: < 65 years or ≥ 65 years) 
 Sex (categorical: Male or Female) 
 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, Pseudoexfoliative Glaucoma, 
Pigmentary Glaucoma, or OHT) 
 Iris Color (categorical: Blue/Gray, Blue/Gray with Slightly Brown,  
Blue/Gray – Brown, Green, Green with Slightly Brown, Green – Brown,  
Yellow – Brown, or Brown) 
 Prior use of IOP-lowering medications (categorical: oral/topical carbonic anhydrase 
inhibitors, alpha agonists, beta-blockers, prostaglandin/prostaglandin analogues, or 
none) 
 Prostaglandin naive (Yes or No) 
 Baseline lens status (categorical: phakic or pseudophakic/aphakic) 
 Baseline mean diurnal IOP score and baseline IOP score at each scheduled timepoint 
(08:00, 10:00, and 16:00) 
 BCVA (logMAR) 
 Central corneal thickness (µm) 
 Glaucomatous optic nerve findings (categorical: none, mild, moderate, or severe) 


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 Anterior chamber angle classification (Shaffer scale; categorical: approximately  
5 degrees or less, approximately 10 degrees, approximately 20 degrees, 
approximately 30 degrees, or approximately 40 degrees or more) 
 Visual field (parameters: glaucoma Hemifield test, visual field mean deviation by 
device, and visual field pattern standard deviation by device) 
7.3. 
Medical and Surgical History 
For this study, medical and surgical history and adverse events will be coded using  
MedDRA 21.1, 2018.  Each medical event will be classified into a SOC and mapped to a 
Preferred Term (PT). 
The medical and surgical history will be summarized for the FAS.  Subjects reporting any 
medical and surgical history at baseline will be tabulated by SOC and PT for each planned 
treatment and overall. 
7.4. 
Protocol Deviations 
In this study, protocol deviations are categorized as follows: 
 Informed Consent 
 Inclusion/Exclusion Criteria 
 Concomitant Treatment  
 Investigational Product  
 Procedures/Tests/Assessments 
 Laboratory  
 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 randomized subjects with any significant protocol deviation(s) will be 
tabulated by deviation category for each planned treatment and overall.  In addition, two listings 
will be provided: (1) all significant protocol deviations and (2) subjects excluded from the per 
protocol population. 
7.5. 
Prior and Concomitant Medications 
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 WHODrug preferred drug name. 
Non-study medications will be summarized for the Safety population.  Subjects taking any prior 
medications will be tabulated by ATC level 3, level 4, and preferred drug name for each actual 


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treatment received and overall.  A subject will be counted at most once for each prior 
medication, even if the subject took the same prior medication on multiple occasions.  Subjects 
taking any concomitant medications will be tabulated similarly.  In addition, prior medications 
and concomitant medications will also be listed, separately. 
7.6. 
Treatment Compliance 
For the purpose of compliance calculation, there will be three study intervals: 
 Baseline Visit to Week 1 
 Week 1 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 (%) = (2*Duration – ∑Miss) / (2*Duration) × 100 
Where 
Duration:The number of days subject should have administered study medication, 
calculated as: 
Study Interval 
Equation for Duration Calculation 
Baseline Visit to Week 1 
Week 1 Visit date – Date of first drug dispensation 
Week 1 to Week 6 
Week 6 Visit date – Week 1 Visit date 
Week 6 to Month 3 
Month 3 Visit date – Week 6 Visit date 
Miss:The number of missed doses since the last visit. 
For subjects in the FAS, the compliance rate will be summarized by post-baseline study interval 
by planned treatment. 
7.7. 
Exposure to Study Medication 
The duration of exposure to a study medication is measured by days on treatment as derived in 
Section 4.1.6.  For subjects in the Safety Population, the duration of exposure will be 
summarized using descriptive statistics, and frequency and percentage of subjects will be 
tabulated by duration category (1-30 days, 31-60 days, or ≥ 61 days) by actual treatment 
received. 


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


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Non-inferiority criteria for primary endpoint: With respect to the primary study objective, 
non-inferiority of DE-117 to Timolol is achieved if the upper limit of the two-sided  
95% confidence interval for the difference in the mean IOP (DE-117 minus Timolol) is  
≤ 1.5 mmHg at all nine timepoints and ≤ 1.0 mmHg at a majority (five or more) of the nine 
timepoints. 
Superiority of DE-117 to Timolol for the primary efficacy endpoint is achieved if the upper limit 
of the two-sided 95% confidence interval for the difference in the mean IOP (DE-117 minus 
Timolol) is < 0 mmHg at all nine timepoints. 
8.1.1.2. 
Key Secondary Endpoints 
8.1.1.2.1. Mean Diurnal IOP at Month 3 
The first key secondary endpoint is mean diurnal IOP in the study eye at Month 3.  The 
following null (versus alternative) hypothesis will be tested: 
H0S1: µT1 – µC1 > Δ versus HAS1: µT1– µC1 ≤ Δ 
where µT1 and µC1 denote the mean diurnal IOP at Month 3 in the DE-117 and Timolol arm, 
respectively, and Δ denotes the non-inferiority margin of 1.5 mmHg.  The primary analysis of 
this key secondary efficacy endpoint will be performed using a MMRM based on the FAS.  The 
model will include treatment, analysis visit (Week 1, Week 6, or Month 3), and  
treatment-by-visit interaction as fixed effects, and baseline mean diurnal IOP at as a covariate.  
Correlations of mean diurnal IOPs within-subject will be modeled using an unstructured 
covariance matrix.  The mathematical model is analogous to the model in the primary efficacy 
endpoint. 
If there are convergence issues, covariance matrix structures other than unstructured will be tried 
in the following order: (1) heterogeneous Toeplitz (TOEPH), (2) heterogeneous autoregressive of 
order 1 (ARH(1)), (3) heterogeneous compound symmetry (CSH), and (4) compound symmetry 
(CS).  The first covariance structure that converges will be used as the primary analysis.  Least 
squares mean diurnal IOP values at Month 3 for each treatment arm and the difference between 
least squares treatment group means and its 95% confidence interval will be reported. 
Non-inferiority of DE-117 to Timolol is achieved for this endpoint if the upper limit of the  
95% confidence interval for the difference between DE-117 and Timolol (DE-117 minus 
Timolol) in the mean diurnal IOP at Month 3 is ≤ 1.5 mmHg.  Superiority of DE-117 to Timolol 
is achieved for this endpoint if the upper limit of the 95% confidence interval is < 0 mmHg. 
8.1.1.2.2. IOP at Nine Timepoints in Study Eyes with Baseline Mean Diurnal 
IOP < 25 mmHg 
The second key secondary endpoint is IOP at each scheduled timepoint (08:00, 10:00, and 16:00) 
at each of three follow-up visits, Week 1, Week 6, and Month 3, in the study eyes with mean 
diurnal IOP < 25 mmHg at the Baseline Visit.  If non-inferiority of DE-117 to Timolol for the 
primary endpoint and the first key secondary endpoint is achieved, the following null (versus 
alternative) hypothesis will be tested for the second key secondary endpoint: 
 


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H0 S2: µT2 – µC2 > Δ,  for at least one timepoint 
versus 
HA S2: µT2 –  µC2 ≤  Δ at all nine timepoints 
where µT2 and µC2 denote the mean IOP values in the DE-117 arm and the Timolol arm, 
respectively, and Δ denotes the non-inferiority margin of 1.5 mmHg or 1.0 mmHg as specified 
below. 
The same MMRM used in the analysis of the primary efficacy endpoint will be used for the 
analysis of the second key secondary endpoint.  Non-inferiority of DE-117 to Timolol for this 
endpoint (i.e., for subjects with baseline mean diurnal IOP < 25 mmHg) is achieved if the upper 
limit of the two-sided 95% confidence interval for the difference in the mean IOP (DE-117 
minus Timolol) is ≤ 1.5 mmHg at all nine timepoints and ≤ 1.0 mmHg at a majority (five or 
more) of the nine timepoints.  Superiority of DE-117 to Timolol for this endpoint (i.e., for 
subjects with baseline mean diurnal IOP < 25 mmHg) is achieved if the upper limit of the  
two-sided 95% confidence interval for the difference in the mean IOP (DE-117 minus Timolol) 
is < 0 mmHg at all nine timepoints. 
8.1.1.2.3. Mean Diurnal IOP at Week 1 
The third key secondary endpoint is mean diurnal IOP in the study eye at Week 1.  If  
non-inferiority of DE-117 to Timolol for the primary and the first two key secondary endpoints 
is achieved, then the following null (versus alternative) hypothesis will be tested for the third key 
secondary endpoint: 
H0S3: µT3 = µC3  versus HAS3: µT3 ≠ µC3 
where µT3 and µC3 denote the mean diurnal IOP at Week 1 in the DE-117 and Timolol arm, 
respectively.  The primary analysis of this key secondary endpoint will be performed using a 
MMRM analogous to the model used for the first key secondary efficacy endpoint (mean diurnal 
IOP at Month 3). 
For the primary and key secondary efficacy endpoints, the testing sequence and multiplicity 
adjustment details are provided in Section 6.4. 
8.1.2. 
Sensitivity Analyses 
For the primary endpoint and the key secondary endpoints, sensitivity analyses will be performed 
to assess the robustness of the results from the primary analysis.  The sensitivity analyses consist 
of two types: (1) assessment based on the PPS and (2) a pattern-mixture model (PMM) approach 
(Table 6).  Unless otherwise specified, for subjects who receive IOP-lowering rescue therapy, 
any IOP values collected after the receipt of rescue therapy will be censored (i.e., treated as 
missing) in the analyses. 
 
 
 


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Table 6: 
Overview of Primary and Sensitivity Analysis Methods 
Primary or 
Sensitivity Analysis 
Statistical Method 
Analysis Population 
Handling of Missing Data 
Primary Analysis 
MMRM 
FAS 
Observed cases 
Sensitivity Analyses 
MMRM 
PPS 
Observed cases 
PMM with 
delta-adjustment 
FAS 
MI 
Abbreviations: FAS = full analysis set; MI = multiple imputation; MMRM = mixed-effects model for repeated 
measures; PMM = pattern-mixture model; PPS = per protocol set. 
To assess the sensitivity to departure from MAR assumption, a PMM with delta-adjustment will 
be applied, as follows: 
a. Use Markov chain Monte Carlo (MCMC) to create monotone missingness first.  Then 
obtain standard multiple imputations under MAR assumptions for missing IOP values 
using monotone regression.  The missing data are filled in and 50 complete datasets 
are created.  The seed that will be used in the SAS program is 13546. 
b. For each IOP value that had been missing because of (1) censoring after having 
received IOP-lowering rescue therapy; or because of (2) early study discontinuation 
due to lack of efficacy or AE, regardless of treatment arm, adjust these values by 
adding delta to the imputed values, where delta = 1.0 mmHg.  The seed that will be 
used in the SAS program is 13546. 
c. Each of the 50 complete datasets will then be analyzed separately using the same 
MMRM as used for the primary analysis. 
d. The estimates obtained from the MMRM analysis of each complete dataset are 
combined for inference purposes. 
e. Repeat step b, c, d, with delta = 2.0, 3.0, 4.0, and 5.0 mmHg.  The larger the value of 
delta that is required to reverse the conclusion of the primary analysis, the more 
robust the conclusion is considered to be. 
The main part of the SAS code for the specified MMRM analysis and PMM are provided in 
Appendix A (Section 12.1) and Appendix B (Section 12.2), respectively. 
For the primary endpoint, in addition to the two types of sensitivity analyses described above, if 
the overall rate of study drug discontinuation due to lack of efficacy or AE is greater than 10% 
and the difference between the rate in the DE-117 and Timolol arms is greater than 5 percentage 
points, a trimmed mean analysis (Permutt et al., 2017) will be conducted as a sensitivity analysis. 
8.2. 
Analyses of Other Secondary Efficacy Endpoints 
Other secondary endpoints to be assessed include: 
 Change and percent change from baseline in IOP at each timepoint/post-baseline visit 
 Change and percent change from baseline in mean diurnal IOP at each post-baseline 
visit 
 Having a mean diurnal IOP reduction ≥ 20%, ≥ 25%, or ≥ 30% from 
Baseline (Visit 2) at each post-baseline visit 


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 Having a mean diurnal IOP ≤ 18mmHg at each post-baseline visit 
For continuous secondary endpoints (change and percent change from baseline in IOP/mean 
diurnal IOP) at Week 1 (Visit 3), Week 6 (Visit 4), and Month 3 (Visit 5), both an analysis using 
a MMRM will be performed and descriptive summaries will be generated.  The MMRM will be 
analogous to the MMRM used in the analysis of the primary endpoint.  For both the analysis 
using MMRM and descriptive summaries of the IOP or mean diurnal IOP (raw) scores, IOP 
values obtained after using rescue therapy will be censored (i.e., treated as missing). 
For the following binary secondary endpoints, the responder rates will be analyzed using the 
Pearson’s chi-square test for a 2×2 contingency table; differences between the DE-117 and 
Timolol arms will be reported along with corresponding p-values: 
 Having a mean diurnal IOP reduction ≥ 20%, ≥ 25%, or ≥ 30% from 
Baseline (Visit 2) at each post-baseline visit 
 Having a mean diurnal IOP ≤ 18mmHg at each post-baseline visit 
8.3. 
Subgroup Analyses 
The homogeneity of treatment effects among prospectively defined subgroups was assessed 
using MMRM analyses of IOP (at each visit and timepoint) and mean diurnal IOP (at each visit) 
for the following subgroups: 
 Age (< 65 or ≥ 65 years) 
 Sex (males or females) 
 Race (White or Black)  
 Primary ocular diagnosis (OAG or OHT) 
 Prior use of IOP-lowering medication (ß-adrenergic antagonist, prostamide or 
prostaglandin analogue, α-adrenergic agonist, carbonic anhydrase inhibitors, or none) 
 Mean diurnal IOP at baseline (< 25 or ≥ 25 mmHg) 
 Lens status (phakic or pseudophakic/aphakic)  
Other subgroup analyses may be performed as deemed necessary. 


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9. 
SAFETY ANALYSES 
The safety-related measures collected in this study include AEs, best-corrected visual acuity,  
slit-lamp biomicroscopy (severity scores for 12 parameters, ophthalmoscopy (cup-to-disc ratio, 
glaucomatous optic nerve severity score, and assessments of retina, macula, choroid, and 
vitreous), and eyelid sulcus/eyelid/eyelash/iris color.  In the event that a subject took both 
DE-117 and Timolol during the study, the subject will be summarized with those receiving 
DE-117. 
All the safety-related measures will be summarized descriptively by actual treatment received on 
the Safety population. 
9.1. 
Adverse Events 
AEs, SAEs, SARs, serious SARs, and significant AEs (AEs leading to study drug 
discontinuation and AEs leading to death) will be tabulated by type of AEs by treatment arm 
using actual treatment received for all AEs, ocular AEs, and non-ocular AEs separately. 
Besides the overall AE summary, AEs, SAEs, SARs, serious SARs will be tabulated by SOC and 
preferred term for all AEs, ocular AEs, and non-ocular AEs separately.  A subject who 
experienced multiple AEs within a SOC or preferred term will be counted only once for that 
SOC or preferred term.  Non-serious AEs (including number of events) and ESIs will also be 
summarized by SOC and preferred term. 
AEs, SAEs, SARs, serious SARs, ocular AEs, AEs leading to death, AEs leading to study drug 
discontinuation, non-TEAEs, and ESIs, if any, will be listed separately. 
9.1.1. 
Ocular Inflammation 
Subjects who developed AEs during the study with one of the following preferred terms will be 
included in the ocular inflammation summary: 
 Anterior chamber cell 
 Anterior chamber flare 
 Eye inflammation  
 Iridocyclitis  
 Iritis 
 Uveitis 
Ocular inflammation leading to study drug discontinuation, requiring steroid treatment, or 
requiring NSAIDs treatment will be summarized at the subject level by frequency and 
percentage separately. 
Ocular inflammation start time (in terms of study day) and duration of the AE will be 
summarized at the eye level using mean, standard deviation, median, minimum, and maximum 
by study eye and fellow eye separately.  To allow for the computation of simple descriptive 
statistics, only subjects who develop ocular inflammation during the study will be used for the 
ocular inflammation start time summary, and only subjects who develop these AEs during the 
study and later resolved will be used in the duration of AE analysis. 


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


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The aforementioned summaries will be performed at the eye level.  All cosmetic change AEs 
will be provided in a listing. 
9.2. 
Best-Corrected Visual Acuity 
BCVA (logMAR scores) and changes from baseline will be summarized by treatment and 
analysis visit for study eyes and fellow eyes, separately.  In addition, any change (worsening or 
improvement) of ≥ 0.2 LogMAR (2 lines) from baseline will be summarized and listed. 
9.3. 
Slit-lamp Biomicroscopy 
For each biomicroscopy parameter, frequency and percentage of rating scores will be 
summarized by analysis visit for study eyes and fellow eyes, separately.  In addition, any 
clinically significant worsening (increase) from baseline will be summarized and listed. 
9.4. 
Ophthalmoscopy 
Cup-to-disc ratio will be summarized with n, mean, standard deviation, median, minimum and 
maximum by treatment and 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 treatment and 
analysis visit for study eyes and fellow eyes, separately.  In addition, subjects with any 
worsening (increase) of ≥ 2 units from baseline will be listed. 
Retina/Macula/Choroid and vitreous will be assessed as normal or abnormal.  Shift from baseline 
at Month 3 will be summarized by treatment on study eyes and fellow eyes separately.  In 
addition, subjects with change from baseline from normal to abnormal in these parameters will 
be listed. 
9.5. 
Eyelid Sulcus, Eyelid, Eyelash, and Iris Color 
For changes from baseline in eyelid pigmentation, eyelid hair growth, eyelash length, eyelash 
thickness, eyelash pigmentation, eyelash number, and iris color/pigmentation, frequency and 
percentage of subjects with No change, Increased, or Decreased will be summarized by treatment 
and analysis visit for study eyes and for fellow eyes.  For changes from baseline in eyelid sulcus, 
count and percentage of changes (Yes) will be summarized by treatment and analysis visit 
(Month 3) for study eyes and for fellow eyes.  In addition, any changes from baseline in eyelid 
sulcus will be listed. 
9.6. 
Vital Signs 
Resting blood pressure (systolic and diastolic) and pulse rate and their change from baseline will 
be summarized by treatment and analysis visit. 
A listing for vital signs will be provided. 


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10. 
ADDITIONS AND CHANGES TO THE PROTOCOL-SPECIFIED 
ANALYSES 
10.1. 
Full Analysis Set Definition 
The full analysis set definition has been updated to add the requirement that baseline IOP data 
has to be present: 
The Full Analysis Set (FAS) will include all randomized subjects who received at least one dose 
of study medication and provided Baseline IOP data (at any timepoint) and at least one  
post-baseline IOP measurement (at any timepoint).  Efficacy analyses will be performed using 
the FAS and summarized by treatment as randomized. 
10.2. 
Key Secondary Endpoint 
An additional key secondary endpoint (IOP at each scheduled timepoint [08:00, 10:00, and 
16:00] at Week 1 [Visit 3], Week 6 [Visit 4], and Month 3 [Visit 5] in the study eyes with mean 
diurnal IOP < 25 mmHg at the Baseline Visit) was added based on analysis results of a recently 
completed study in Asia. 
10.3. 
Sensitivity Analysis of the Primary and Secondary Efficacy 
Endpoints 
Protocol Amendment 1 (Version 1.1) Section 14.5, Handling of Missing Values, specified a 
sensitivity analysis of the primary efficacy endpoints and the secondary binary IOP endpoints 
(Month 3) in which missing values would be imputed using the last-observation-carried-forward 
(LOCF) approach.  The LOCF approach is removed from the sensitivity analyses because the 
PMM generalizes the MMRM to include mixed missing data mechanisms beyond the MAR 
assumption of the MMRM.  Thus, the PMM is sufficient to evaluate the robustness of the results 
from the MMRM. 


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


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12. 
APPENDICES 


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