Clinical trial NCT04133311
Conditions: Open-Angle Glaucoma or Ocular Hypertension Ocular Surface Disease
Keywords: IOP OSD
Sponsor: Santen SAS
Start date: 2019-04-10; Completion date: 2022-10-26
Enrollment: 386 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase III, Multinational, Multicenter, Investigator-Masked, Randomized, Active-Controlled Trial, comparing the efficacy and safety of DE-130A with Xalatan® in Patients with Open-Angle Glaucoma or Ocular Hypertension over a 3-Month period, followed by a 12-Month Follow-Up with Open-Label DE-130A Treatment.

Detailed description:
Phase III, prospective, interventional, multinational, multicentre, investigator-masked, randomized, active-controlled trial

Study duration:

* 5 days to 5-week washout period
* 15 months for the first 130 patients
* 12 weeks for the next 250 patients

Patients will attend 6 visits following the wash-out phase (up to 5 weeks):

* Period 1 (3-month investigator-masked treatment period, DE-130A vs Xalatan®): Randomization/Baseline visit (Day 1), Week 4 (±3 days) and Week 12 (±3 days)
* Period 2 (12-month follow-up from Week 12, open-label DE-130A treatment for the first 130 patients who complete their week 12 visit and agree to participate in the open-label period of the study): Month 6 (± 7days), Month 9 (±7 days) and Month 15 (± 1 week) visits.

Arms: arm 1: Instillation of one drop, once daily in the evening (9 pm ±1 hour) in the conjunctival sac of the affected eye(s). Both eyes will be treated unless the patient suffers from unilateral OAG/OHT arm 2: Instillation of one drop, once daily in the evening (9 pm ± 1 hour) in the conjunctival sac of the affected eye(s). Both eyes will be treated unless the patient suffers from unilateral OAG/OHT arm 3: After 12 weeks, continue to use DE-130A once daily for an additional 12 months. arm 4: After 12 weeks, use DE-130A instead of Xalatan® once daily for an additional 12 months.
Interventions: intervention 1: DE-130A intervention 2: Xalatan® intervention 3: DE-130A/DE-130A intervention 4: Xalatan®/DE-130A
Intervention descriptions: intervention 1: Latanoprost 50 microg/ml eye drops emulsion, preservative-free eye drops emulsion in single-dose containers. intervention 2: Latanoprost 50 microg/ml eye drops solution, eye drops in 2.5 ml dropper containers. intervention 3: After Week 12, received DE-130A continuously. intervention 4: From week 12 onwards, DE-130A was continued to be administered instead of Xalatan®.

Protocol documents:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:   
A Phase III, Multinational, Multicenter, Investigator-Masked, 
Randomized, ActiveControlled Trial, comparing the efficacy and 
safety of DE-130A with Xalatan® in Patients with Open-Angle 
Glaucoma or Ocular Hypertension over a 3-Month period, followed 
by a 12-Month Follow-Up with Open-Label DE-130A Treatment. 
 
 
NCT Number:  
 NCT04133311 
 
Date of the document: 
 26 February 2021 
 
 
 


 
 
 
PROTOCOL 0130A01SA 
A PHASE III, MULTINATIONAL, MULTICENTER, INVESTIGATOR-MASKED, RANDOMISED, 
ACTIVE-CONTROLLED TRIAL, COMPARING THE EFFICACY AND SAFETY OF DE-130A 
WITH XALATAN®  IN PATIENTS WITH OPEN-ANGLE GLAUCOMA OR OCULAR 
HYPERTENSION OVER A 3-MONTH PERIOD, FOLLOWED BY A 12-MONTH FOLLOW-UP 
WITH OPEN-LABEL DE-130A TREATMENT. 
 
Sponsor: 
SANTEN  SAS 
Genavenir IV, 1 rue Pierre Fontaine 
F-91058 Evry, France 
Study Number: 
0130A01SA 
IND Number: 
N/A 
EudraCT Number: 
2017-004262-95 
Compound: 
DE-130A (latanoprost 50 microg/ml eye drops emulsion, SD) 
Date: 
Original Protocol Version 4.0  17 
October 2018  
Amendment 1 Version 5.0   
26 February 2021  
 
 
 
 
 
CONFIDENTIAL PROPERTY OF SANTEN 
This document is a confidential communication of Santen. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Santen except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study. 
    
 


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INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Summary of Product 
characteristics, and any other product information provided by the sponsor. I agree to conduct 
this study in accordance with the requirements of this protocol and also protect the rights, safety, 
privacy, and well-being of study patients in accordance with the following: 
 
The ethical principles that have their origin in the Declaration of Helsinki. 
 
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline. 
 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 
Regulatory requirements for reporting serious adverse events defined in Section 12.2.4.3 of 
this protocol. 
 
Terms outlined in the Clinical Study Site Agreement. 
I confirm my responsibilities noted on Appendix B of this Protocol. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol. 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State) 
Location of Facility (Country) 
Signature of Investigator 
Date 


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1. 
SYNOPSIS 
Name of Sponsor/Company: SANTEN SAS  
 
Name of Active Ingredient: Latanoprost 
Title of Study: A Phase III, Multinational, Multicenter, Investigator-Masked, Randomised, 
Active-Controlled Trial, comparing the efficacy and safety of DE-130A with Xalatan®  in 
Patients with Open-Angle Glaucoma or Ocular Hypertension over a 3-Month period, 
followed by a 12-Month Follow-Up with Open-Label DE-130A Treatment 
Coordinating Investigators: 
Studied period (years):  
Estimated date first patient enrolled:  February 2019 
Estimated date last patient completed: Nov2022 
Phase of development:  
III 
Objectives:  
Primary: 
 To demonstrate that the intraocular pressure (IOP) reducing effect of DE-130A 
(latanoprost 50 microg/ml preservative-free eye drops emulsion) is non-inferior to that of 
Xalatan® [latanoprost 50 microg/ml Benzalkonium Chloride (BAK)-preserved eye drops 
solution], in patients with Open-Angle Glaucoma (OAG) or Ocular Hypertension (OHT) at 
Week 12 without using any rescue medication(s). 
Secondary: 
 To compare the effect on improving Ocular Surface Disease (OSD) signs and symptoms 
between treatment groups over 3 months (Period 1). 
 To estimate the effect of DE-130A on OSD signs and symptoms improvement up to 15 
months (Periods 1 & 2). 
 To compare the efficacy on IOP reduction between treatment group  over 3 months 
(Period 1). 
 To estimate the effect of DE-130A on IOP upto 15 months (Periods 1 & 2). 
 To estimate the local ocular tolerance and systemic safety of the two treatments over 3 
months (Period 1). 
 To evaluate the local ocular tolerance and systemic safety of DE-130A up to 15 months 
(Periods 1 & 2). 
Methodology:  
Phase III, prospective, interventional, multinational, multicentre, investigator-masked, 
randomised, active-controlled trial 
Study duration:  


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 5 days to 6-week washout period  
 15 months for the first 130 patients 
 12 weeks for the next 250 patients 
 
Patients will attend 6 visits following the wash-out phase (up to 6 weeks):  
 Period 1 (3-month investigator-masked treatment period, DE-130A vs Xalatan®): 
Randomisation/Baseline visit (Day 1), Week 4 (±3 days) and Week 12 (±3 days) 
 Period 2 (12-month follow-up from Week 12, open-label DE-130A treatment for the 
first 130 patients who complete their week 12 visit and agree to participate in the open-
label period of the study): Month 6 (± 7days), Month 9 (±7 days) and Month 15 (± 1 
week) visits. 
Number of patients (planned):  
Approximately 380 patients with Open-Angle Glaucoma (OAG), or ocular hypertension 
(OHT) (190 in DE-130A group and 190 in Xalatan® group) will be randomised in this study 
to obtain 173 evaluable patients per treatment group at Week 12 (assumed dropout rate of 
10%).  
A safety follow up of 12 months is planned for the first 130 patients who will attend the Week 
12 visit and agree to participate in the open-label period of the study. They will then be treated 
with DE-130A in an open-label fashion. 
Criteria for inclusion:  
Patient eligibility is determined according to the following inclusion criteria: 
1. Male or female, 18 years of age or older 
2. The patient has signed and dated a written informed consent form and any 
required privacy authorization prior to the conduct of any study procedures.  
3. Diagnosis of OAG (primary open angle glaucoma, pseudo exfoliative glaucoma, 
or pigmentary glaucoma), or OHT in eligible eye(s) currently on monotherapy. 
4. Unilateral OAG, or OHT are permissible as long as the physician does not 
anticipate significant IOP changes to the fellow eye that would require treatment 
during the duration of the study.   
5. Current treatment with monotherapy for OAG or OHT with a controlled IOP ≤ 18 
mmHg in each eye (pre-washout). 
6. Stable visual field (based on at least two visual fields available within the last 18 
months prior to screening, including one in the last 6 months; A visual field test 
will be performed at screening if not already performed within the last 6 months 
prior to screening) in each eye. If historical visual fields are not available within the 
last 18 months prior to screening, but at least two OCTs (optical coherence 
tomography) are available, including one in the last 6 months and are stable, the 
patient can be enrolled in the study if a visual field test is also performed at 


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screening and shows no defect or only an early visual field loss in either eye (mean 
deviation lesser than -6 dB). 
7. Post-washout IOP ≥ 22 mmHg in at least one eye (defined as baseline visit [Day 1] 
by IOP measurement at both 9:00 am ±1 hour and 4:00 pm ±1 hour). If IOP is <22 
mmHg, the wash-out period can be extended and the IOP should be re-assessed two 
to three days after the first measurement. If the IOP is still < 22 mmHg at the second 
measurement, a third assessment should be performed two to three days after the 
second measurement. If the IOP is still < 22 mmHg at the third  measurement, the 
patient cannot be randomized in the study. 
8. Post-washout IOP ≤ 32 mmHg (defined as baseline visit [Day 1] by IOP 
measurement at both 9:00 am ±1 hour and 4:00 pm ±1 hour) in both eyes.  
9. Ability to discontinue their current topical IOP-lowering medication for the 
required washout period. Washout periods should be as follows;  
 Prostaglandin analogs  = 4 weeks 
 Topical beta blockers ≥ 3 weeks and ≤ 4 weeks 
 Topical carbonic anhydrase inhibitors  ≥ 5 days and ≤ 4 weeks 
 All other IOP lowering medication ≥ 2 weeks and ≤ 4 weeks 
10. Snellen best corrected visual acuity score of 20/100 or better in each eye.  
11. Patient must be willing to discontinue wearing contact lenses during the study. 
12. Adequate health for study participation as determined by the investigator. 
13. In the opinion of the investigator, the patient is capable of understanding and 
complying with protocol requirements.  
14. Patient must be willing and able to undergo and return for scheduled study-related 
examinations.  
Exclusion criteria: 
Any patient who meets any of the following criteria will not qualify for entry into the 
study: 
1. Any form of glaucoma other than primary open angle glaucoma, pseudo 
exfoliative glaucoma, and pigmentary glaucoma in either eye.  
2. IOP at any time point during the Screening or Baseline visits (Visits 1 or 2) of > 
32 mmHg in either eye.  
3. Current treatment for glaucoma with a fixed-combination therapy or more than 
one drug in either eye or with an oral drug within 6 months prior to screening. 
4. Corneal abnormalities that would interfere with accurate IOP readings with an 
applanation tonometer in either eye. 


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5. Central corneal thickness  ≤ 480 µm or ≥ 600 µm in either eye (historical value or 
at the screening visit) 
6. Significant visual field loss (absolute defect in the 10° central point or mean 
deviation worse than -12 dB) or progressive field loss during the year before 
screening in either eye. 
7. Significant optic nerve abnormality, other than glaucomatous abnormalities in the 
opinion of the investigator as determined by ophthalmoscopy in either eye. 
8. Significant changes of the optic neuropathy (e.g. increase cupping since the last 
examination, optic nerve hemorrhage) in either eye. 
9. Inability to visualize the patient’s optic nerve in either eye. 
10. Gonioscopy consistent with potential angle closure glaucoma in either eye. 
11. Patients with severe blepharitis and/or Meibomian Gland Disease (MGD). 
Patients enrolled with mild to moderate blepharitis and/or MGD should be treated 
as appropriate during the study in either eye. 
12. Use of oral or topical ophthalmic steroid within the past 14 days from screening 
date, or anticipated need for ocular steroid treatment during the study in either 
eye. 
13. Use of intravitreal or peribulbar injection of depot steroid or placement of an 
intravitreal steroid implant within the past 3 months from screening date in either 
eye. 
14. Known allergy or sensitivity to the study medications.  
15. Known hypersensitivity to sulfonamides, severe renal impairment or 
hyperchloraemic acidosis.  
16. Active or expected ocular allergy during the period 1. 
17. Any active ocular disease (e.g. uveitis, ocular infection, severe dry eye with CFS 
grade 4 or more on the modified Oxford scale) in either eye. Patients may have 
mild cataracts, age-related maculopathy or background diabetic retinopathy if, in 
the opinion of the Investigator, it would not interfere with the conduct of the 
study. 
18. Intraocular surgery within 6 months prior to screening in either eye. 
19. Past history of any filtering surgery for glaucoma in either eye. 
20. Refractive surgery of any type within 1 year prior to screening in either eye. 
21. Uncontrolled systemic disease of any type.  
22. Anticipated alteration in chronic therapy with or introduction of agents known to 
have a substantial effect on IOP (e.g., alpha-adrenergic agonists, beta-adrenergic 
antagonists, calcium channel blockers, ACE inhibitors and/or angiotensin II 
receptor blockers), unless the subject and the medication dosage have been stable 


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for three months prior to the screening visit and the dosage is not expected to 
change during the study. 
23. Anticipated change in dosage of or introduction of new medications for chronic 
cardiac, pulmonary or hypertensive conditions. 
24. Females who are pregnant or lactating and females of child-bearing potential who 
are not using a medically acceptable, highly effective method of birth control. 
25. Current enrolment in an investigational drug or device study or participation in 
such a study within 30 days prior to screening. 
26. History of drug or alcohol abuse.  
27. Patient has any condition or situation that, in the Investigator’s opinion, might 
confound the results of the study, may put the patient at significant risk or might 
interfere with the patient’s ability to participate in the study. 
Study drug, dosage, mode and duration of administration:  
Study drug: DE-130A (latanoprost 50 microg/ml eye drops emulsion, SD) eye drops emulsion 
in single-dose containers. 
Regimen: Instillation of one drop, once daily in the evening (9 pm ±1 hour) in the 
conjunctival sac of the affected eye(s). Both eyes will be treated unless the patient suffers 
from unilateral OAG/OHT. 
Duration of treatment: 3 months during Period 1 (randomised, investigator-masked 
treatment) and up to 12 months during Period 2 (open-label DE-130A 12-month extension 
for the first 130 patients who complete their Week 12 visit and agree to participate in the 
open-label period of the study). 
The period 2 will be open in some countries only. 
Comparator, dosage, mode and duration of administration:  
Investigational product: Xalatan® (latanoprost 50 microg/ml eye drops solution) eye drops in 
2.5 ml dropper containers. 
Regimen: Instillation of one drop, once daily in the evening (9 pm ± 1 hour) in the 
conjunctival sac of the affected eye(s). Both eyes will be treated unless the patient suffers 
from unilateral OAG/OHT . 
Duration of treatment: 3 months during Period 1 (randomised, investigator-masked 
treatment) 
Wash-out phase therapy: 
At screening visit, prior therapies for OAG or OHT must be discontinued during a wash-out 
phase of at least 5 days and up to 6 weeks (according to the IOP lowering medications 
currently used at screening visit). Washout periods should be as follows: 
• 
Prostaglandin analogs = 4 weeks 
• 
Topical beta blockers ≥ 3 weeks and ≤ 4 weeks 
• 
Topical carbonic anhydrase inhibitors  ≥ 5 days and ≤ 4 weeks 


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• 
All other IOP lowering medication ≥ 2 weeks and ≤ 4 weeks 
During this wash-out period, topical IOP-lowering medication will be replaced by 
brinzolamide* (Azopt®) one drop twice daily. Then brinzolamide will be stopped 5 days before 
randomisation (6 to 7 days if over the weekend). At baseline, if IOP is <22 mmHg, the wash-
out period can be extended and the IOP should be re-assessed two to three days after the first 
measurement. If the IOP is still < 22 mmHg at the second measurement, a third assessment 
should be performed two to three days after the second measurement. If the IOP is still < 22 
mmHg at the third  measurement, the patient cannot be randomized in the study. 
 
*Patients already receiving brinzolamide prior to screening visit will have to stop their 
treatment for a 5-day washout before randomisation (without any need to receive again the 
brinzolamide provided by the Sponsor). 
Criteria for evaluation: 
Efficacy: 
The primary efficacy endpoint is the change from baseline in peak (9:00 am ± 1 hour) and 
trough (4:00 pm ± 1 hour) IOPs, respectively, at Week 12 between the two treatment groups 
in the study eye.  
The key secondary endpoints are: 
• 
Change from baseline in CFS score in the study eye at Week 12 in patients with 
baseline CFS ≥ 1. 
• 
Change from baseline in OSD symptom score (average of 3 symptoms: dry eye 
sensation, blurred/poor vision and burning/stinging/itching) in the study eye at Week 
12 in patients with baseline symptom average score>0. 
Other secondary efficacy endpoints are: 
• 
Ocular surface disease related endpoints:  
o CFS in the study eye at Week 4 in subjects with baseline CFS ≥ 1 
o Tear film break-up time (TFBUT) in the study eye at Week 4 and Week 12 in 
subjects with baseline TFBUT ≤ 10 
o Conjunctival hyperemia (measured by slit lamp scored using the photographic 
scale derived from McMonnies scale [1 to 6]) in the study eye at Week 4, Week 
12 
o Conjunctival fluorescein staining in the study eye at Week 4 and Week 12 in 
subjects with baseline conjunctival fluorescein staining ≥ 1 
o Dry eye sensation symptom in the study eye at Week 4 and Week 12 in 
subjects with baseline dry eye sensation symptom in mild, moderate, or severe  
o Blurred/poor vision symptom in the study eye at Week 4 and Week 12 in 
subjects with baseline blurred/poor vision symptom in mild, moderate, or 
severe  


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o Burning/stinging/itching symptom in the study eye at Week 4 and Week 12 in 
subjects with baseline burning/stinging/itching symptom in mild, moderate, or 
severe  
o Slit lamp examination (Meibomian gland dysfunction, conjunctiva chemosis, 
lids and tear film debris) in the study eye at Week 4 and Week 12 
o CFS in the study eye at Month 6, Month 9 and Month 15/early termination in 
subjects with baseline CFS ≥ 1 
o Tear film break-up time (TFBUT) in the study eye at Month 6, Month 9 and 
Month 15/early termination in subjects with baseline TFBUT ≤ 10 
o Conjunctival hyperemia (measured by slit lamp scored using the photographic 
scale derived from McMonnies scale [1 to 6]) in the study eye at Month 6, 
Month 9 and Month 15/early termination  
o Conjunctival fluorescein staining in the study eye at Month 6, Month 9 and 
Month 15/early termination in subjects with baseline conjunctival fluorescein 
staining ≥ 1 
o Dry eye sensation symptom in the study eye at Month 6, Month 9 and Month 
15/early termination in subjects with baseline dry eye sensation symptom in 
mild, moderate, or severe  
o Blurred/poor vision symptom in the study eye at Month 6, Month 9 and 
Month 15/early termination in subjects with baseline blurred/poor vision 
symptom in mild, moderate, or severe  
o Burning/stinging/itching symptom in the study eye at Month 6, Month 9 and 
Month 15/early termination in subjects with baseline burning/stinging/itching 
symptom in mild, moderate, or severe  
o Slit lamp examination (Meibomian gland dysfunction, conjunctiva chemosis, 
lids and tear film debris) in the study eye at Month 6, Month 9 and Month 
15/early termination 
 
• 
IOP related endpoints: 
o Change from baseline in mean diurnal IOP in the study eye at Week 12 
o Change from baseline in peak, trough, and mean diurnal IOP in the study eye 
at Week 4 
o Peak, trough, and mean diurnal IOP response in the study eye at Week 4 and 
Week 12: 
▪ IOP 20% response (reduction in mean IOP of ≥ 20% from 
Baseline at the specified follow-up visit)  
▪ IOP 25% response (reduction in mean IOP of ≥ 25% from 
Baseline at the specified follow-up visit)  
▪ IOP 30% response (reduction in mean IOP of ≥ 30% from 
Baseline at the specified follow-up visit)  


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▪ IOP < 18 mmHg response (mean IOP < 18 mmHg at the 
specified follow-up visit) 
o Morning (9:00 am ± 1 hour) IOP in the study eye of patients treated with DE-
130A at Month 6, Month 9, Month 15/early termination (Period 2) and change 
from baseline at each Period 2 visit 
• 
Subject global rating of treatment at Month 15/early terminationand  Week 12. 
• 
Quality of life (Glaucoma Quality of Life-15) scores at Baseline visit, Week 12, and 
Month 15/early termination visits. 
Safety: 
In the Safety population, at all visits and for each treatment (Period 1) and for the Open-
Label population for DE-130A at all visits (Period 2 and Periods 1 & 2 combined), safety and 
tolerability endpoints are: 
• 
The incidence and severity of ocular and systemic adverse events    
• 
Best-corrected distance visual acuity (BCDVA) 
• 
Slit lamp examination (lashes, anterior chamber and lens). 
• 
Dilated and undilated (for cup-to-disc ratio) fundoscopy. 
Statistical methods: 
Sample size 
Sample size was calculated assuming a mean difference in IOP change from baseline of 0 
mmHg and a common standard deviation of 4.26 mmHg in the peak or trough IOPs, 
respectively, for the comparison between the DE-130A and the Xalatan® (control) groups. A 
total sample size of approximately 380 subjects (190 per treatment arm) will provide 90% 
power to demonstrate the non-inferiority of the DE-130A group to the control group (one-sided 
α = 0.025) for non-inferiority margin of 1.5 mmHg, assuming 10% dropout rate. 
Randomisation 
Patients will be randomly assigned in a 1:1 ratio to receive either DE-130A (experimental) or 
Xalatan® (comparator) for 3 months. To minimize the effect of baseline OSD severity, 
randomisation will be stratified according to the CFS score at Baseline visit (CFS ≤ 1 and ≥ 2, 
modified Oxford scale). 
Study eye 
Data collection will be done on both eyes, however, efficacy analyses will only be performed 
on the study eye, which is defined as the eye that qualifies per inclusion/ exclusion criteria at 
the Baseline Visit. If both eyes are eligible, the eye with the higher IOP at the Baseline Visit 
will be chosen. If both eyes have the same IOP value, the eye with the higher CFS at the 
Baseline Visit will be chosen. If both eyes have the same IOP and CFS values, then the right 
eye will be designated as the study eye. 
Analysis Populations 
The following analysis populations are considered: 


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 The Full Analysis Set (FAS) population consists of all randomised subjects who 
received at least one dose of the study medication and provided at least one post-
baseline IOP measurement at peak and trough timepoints, separately. The FAS 
population will be the analysis population for  all efficacy endpoints in Period 1 and 
will use treatment as randomised. 
 The Safety population consists of all subjects randomized in the study who received 
at least one dose of the study medication. The Safety population will be the analysis 
population for all safety analyses in Period 1 and will use treatment as actually received. 
 The Glaucoma/OHT Per-Protocol (PP) population will be a subset of the FAS 
subjects. It includes all FAS subjects without any of the major protocol deviations that 
could affect the primary efficacy endpoint. The PP population will be used for 
sensitivity analyses of the primary efficacy endpoints in Period 1 and will use treatment 
as randomised.  
 The Ocular Surface Disease Per-Protocol (PP) population will be a subset of the FAS 
subjects. It includes all FAS subjects without any of the major protocol deviations that 
could affect the key secondary endpoints. This population will be used for sensitivity 
analyses of the key secondary endpoints in Period 1 and will use treatment as 
randomised. 
 The Open-Label Population will be a subset of the FAS subjects who complete their 
Week 12 Visit and agree to participate in the open-label period of the study, and 
received at least one dose of the study medication during the open-label period and 
provided at least one morning IOP measurement after the Week 12 Visit.This 
population will be the analysis population for the analyses of efficacy endpoints in 
Period 2 and for Periods 1 & 2 combined data and will use treatment as randomised. 
Analysis of Demographics and Baseline Characteristics 
Descriptive summaries will be performed for demographic (including age, gender, race, 
ethnicity, female patients’ menopausal status) and baseline characteristics variables 
(including time since diagnosis, past surgery or laser treatment in the study eye, and smoking 
status). They will be summarized by treatment groups for the overall FAS population, Safety 
population, Open-label population, separately.  
In addition, medical history (ocular and systemic), and prior and concomitant medication use 
will be summarized by treatment group for the overall FAS population.  
Analysis of Primary and Key Secondary Efficacy Endpoints 
The primary efficacy endpoint is the change from baseline in peak and trough IOP, 
respectively, between the DE-130A group and the Xalatan® group in the study eye at Week 
12. Statistical analysis will be performed using a  mixed-effects model for repeated measures 
(MMRM) on observed cases collected up to Week 12 based on FAS population. A separate 
MMRM model will be performed for IOP at peak and trough, respectively. The model will 
include treatment, visit, treatment-by-visit interaction and country as fixed effects, baseline 
IOP at the respective timepoint (peak or trough) as covariates. Non-inferiority will be 


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established if the upper limit of the one-sided 97.5% confidence intervalis less than or equal to 
the non-inferiority margin of 1.5 mmHg at both the peak and trough timepoints at Week 12. 
Superiority is achieved with respect to this endpoint if the upper limit of the one-sided 97.5% 
confidence interval is < 0 mmHg for both timepoints at Week 12.  
 
If non-inferiority in the primary endpoint is achieved, the two key secondary endpoints will be 
tested for superiority, sequentially according to hierarchical fixed procedure. MMRM models 
will be fitted for each key secondary endpoint using a similar model setting as described for the 
analysis of the primary efficacy endpoint.  Fixed sequence procedure will be applied to control 
the overall Type I error rate across all hypotheses in the primary and key secondary endpoints 
at the 0.05 level. 
 
Analysis of Other Secondary Efficacy Endpoints 
Ocular surface disease Assessments 
Change from baseline in Conjunctival fluorescein staining, TFBUT and each individual 
symptom score in the study eye at each analysis visit in Period 1 will be compared between 
treatment groups using MMRM on observed cases. More details on the model specifications will be 
provided in the SAP.   
Percentage of patients with conjunctival hyperemia (measured by slit lamp scored using the 
photographic scale derived from McMonnies scale (1 to 6))in the study eye at each analysis 
visit in Period 1 will be compared between treatment groups using a Chi-squared test or 
Fisher’s Exact test wherever appropriate for the FAS population. 
Artificial tears use during Period 1will be summarised by treatment group as a continuous 
variable as well as by percentage of patients who use artificial tears at each analysis visit.. 
CSF, corneal and conjunctival fluorescein staining, TFBUT, symptom scores [3-symptom 
average and individual symptom score], and slit lamp examination and their change from 
baseline at each visit will be summarized descriptively by treatment group. 
Quality of Life Assessments 
Mean scores of quality of life (Glaucoma Quality of Life-15), and their change from baseline 
(Period 1 and Periods 1 & 2) and change from Week 12 (Period 2) will be summarized by 
study period,  analysis visit and by treatment group (Period 1), for the FAS population (Period 
1), for the Open-Label Population (Period 2, Periods 1 & 2 combined). 
Subjects Global Rating of Treatment 
Subjects global rating of treatment at Week 12/early termination will be summarized by 
treatment groups for the FAS population. Also, it will be summarized at Month 15/early 
termination for the Open-Label Population. 
 


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IOP Assessments 
Changes in peak, trough, and mean diurnal IOPs at each analysis will be summarized on the 
study eye by treatment group.  
Peak, trough, and mean diurnal IOP responses in the study eye (IOP 20%, 25%, 30% responses, 
and IOP < 18 mmHg response) at each analysis visit will be summarized by treatment group.  
For patients participating in the safety follow-up, change from baseline and change from Week 
12, respectively, in mean morning (9:00 am ± 1 hour) IOP will be summarized for the Open-
Label population and for CFS subgroups at Month 6, Month 9 and Month 15/early termination.  
Analysis of Safety and Tolerability Endpoints 
Safety and tolerability endpoints will be summarized for the following three time periods:  
 Period 1 (Day 1 to Week 12 Visit): for whole Safety population by treatment group  
 Period 2 (Week 12 Visit to Month 15 Visit/early termination): for all subjects who 
entered into the open-label period (Open-Label Safety population) 
 Entire study period (Day 1 to Month 15/early termination): for all subjects who 
entered into the open-label period (Open-Label Safety population). 
Adverse Events 
An adverse event is treatment-emergent (TEAE) if it occurs or worsens after the first dose of 
study treatment. A suspected adverse reaction (SAR) is any adverse event for which there is a 
reasonable possibility that the study drug or study procedure caused the adverse event. 
Adverse events will be coded using the MedDRA dictionary. Frequencies and percentages will 
be given as follows:  1) Overall summary; 2) by system organ class and preferred term, 3) by 
system organ class, preferred term and maximal severity, 4) by system organ class, preferred 
term and relationship to study medication and study procedure, respectively, and 5) by system 
organ class, preferred term, maximal severity, and relationship to study medication  and study 
procedure, respectively.  
Separate analyses will be performed for AEs, SARs, SAEs, serious SARs, and for ocular and 
non-ocular events. Ocular events will be summarized for the study eye and the fellow eye 
separately. 
Other Safety Assessments 
Other safety assessment parameters (e.g. slit lamp examination, dilated fundoscopy, BCDVA, 
and visual field) will be summarized by analysis visit. They will be summarized for the study 
eye and the fellow eye separately. Pregnancy test results will be provided in a listing. 
Interim Analysis 
There is no planned interim analysis for this study. 
 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............15 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................22 
4. 
INTRODUCTION ......................................................................................................24 
4.1. 
Background on DE-130A ...........................................................................................26 
4.1.1. 
Background information on the product .....................................................................26 
4.1.2. 
Non-clinical development ...........................................................................................26 
4.1.3. 
Clinical development ..................................................................................................28 
4.2. 
Rationale for the Proposed Study ...............................................................................28 
4.3. 
Benefit Risk Assessment ............................................................................................30 
5. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................31 
5.1. 
Primary Objective .......................................................................................................31 
5.2. 
Secondary Objectives .................................................................................................31 
5.3. 
Endpoints ....................................................................................................................31 
5.3.1. 
Primary Efficacy Endpoint .........................................................................................31 
5.3.2. 
Key Secondary Endpoints ...........................................................................................31 
5.3.3. 
Other Secondary Efficacy Endpoints ..........................................................................31 
5.3.4. 
Safety and Tolerability Endpoints ..............................................................................33 
6. 
INVESTIGATIONAL PLAN .....................................................................................34 
6.1. 
Overall Study Design ..................................................................................................34 
6.2. 
Number of Subjects ....................................................................................................37 
6.3. 
Dose Adjustment Criteria ...........................................................................................38 
6.3.1. 
Efficacy Criteria for Adjustment or Stopping Doses ..................................................38 
6.3.2. 
Safety Criteria for Adjustment or Stopping Doses .....................................................38 
6.3.3. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses ....................................38 
6.4. 
Criteria for Study Termination ...................................................................................38 
6.5. 
End of Trial .................................................................................................................38 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................39 


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7.1. 
Demographic, Baseline Characteristics, and Medical History ...................................39 
7.2. 
Subject Inclusion Criteria ...........................................................................................39 
7.3. 
Subject Exclusion Criteria ..........................................................................................40 
7.4. 
Screen Failure .............................................................................................................42 
7.5. 
Subject Withdrawal Criteria .......................................................................................42 
7.6. 
Procedures for Discontinuation or Withdrawal of a Patient .......................................43 
7.7. 
Completed Enrolment .................................................................................................43 
8. 
TREATMENT OF SUBJECTS ..................................................................................44 
8.1. 
Description of Study Drug ..........................................................................................44 
8.1.1. 
DE-130A .....................................................................................................................44 
8.1.2. 
Xalatan® ......................................................................................................................44 
8.2. 
Azopt®.........................................................................................................................44 
8.3. 
Concomitant Medications/Therapies ..........................................................................45 
8.4. 
Treatment Compliance ................................................................................................45 
8.5. 
Randomisation and Masking ......................................................................................45 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................47 
9.1. 
Study Drug ..................................................................................................................47 
9.2. 
Study Drug Packaging and Labeling ..........................................................................47 
9.2.1. 
Investigator-masked study treatment sequence of Period 1 .......................................47 
9.2.2. 
Open-label DE-130A of Period 2 ...............................................................................47 
9.3. 
Study Drug Storage .....................................................................................................48 
9.4. 
Study Drug Preparation ..............................................................................................48 
9.5. 
Administration ............................................................................................................48 
9.6. 
Study Drug Accountability and Destruction ...............................................................48 
10. 
SCHEDULE OF OBSERVATIONS AND PROCEDURES .....................................50 
10.1. 
Screening ....................................................................................................................55 
10.2. 
Investigator-masked treatment Phase (Period 1) ........................................................55 
10.2.1. 
Baseline: Day 1 ...........................................................................................................55 
10.2.2. 
Week 4 (±3 days) ........................................................................................................56 
10.2.3. 
Week 12 (±3 days) - End of study visit of the other patients than the 130 first 
completers ...................................................................................................................57 
10.3. 
Open-label DE-130A treatment Phase (Period 2) ......................................................57 


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10.3.1. 
Month 6 (± 7 days) and Month 9 (±7 days) ................................................................57 
10.3.2. 
Month 15 (±7 days) - End of study visit of the 130 first completers of Period 
1 ..................................................................................................................................58 
10.3.3. 
Unscheduled Visit .......................................................................................................58 
11. 
ASSESSMENT OF EFFICACY ................................................................................60 
11.1. 
Tonometry for measurement of Intraocular Pressure (IOP) (mmHg) ........................60 
11.2. 
Corneal and Conjunctival Fluorescein Staining .........................................................60 
11.3. 
Tear Film Break-Up Time ..........................................................................................60 
11.4. 
Slit lamp examination .................................................................................................61 
11.5. 
Dilated and undilated fundoscopy ..............................................................................61 
11.6. 
Use of Concomitant Artificial Tears...........................................................................61 
11.7. 
Symptom Assessment .................................................................................................61 
11.8. 
Subject global rating of treatment ...............................................................................61 
11.9. 
Quality of Life Questionnaires ...................................................................................63 
11.9.1. 
Glaucoma Quality of Life-15 ......................................................................................63 
11.10. 
Exploratory investigations ..........................................................................................63 
12. 
ASSESSMENT OF SAFETY .....................................................................................64 
12.1. 
Safety Parameters .......................................................................................................64 
12.1.1. 
Best Corrected Distance Visual Acuity (BCDVA) ....................................................64 
12.1.2. 
Slit lamp examination .................................................................................................64 
12.1.3. 
Adverse Events (AEs) .................................................................................................64 
12.1.4. 
Pregnancy Screen ........................................................................................................64 
12.2. 
Adverse Events and Other Safety Information ...........................................................64 
12.2.1. 
Definitions ..................................................................................................................64 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................64 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................65 
12.2.1.3. 
Case of Special Interest (CSI) .....................................................................................66 
12.2.1.4. 
Pregnancy Reports ......................................................................................................66 
12.2.2. 
Assessment of Adverse Events ...................................................................................66 
12.2.2.1. 
Seriousness .................................................................................................................67 
12.2.2.2. 
Causality to Study Drug or Artificial Tears ................................................................67 
12.2.3. 
Relationship to Study Procedures ...............................................................................67 


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12.2.3.1. 
Severity .......................................................................................................................68 
12.2.4. 
Expectedness ...............................................................................................................68 
12.2.5. 
Reporting of Safety Information .................................................................................68 
12.2.5.1. 
Reporting of Adverse Events ......................................................................................68 
12.2.5.2. 
Reporting of Case of Special Interest and Pregnancy ................................................69 
12.2.5.3. 
Expedited reporting ....................................................................................................69 
12.2.5.4. 
Follow-up of Adverse Events .....................................................................................70 
12.2.6. 
Documentation of Safety Information ........................................................................70 
13. 
STATISTICS ..............................................................................................................71 
13.1. 
General Considerations ...............................................................................................71 
13.1.1. 
Sample Size ................................................................................................................71 
13.1.2. 
Study Eye ....................................................................................................................71 
13.1.3. 
Multiple Comparisons/Multiplicity ............................................................................71 
13.2. 
Analysis Populations ..................................................................................................72 
13.3. 
Analysis of Demographics and Baseline Characteristics ...........................................73 
13.4. 
Efficacy analyses ........................................................................................................73 
13.4.1. 
Analysis of Primary Efficacy Endpoint ......................................................................73 
13.4.2. 
Analysis of Secondary Efficacy Endpoints ................................................................74 
13.4.2.1. 
Analysis of the Key Secondary Endpoints .................................................................74 
13.4.2.2. 
Analysis of the Other Secondary Endpoints ...............................................................75 
13.5. 
Analysis of Safety and Tolerability Endpoints ...........................................................76 
13.5.1. 
Adverse Events ...........................................................................................................76 
13.5.2. 
Other Safety Assessments ...........................................................................................76 
13.6. 
Interim Analysis ..........................................................................................................76 
13.7. 
Handling of Missing Values .......................................................................................76 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................78 
14.1. 
Study Monitoring ........................................................................................................78 
14.2. 
Audits and Inspections ................................................................................................78 
14.3. 
Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) .................79 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................80 
16. 
ETHICS ......................................................................................................................81 


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16.1. 
Ethics Review .............................................................................................................81 
16.2. 
Ethical Conduct of the Study ......................................................................................81 
16.3. 
Written Informed Consent ..........................................................................................81 
17. 
DATA HANDLING AND RECORD KEEPING ......................................................82 
17.1. 
Inspection of Records .................................................................................................82 
17.2. 
Retention of Records ..................................................................................................82 
17.3. 
Source Documents ......................................................................................................82 
17.4. 
Data Collection ...........................................................................................................83 
18. 
PUBLICATION POLICY ..........................................................................................84 
19. 
LIST OF REFERENCES ............................................................................................85 
20. 
APPENDICES ............................................................................................................89 
Appendix A-I  Symptom Assessments........................................................................................89 
Appendix A-II  Slit lamp examination ........................................................................................90 
Appendix A-III  Corneal and Conjunctival Fluorescein Staining ...............................................93 
Appendix A-IV  Intraocular Pressure measurement ...................................................................94 
Appendix A-V  Glaucoma Quality of Life-15 ............................................................................96 
Appendix A-VI  Dilated fundoscopy ..........................................................................................97 
Appendix B Responsibilities of the Investigator.........................................................................98 
Appendix C Elements of the Patient Informed Consent ...........................................................100 
Appendix D Investigator Consent to Use of Personal Information ..........................................102 
Appendix E Declaration of Helsinki .........................................................................................103 
Appendix F - Protocol Amendment 01 Modification Summary ...............................................108 
Adverse Events ............................................................................................................................131 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................22 
Table 3: 
Study Design and Schedule of Assessments ..............................................................51 
Table 4:  Protocol 0130A01SA, Amendment 01 Modifications..................................................108 
 


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LIST OF FIGURE(S) 
Figure 1: 
Study Design and Schedule of Assessments ..............................................................35 
 
  


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
API 
Active Pharmaceutical Ingredient 
AR 
Adverse Reaction 
AT  
Artificial Tears 
BAK 
Benzalkonium Chloride 
BCDVA 
Best Corrected Distance Visual Acuity 
C/D 
Cup-to-Disc ratio 
CKC 
Cetalkonium Chloride 
CFS 
Corneal Fluorescein Staining 
CHMP 
Committee for Medicinal Products for Human Use 
CRO 
Contract Research Organization 
CSI 
Case of Special Interest 
DED 
Dry Eye Disease 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FP 
Prostaglandin F 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practices 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INN 
International Nonproprietary Name 
IOP 
Intraocular Pressure 
IOP-L drug 
Intraocular Pressure Lowering drug 
IWRS 
Interactive Web Response System 
LASEK 
Laser Epithelial Keratomileusis 
LASIK 
Laser in Situ Keratomileusis 


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Abbreviation or Specialist Term 
Explanation 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MCT 
Medium Chain Triglycerides 
MedDRA 
Medical Dictionary for Regulatory Affairs 
MMRM 
Mixed Model of Repeated Measures 
OHT 
Ocular Hypertension 
OSD 
Ocular Surface Disease 
OSDI 
Ocular Surface Disease Index  
PI 
Principal Investigator 
The investigator who leads the study conduct at an 
individual study center.  Every study center has a principal 
investigator. 
POAG 
Primary open-angle glaucoma 
PRK 
Photorefractive Keratectomy 
QD 
Quaque Die 
QOL 
Quality of Life 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
SV 
Safety Vigilance 
TFBUT 
Tear Film Breakup Time 
TEAE 
Treatment Emergent Adverse Event 
VA 
Visual Acuity 
TFLL 
Tear Film Lipid Layer 
WHO-DRUG 
World Health Organization Drug 


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4. 
INTRODUCTION 
Glaucoma and IOP 
Glaucoma is a chronic degenerative optic neuropathy that can be distinguished from most other 
forms of acquired optic neuropathy by the characteristic appearance of the optic nerve. Glaucoma 
is the second leading cause of blindness in Europe (EGS, 2017 (1)). In most Western countries, 
glaucoma diagnosis is often made late (Martus, 2005 (2)); approximately half of patients with 
manifest glaucoma are undiagnosed (Tielsch, 1991; Mitchell, 1996; Quigley, 2003 (3-5)). 
In glaucoma, the neuroretinal rim of the optic nerve becomes progressively thinner, thereby 
enlarging the optic-nerve cup. Glaucoma encompasses a group of diseases and is classified by the 
appearance of the iridocorneal angle (anterior-segment variations) that can elevate intraocular 
pressure (Kwon, 2009 (6)). There are open-angle, closed-angle, and developmental categories 
which are further divided into primary and secondary types. Primary open-angle glaucoma 
(POAG) is the most common type in western countries. POAG is a chronic optic neuropathy which 
occurs with an open angle in the absence of any explanatory causes. While there is no standard 
definition, current criteria require the presence of visual field and optic disc damage. OAG can 
occur at any level of intraocular pressure (IOP); with or without elevated IOP; the latter is 
sometimes called normal-tension glaucoma (Leske, 2007; Kwon, 2009 (6, 7)). However elevated 
IOP is the main risk factor for OAG development and reduction of IOP has been demonstrated to 
protect against further damage to the optic nerve, even in patients with normal tension glaucoma. 
Other risk factors of POAG than older age are black race, elevated IOP, family history of POAG, 
myopia or vascular factors (Kwon, 2009 (6)). 
Up to 10% of people over 40 years of age have IOPs above 21 mmHg (normal range 10 to 21 
mmHg); those who have such high pressures but no optic-nerve damage are considered to have 
ocular hypertension. In medical practice, patients who have ocular hypertension should be 
periodically examined (optic nerve, visual fields) to determine whether there is evidence of a 
progressive damage which would indicate the need to start with treatment. However, a high IOP 
without optic-nerve damage, in some cases (e.g. additional risk factors for glaucoma) may be 
treated. 
Glaucoma and ocular surface disease 
Glaucoma and ocular surface disease (OSD) signs and symptoms commonly occur together, and 
this overlap suggests an association between the two diseases. It is estimated that 50% to 60% of 
glaucoma patients have symptoms of OSD, eg. keratitis, conjunctivitis and lid disease (Leung, 
2008; Fechtner, 2010 (8, 9)). Abnormal tear film break-up time (TFBUT) with elevated Ocular 
Surface Disease Index (OSDI) and lissamine green scores were frequent in glaucoma patients 
when compared with controls (Saade, 2015 (10)). OSD has been found to be aggravated by the use 
of preserved topical intraocular pressure (IOP) lowering drugs (Pisella et al, 2002; Baudouin, 2010 
(11, 12)), and to play an important role in patient satisfaction and compliance (Lemij, 2015 (13)). 
In addition, Batra and collaborators recently demonstrated that OSD management resulted in 


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improved IOP control, suggesting that improving the ocular surface condition may help in the 
control of IOP (Batra, 2014 (14)). 
Management of Glaucoma  
The current therapeutic approach in open angle glaucoma is lowering IOP by pharmacological 
means, surgery, micro-invasive surgery, or with laser therapy to preserve visual function (Conlon 
et al, 2016; The glaucoma laser trial (GLT), 1995 (15, 16)). It is generally accepted that 
pharmacological treatments should be the first step, and the initial target IOP for each patient 
should be chosen individually according to the current amount of optic damage and the pressure 
at which the damage occurred, and that  the target IOP will be further adjusted according to the 
disease progression in subsequent examinations of visual field. Although different clinical aspects 
will guide the choice of the target initial pressure, it is common to pursue a decrease in the IOP 
between 20% and 40% depending on the degree of associated damage. Once the patient has 
achieved a “safe” IOP at which the disease does not progress, additional lowering of the IOP would 
provide marginal benefit entailing a higher risk of adverse reactions. 
The common goal among the various therapies is to lower the IOP to prevent loss of visual fields 
from excessive pressure on the optic nerve. The IOP level remains the only major glaucoma risk 
factor known to be modifiable. For that reason, there has been long-standing interest in the 
potential of IOP-lowering treatment to decrease OAG risk. Several clinical trials have 
demonstrated the effectiveness of lowering IOP to reduce visual field loss, at the various stages of 
the disease whether of the ‘high pressure’ or ‘’normal pressure’ variety as well as reducing the 
conversion of OHT to POAG (EGS, 2017b (17)). 
Several major classes of therapeutic agents are used in the treatment of glaucoma (EGS, 2017b 
(17)). IOP-L drugs may act in four ways: increasing outflow through the trabecular meshwork; 
increasing uveoscleral outflow; decreasing episcleral venous pressure; and decreasing aqueous 
humor production. Until today, the mechanism of action of IOP-L drugs consists of either 
decreasing aqueous fluid production in the ciliary epithelium, improving aqueous outflow via the 
trabecular meshwork (responsible for 80% of normal outflow) or increasing the uveoscleral route 
(20%), or a combination of both (Parikh, 2008 (18)). Recently, a new therapeutic class, the rho 
kinase and norepinephrine transporter inhibitor (netarsudil), has been developed. It increases the 
outflow from the trabecular meshwork, and may also lower episcleral venous pressure (Lin, 2018 
(19)). In 2018, netarsudil ophthalmic solution was approved by the FDA (Choy, 2018 (20)). 
There are thus five classes of topical antiglaucoma drugs administered as first therapy:  
 Prostaglandin analogues (including prostamins) that increase uveoscleral outflow 
 Beta-receptors agonists (non-selective beta-blockers or selective beta-1-blockers) that 
decrease aqueous production 
 Carbonic anhydrase inhibitors (topical or systemic) that decrease aqueous production 
 Alpha-2 selective adrenergic agonists that decrease aqueous production, and are 
associated with an increase in uveoscleral outflow for brimonidine 


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 Rho kinase and norepinephrine transporter inhibitors which exhibit additive  effects with 
latanoprost. 
Prostaglandin treatment has been shown to provide patients with the highest reduction of IOP 
followed by non-selective b-blockers, alpha-adrenergic agonists, selective b-blockers and at last 
topical carbonic anhydrase inhibitors (van der Valk, 2005 (22)). A recent study showed longer 
visual field preservation in patients with POAG treated with latanoprost compared to those treated 
with placebo (Garway-Health, 2015(21)). Medical treatment is initiated with a topical ophthalmic 
drug (eye drops) and if necessary, a second topical drug is added (EGS, 2017b (17)). 
 
4.1. 
Background on DE-130A 
Santen is currently developing the product DE-130A (formerly NOVA21027 of Novagali Pharma 
today part of SANTEN) which is a preservative-free, sterile ophthalmic emulsion containing 
latanoprost 50 microg/ml intended for topical use for the treatment of elevated intraocular pressure 
in patients with open angle glaucoma and/or ocular hypertension. It is a new formulation of the 
reference IOP lowering medication, Xalatan® (latanoprost 50 microg/ml eye drops solution – 
Pfizer), which was registered in Europe first in December 1996. These two medicinal products 
mainly differ by their pharmaceutical form, Xalatan® being a BAK-preserved eye drops solution 
in a 2.5 ml dropper container while DE-130A is an unpreserved emulsion in a single-dose container. 
4.1.1. 
Background information on the product 
Latanoprost (INN) is a well-known substance, a prostaglandin-analogue isopropyl ester prodrug 
which per se is inactive, but after hydrolysis to the acid of latanoprost becomes biologically active. 
This prostanoid selective prostaglandin F (FP) receptor agonist is believed to reduce the intraocular 
pressure (IOP) by increasing the outflow of aqueous humor. Studies in animals and man suggest 
that the main mechanism of action is increased uveoscleral outflow.  
The cationic emulsions in general (Lallemand, 2012; Daull, 2014; Amrane, 2014; Robert, 2016; 
Leonardi, 2016; Baudouin, 2017 (23-28)), and of latanoprost in particular (Liang, 2009; Daull, 
2012; Daull, 2014; Daull, 2017 (24, 29-31)) were demonstrated to be safe and well tolerated by 
the ocular surface in animal models and patients. 
4.1.2. 
Non-clinical development 
Regarding the active pharmaceutical ingredient (API) used in DE-130A, the ocular as well as 
systemic toxicity of latanoprost has been investigated in several animal species. In animal studies, 
latanoprost has not been found to have sensitising properties.  
In chronic ocular toxicity studies, increased palpebral fissure has been reported at latanoprost 6 
µg/eye/day, this reversible effect has not been seen in humans. Latanoprost was found negative in 
reverse mutation tests in bacteria, gene mutation in mouse lymphoma and mouse micronucleus 
test. Chromosome aberrations were observed in vitro with human lymphocytes, and this indicates 


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that it is a class effect. Latanoprost has not been found to have any effect on male or female fertility 
in animal studies. No teratogenic potential has been detected with latanoprost. 
Regarding the vehicle used for the drug product DE-130A, latanoprost is formulated in a cationic 
emulsion based on the Novasorb® technology (Lallemand, 2012 (23)).  
The cationic emulsion vehicles possess protective properties for tear film stabilization via its 
interactions with the tear film lipid layer (TFLL) (meibum films) of the tear (Georgiev, 2016; 
Georgiev, 2017 (32, 33)), and help in the prevention of tear film break-up via the interaction of 
cetalkonium chloride (CKC) with the polar lipids of the TFLL (Cwiklik, 2017 (34)). In addition to 
these mechanical actions, the cationic emulsion also harbour intrinsic anti-inflammatory properties 
(Daull, 2016a ; Daull, 2016b (35, 36)) that help in the management of ocular surface inflammation, 
often present on the ocular surface of glaucoma patients, and wound healing properties (Liang, 
2009 (29)). Indeed, latanoprost formulated in cationic emulsion is safe (Daull, 2012 (30)) and 
appears a promising formulation for the management of ocular hypertension and ocular surface 
dryness and subclinical inflammation (Daull, 2017 (31)). 
Furthermore, when compared to either saline or anionic emulsions, submicron cationic emulsions 
have been shown to optimize ophthalmic topical drug delivery after instillation of one single drop 
(Tamilvanan, 2004; Calvo, 1996; Sahin, 2008; Tunc, 2006 (37-40)). 
The non-clinical data generated by Santen during DE-130A development (pharmacodynamics, 
pharmacokinetic and local tolerance) are detailed in the Investigator’s brochure.  DE-130A and 
Xalatan® share a similar pharmacodynamic profile (Study PCS09B001 – non-GLP). Both 
products have efficiently reduced high IOP in monkey glaucomatous eyes.  
The pharmacokinetic and toxicokinetic profiles of DE-130A (local biodistribution and systemic 
exposition) were characterized and compared to the one obtained with Xalatan®. DE-130A has a 
PK profile slightly inferior at short time points when compared to Xalatan®, as reflected by its 
lower exposition (AUC). However, the concentrations observed at 4h and 6h were similar for both 
formulations, suggesting that over a 24h period following a single instillation, DE-130A and 
Xalatan® have the same PK profile from the time point 4h until 24h. Thus, except for some short 
time points DE-130A and Xalatan® are comparable. DE-130A has a slower absorption rate, which 
is compensated by a longer exposition of the emulsion onto the eye surface. The latter being 
responsible for DE-130A concentrations observed at time points 4h and after. 
The local tolerance of DE-130A was assessed on ocular surface and in the nasal mucosa, and 
compared to that of Xalatan® in rabbits (Study To458 – GLP). DE-130A was well tolerated in the 
eye and did not induce any significant changes in the nasal mucosa. The UV-LLNA study (41506 
TSS – GLP) demonstrated that cationic emulsion vehicle containing 0.005% CKC did not show 
any phototoxic or photosensitizing (photoallergic) potential. 
Taking into account the legal basis of the DE-130A dossier, Article 10(3) of Directive 
2001/83/EC, Santen is not anticipating performing any additional non-clinical studies. 


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4.1.3. 
Clinical development 
Patients with mean baseline IOP of 24-25 mmHg who were treated for 6 months with latanoprost 
one drop once daily demonstrated 6-8 mmHg reductions in intraocular pressure (Patel,1996; 
Baudouin, 2006 (41, 42)). Long-term trials (up to 5 years) have shown that latanoprost 
monotherapy provides clinically significant and sustained IOP reduction (Alm, 2004 (43)).This 
drug is probably one of the most potent IOP-lowering medications currently available and has 
become one of the most useful antiglaucoma agents.  
The cationic emulsion of latanoprost 50 microg/ml eye drops emulsion, SD (DE-130A) has been 
evaluated in two phase II clinical trials conducted by Santen.  
DE-130A was compared to Travatan Z® in subjects with glaucoma or OHT and OSD over a 3-
month treatment period, in the USA (NVG10E118). The 95% confidence interval of the difference 
between treatment groups suggests at least the non-inferiority of DE-130A versus Travatan Z® in 
lowering IOP in patients suffering from OAG or OHT. The analysis of signs and symptoms of 
OSD in these subjects also suffering from OSD showed a statistically significant treatment group 
effect for corneal fluorescein staining (CFS) in favor of DE-130A associated with greater decrease 
in artificial tears usage in the DE-130A group compared with the Travatan Z® group. The safety 
analysis demonstrated the good safety profile of DE-130A, comparable to that of Travatan Z®. 
No safety concerns were raised as a result of this study. 
The second study (NVG09E115) assessed the efficacy and safety of a 3-month DE-130A treatment 
period after a switch from Xalatan®, in IOP-controlled patients with OAG or OHT (IOP 
≤22mmHg) (BAK-preserved latanoprost treatment either in monotherapy or in non-fixed 
combination with BAK-free anti-hypertensive treatment(s) for at least one month) and OSD, in 
France. The mean IOP improvement after the switch to DE-130A , with a mean change from 
baseline of-0.6mmHg at D28  and  -0.8mmHg at D84 (Study NVG09E115 – CSR). An 
improvement in the preexisting mild to moderate signs and symptoms of OSD was observed with 
during the study. DE-130A was very well tolerated and local tolerance after instillation improved, 
in particular for Burning/Stinging which was the most impairing symptom after instillation of 
Xalatan®. 
DE-130A effectively and safely lowered IOP and significantly reduced the signs and symptoms of 
these patients with OSD, demonstrating the benefits of the cationic emulsion on the mechanisms 
underlying OSD beyond it being preservative-free. These benefits may represent an important 
improvement in overall quality of life and convenience for OHT or glaucoma patients with OSD. 
 
4.2. 
Rationale for the Proposed Study 
The current pharmacological therapeutic approach in open angle glaucoma or ocular hypertension 
is lowering IOP. Otherwise, ocular surface disease (OSD) signs and symptoms are commonly 
associated with glaucoma, as 50% to 60% of glaucoma patients present with symptoms of OSD. 
A therapy which results in both lowering IOP and improving OSD signs and symptoms may thus 
positively impact patients’ quality of life and compliance with treatment.  


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At this stage of the development of DE-130A, a comparison to the reference IOP lowering agent 
(latanoprost) in a different formulation needs to be conducted. In line with the overall development 
program and with the “Guideline on the choice of the non-inferiority margin” (Doc. Ref. 
EMEA/CPMP/EWP/2158/99), the non-inferiority study design seems appropriate to compare DE-
130A with a different latanoprost eye drop solution. Latanoprost is available as Xalatan® in 
multidose containers or as Monoprost® in single dose containers (packaging similar to DE-130A). 
Monoprost® has only showed a non-inferiority to Xalatan®, and as mentioned in the CHMP 
advise (EMA/CHMP/SAWP/797001/2017), the comparison to preservative-free Monoprost® in 
single dose containers would have led to a questionable double bridging exercise from a scientific 
perspective; even though the comparison between DE-130A and Xalatan® prevents a double-
masked study. In fact, a double-masked study comparing DE-130A with Xalatan® would have 
required a double instillation of the active product and the placebo of the other study treatment 
(which may have led to bias by modifying the contact time of the study treatment). The 
formulations of DE-130A (preservative-free ophthalmic oily emulsion of latanoprost) and of 
Xalatan® (BAK-preserved eye drops solution) are most likely to exibit significantly different 
physicochemical properties, such as viscosity or surface-tension. Furthermore the high viscosity 
of DE-130A may impact the contact time of the active compound with the ocular surface. 
In the proposed non-inferiority study, to approximate the peak and trough times, the IOP will be 
measured at 9:00 (±1 hour) am and 4:00 (±1 hour) pm, and will be used to assess the primary 
efficacy endpoint and secondary endpoints during a 3-month period with randomised investigator-
masked medication. The chosen non-inferiority margin of 1.5 mmHg is well below (Musch, 2006 
(44)) the effect of the active control (−8.6±2.6 mmHg, Rouland, 2013 (45)). In addition to the 
comparison of peak, trough, and mean diurnal IOP, the rates of different responders (defined by a 
reduction in mean IOP of ≥ 20%, ≥ 25%, and ≥ 30%, and a mean IOP < 18mm Hg) will be 
compared between treatment groups.  
Regarding the OSD, the potential positive impact of the cationic formulation of DE-130A on OSD 
signs (using TFBUT, slit lamp examination, corneal, and conjunctival fluorescein staining with 
modified Oxford scale) and symptoms (using 3-symptom assessment) will be compared with the 
effect on OSD of the BAK-preserved Xalatan®. Furthermore the quality of life impact will also 
be compared between treatment groups. 
In this context, to ascertain the efficacy and safety according to patients severity, the randomisation 
will be stratified in order to prevent to high heterogeneity between treatment groups, with two 
OSD classes (baseline CFS≤1 and ≥2, modified Oxford scale).  
Regarding the trial duration, the previous trials with DE-130A had a duration of 3 months, in 
particular DE-130A ophthalmic emulsion has demonstrated its efficacy in controlling IOP over a 
3-month treatment period after a switch from Xalatan®. Three-month treatment duration is thus 
consistent to assess the IOP reducing effect. However in order to provide long-term additional data 
on the safety and tolerability of DE-130A, a 12-month follow-up with open-label DE-130A is to 
be offered to 130 patients (whatever their randomised treatment is) who complete their Week 12 


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Visit and agree to participate in the open-label period of the study. During this safety follow-up, 
only the peak IOP will be measured in order to minimize patients’ burden. 
In order to compare patients with the most homogenous IOP baseline, the study treatment period 
will be preceded by a wash-out period of previous glaucoma medications. Regarding OSD, the use 
of artificial tears (AT) will be protocolized (i.e. ATs with main impact on OSD will be excluded 
and the use of authorized AT will be in agreement with the SmPCs) to allow a comparison between 
treatment groups. 
As a result, the planned multinational, multicenter, investigator-masked, randomised, active-
controlled phase III clinical trial (0130A01SA) aims to demonstrate the non-inferiority of DE-
130A ophthalmic emulsion (cationic emulsion of latanoprost 50 microg/ml eye drops) compared 
to BAK-preserved latanoprost 50 microg/ml eye drops ophthalmic solution (Xalatan®) instilled 
once daily to patients suffering from OAG or OHT. Secondary objectives will include the 
comparison of the efficacy between treatment groups regarding IOP and OSD, and their 
safety/tolerability over the 3-month treatment period. In a subgroup of patients eligible for 12-
month follow-up with open-label DE-130A administration, the same objectives will be assessed 
over a 15-month study period. 
4.3. 
Benefit Risk Assessment  
The patients participating in the study will benefit either from the reference product (Xalatan®) to 
treat their OAG or OHT, or from DE-130A a novel BAK-free formulation of latanoprost with 
potential impact on OSD frequently observed in patients with OAG, in addition to the expected 
IOP-lowering effect. 
After the 3-month treatment period, a 12-month safety follow-up with open-label DE-130A is to 
be offered to the first 130 patients (whatever their randomised treatment is), who complete their 
Week 12 Visit and agree to participate in the open-label period of the study, in order to provide 
them the opportunity to continue their treatment with open-label DE-130A. The supernumerary 
patients will exit the study at Week 12. 
After the study end, patients will receive the best available treatment in the investigator’s opinion 
for OAG or OHT.  
 
Furthermore, patients will benefit from a close follow-up by the investigators (at Week 4 and Week 
12) which is not the case in the usual clinical setting during the first 3 months of a new treatment 
regime, and those patients entering the 12-month study extension will benefit from biannual visits. 
The risks related to the participation in the study are the adverse events listed in the investigator’s 
brochure, the potential risk of allergy to fluorescein, and anaesthetic eye drops or artificial tears.  
In light of the points listed above the benefit risk profile is considered to be favourable. 
 


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5. 
TRIAL OBJECTIVES AND ENDPOINTS 
5.1. 
Primary Objective 
The primary objective of the study is to demonstrate that the IOP reducing effect of DE-130A 
(latanoprost 50 microg/ml preservative-free eye drops emulsion) is non-inferior to that of 
Xalatan® (latanoprost 50 microg/ml BAK-preserved eye drops solution), in patients with OAG or 
OHT at Week 12 without using any rescue medication(s). 
5.2. 
Secondary Objectives 
The secondary objectives are: 
 To compare the effect on improving OSD signs and symptoms between treatment groupsover 
3 months (Period 1). 
 To estimate the effect of DE-130A on OSD signs and symptoms improvement up to 15 
months (Periods 1 & 2). 
 To compare the efficacy on IOP reduction between treatment groups over 3 months (Period 
1). 
 To estimate the effect of DE-130A on IOP up to 15 months (Periods 1 & 2). 
 
To estimate the local ocular tolerance and systemic safety of the two treatments over 3 
months (Period 1). 
 To estimate the local ocular tolerance and systemic safety of DE-130A up to 15 months 
(Periods 1 & 2). 
5.3. 
Endpoints 
5.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in peak (9:00 am ± 1 hour) and trough 
(4:00 pm ± 1 hour) IOPs, respectively, at Week 12 between the two treatment groups in the study 
eye.  
5.3.2. 
Key Secondary Endpoints 
The key secondary endpoints are: 
 Change from baseline in CFS score in the study eye at Week 12 in patients with baseline 
CFS ≥ 1. 
 Change from baseline in OSD symptom score (average of 3 symptoms: dry eye sensation, 
blurred/poor vision and burning/stinging/itching) in the study eye at Week 12 in patients 
with baseline symptom average score >0. 
5.3.3. 
Other Secondary Efficacy Endpoints 
The other secondary efficacy endpoints are: 


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 Ocular surface disease related endpoints: 
o CFS in the study eye at Week 4 in subjects with baseline CFS ≥ 1 
o Tear film break-up time (TFBUT) in the study eye at Week 4 and Week 12 in 
subjects with baseline TFBUT ≤ 10. 
o Conjunctival hyperemia (measured by slit lamp scored using the photographic 
scale derived from McMonnies scale [1 to 6]) in the study eye at Week 4, Week 12. 
o Conjunctival fluorescein staining in the study eye at Week 4 and Week 12 in 
subjects with baseline conjunctival fluorescein staining ≥ 1. 
o Dry eye sensation symptom in the study eye at Week 4 and Week 12 in subjects 
with baseline dry eye sensation symptom in mild, moderate, or severe.  
o Blurred/poor vision symptom in the study eye at Week 4 and Week 12 in subjects 
with baseline blurred/poor vision symptom in mild, moderate, or severe.  
o Burning/stinging/itching symptom in the study eye at Week 4 and Week 12 in 
subjects with baseline burning/stinging/itching symptom in mild, moderate, or 
severe.  
o Slit lamp examination (Meibomian gland dysfunction, conjunctiva chemosis, lids 
and tear film debris) in the study eye at Week 4 and Week 12. 
o CFS in the study eye at Month 6, Month 9 and Month 15/early termination in subjects 
with baseline CFS ≥ 1. 
o Tear film break-up time (TFBUT) in the study eye at Month 6, Month 9 and Month 
15/early termination in subjects with baseline TFBUT ≤ 10. 
o Conjunctival hyperemia (measured by slit lamp scored using the photographic 
scale derived from McMonnies scale [1 to 6]) in the study eye at Month 6, Month 9 
and Month 15/early termination.  
o Conjunctival fluorescein staining in the study eye at Month 6, Month 9 and Month 
15/early termination in subjects with baseline conjunctival fluorescein staining ≥ 1. 
o Dry eye sensation symptom in the study eye at Month 6, Month 9 and Month 
15/early termination in subjects with baseline dry eye sensation symptom in mild, 
moderate, or severe.  
o Blurred/poor vision symptom in the study eye at Month 6, Month 9 and Month 
15/early termination in subjects with baseline blurred/poor vision symptom in mild, 
moderate, or severe. 
o Burning/stinging/itching symptom in the study eye at Month 6, Month 9 and Month 
15/early termination in subjects with baseline burning/stinging/itching symptom in 
mild, moderate, or severe.  
o Slit lamp examination (Meibomian gland dysfunction, conjunctiva chemosis, lids 
and tear film debris) in the study eye at Month 6, Month 9 and Month 15/early 
termination. 
 IOP related endpoints: 
o Change from baseline in mean diurnal IOP in the study eye  at Week 12 


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o Change from baseline in peak, trough, and mean diurnal IOPs in the study eye at 
Week 4 
o Peak, trough and mean diurnal IOP response in the study eye at Week 4 and Week 
12: 
▪ IOP 20% response (reduction in mean IOP of ≥ 20% from Baseline 
at the specified follow-up visit)  
▪ IOP 25% response (reduction in mean IOP of ≥ 25% from Baseline 
at the specified follow-up visit)  
▪ IOP 30% response (reduction in mean IOP of ≥ 30% from Baseline 
at the specified follow-up visit)  
▪ IOP < 18 mmHg response (mean IOP < 18 mmHg at the specified 
follow-up visit) 
o Morning (9:00 am ± 1 hour) IOP in the study eye of patients treated with DE-130A 
enrolled in Period 2 at Month 6, Month 9, Month 15/early termination (Period 2) 
and change from baseline at each Period 2 visit. 
 Subject global rating of treatment at Month 15/early termination and  Week 12.  
 Quality of life (Glaucoma Quality of Life-15) scores at Baseline visit, Week 12, and Month 
15/early termination visits. 
5.3.4. 
Safety and Tolerability Endpoints 
In the Safety population, at all visits and for each treatment (Period 1) and for the Open-Label 
population for DE-130A at all visits (Period 2 and Periods 1 & 2 combined), safety and tolerability 
endpoints are: 
• 
The incidence and severity of ocular and systemic adverse events    
• 
Best-corrected distance visual acuity (BCDVA) 
• 
Slit lamp examination (lashes,anterior chamber and lens) 
• 
Dilated and undilated (cup-to-disc ratio) fundoscopy 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
The proposed 3-month phase III study is a prospective, interventional, multinational, multicentre 
investigator-masked, randomised, active-controlled trial to demonstrate the non-inferior IOP 
reducing effect of DE-130A (latanoprost 50 microg/ml preservative-free eye drops emulsion) 
compared to Xalatan® (latanoprost 50 microg/ml BAK-preserved eye drops emulsion) over a 12 
weeks treatment period (Period 1) in patients with OAG or OHT. In addition, after Week 12, a 12-
month follow-up with open-label DE-130A in a subgroup of patients (n=130) will estimate the 
long-term safety and tolerance and explore the long-term efficacy of DE-130A (Period 2). This 
Period 2 will be open in some countries only. 
After a wash-out phase (5 days to 6 weeks) depending on previous IOP lowering medications 
patients will enter: 
• 
A investigator-masked randomised 12-week treatment period (Period 1, DE-130A and 
Xalatan® groups randomised in 1:1 ratio),  
• 
Followed by a 12-month open-label follow-up treatment period (Period 2, open-label DE-
130A once daily) only for the first 130 patients who complete the Week 12 visit and agree 
to participate in the open-label period of the study  
The study duration (including the wash-out period) will be up to 17 months, and patients will 
attend up to 6 scheduled visits after Screening visit (Table 3). 
In order to assess the primary endpoint, patients will be randomly (1:1) allocated to either DE-
130A or Xalatan® once daily in the evening for Period 1 (Figure 1). Furthermore, in order to 
minimize the effect of baseline ocular surface disease severity, the randomisation will be stratified 
by baseline CFS scores (CFS ≤ 1 vs. CFS ≥ 2, modified Oxford scale). 
 
 
 
 
 
 
 
 
 
 
 


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Figure 1: 
Study Design and Schedule of Assessments 
 
 
IOP-L drug: intraocular pressure lowering drug  
Notes:  
* Start of the open-label DE-130A 12-month safety follow-up for the first 130 patients who complete their Week 12 visit and 
agree to participate in the open-label period of the study. 
** End of study for patients who do not participate in the open-label period of the study. 
*** Brinzolamide will be stopped 5 days before randomisation (6 to 7 days if over the weekend). At Day 1, if IOP is <22 mmHg, 
the wash-out period can be extended and the IOP should be re-assessed two to three days after the first measurement. If the IOP 
is still < 22 mmHg at the second measurement, a third assessment should be performed two to three days after the second 
measurement. If the IOP is still < 22 mmHg at the third  measurement, the patient cannot be randomized in the study. 
 
Study visit schedule and assessments are summarized in Table 3. 
 Wash-out Phase  
After the signing of the informed consent and upon completion of the Screening Visit, all eligible 
study participants will undergo a wash-out phase. 
Prior therapies for OAG or IOP must be discontinued during a wash-out phase of at least 5 days 
and up to 6 weeks (according to the IOP lowering medications currently used at the Screening 
Visit). Washout periods should be as follows: 
• 
Prostaglandin analogs  = 4 weeks 
• 
Topical beta blockers ≥ 3 weeks and ≤ 4 weeks 
• 
Topical carbonic anhydrase inhibitors  ≥ 5 days and ≤ 4 weeks 
• 
All other IOP lowering medication ≥ 2 weeks and ≤ 4 weeks 
During this wash-out period, topical IOP-lowering medication will be replaced by brinzolamide* 
(Azopt®) one drop twice daily. Then brinzolamide will be stopped 5 days (6 to 7 days if over the 
weekend) before randomisation.  


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*Patients already receiving brinzolamide prior to the Screening Visit will have to stop their 
treatment for a 5-day washout phase before randomisation (without needing to receive again the 
brinzolamide provided by the Sponsor). 
Five days before the Baseline Visit, brinzolamide will end (5-day period without IOP lowering 
medication) as the purpose of the wash-out phase is to select patients for study inclusion with a 
post-washout peak IOP ≥ 22 mmHg and ≤ 32 mmHg (defined as the Baseline Visit [Day 1] mean 
IOP at 9:00 am [±1 hour], see Appendix A-IV) in at least one eye. At baseline, if IOP is <22 
mmHg, the wash-out period can be extended and the IOP should be re-assessed two to three days 
after the first measurement. If the IOP is still < 22 mmHg at the second measurement, a third 
assessment should be performed two to three days after the second measurement. If the IOP is still 
< 22 mmHg at the third  measurement, the patient cannot be randomized in the study.  
Brinzolamide will be provided by the Sponsor. During the wash-out phase protocol-authorised 
artificial tears (AT, see Section 8.2) are allowed but within the SmPC recommendations. 
After the 5 days (6 to 7 days if over the weekend) without any IOP-lowering medication at the end 
of the wash-out phase, patients will undergo the Baseline Visit (Day 1). Patients who meet the 
inclusion criteria for IOP ≥ 22 mmHg and ≤ 32 mmHg [defined by a mean IOP at 9:00 am (±1 
hour)] in at least one eye will be randomised in 1:1 ratio to either DE-130A or Xalatan® (one drop 
once daily in the evening) for Period 1 of the study. Patients not fulfilling the inclusion criteria 
following the wash-out phase will be withdrawn from the study without having received the study 
medication, and they will start the best treatment for their condition according to their 
ophthalmologist’s opinion.  
Eligible patients will thus enter the Study Treatment Periods. 
 Study Treatment Period 1  
During Baseline Visit (Day 1), patients will be instructed to instil one drop of the investigator-
masked study treatment once daily in the affected eye(s) (unilateral or bilateral OAG/OHT), and 
they will be scheduled for 2 additional study visits [Week 4 (± 3 days), Week 12 (± 3 days)] to 
assess the peak and trough IOPs [at 9:00 am (±1 hour) and 4:00 pm (±1 hour), respectively].  
The following other assessments will be performed prior to the morning (9:00 am ±1 hour) IOP 
measurement: 
• 
Evaluation of OSD signs [corneal and conjunctival fluorescein staining (scored with 
modified Oxford Scale), tear film break-up time (TFBUT)], 
• 
Completion of quality of life questionnaires (Glaucoma Quality of Life-15),  
• 
Evaluation of ocular tolerance [including slit lamp biomicroscopy and best corrected visual 
acuity (BCVA)] and systemic safety (medical/medication update). 
• 
Assessement of the Subject Global Rating of Treatment, at Week 12 visit. 
At Week 12, after the trough IOP (4:00 pm), a dilated fundoscopy will be carried out. 
At Week 12 and early termination visit, a urine pregnancy test will be performed on all females of 
childbearing potential. 


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At Week 12, the 130 first patients who complete Period 1 and agree to the open-label follow-up 
will enter Study Treatment Period 2, while the supernumerary patients will exit the study.   
 
 
 Study Treatment Period 2  
At Week 12 visit, the eligible patients for Period 2 will start the 12-month open-label treatment 
Period 2 study: 
During Period 2, 3 additional study visits [Month 6 (±7days), Month 9 (± 7 days), and Month 15 
(± 7 days)] will be scheduled to assess the safety and tolerability of DE-130A. The morning IOP 
[at 9:00 am (±1 hour)] will be measured. 
The following other assessments will be performed prior to the IOP measurement: 
• 
Evaluation of OSD signs [corneal and conjunctival fluorescein staining (scored with 
modified Oxford Scale), tear film break-up time (TFBUT)], 
• 
Completion of  quality of life questionnaires (Glaucoma Quality of Life-15),  
• 
Evaluation of ocular tolerance [including slit lamp biomicroscopy and best corrected visual 
acuity (BCVA)] and systemic safety (medical/medication update). 
• 
Assessement of the Subject Global Rating of Treatment, only at Month 15 visit. 
At Month 15 Or early termination visit, women of childbearing potential will performed a urine 
pregnancy test. 
At Month 15 visit, after the morning IOP, a dilated fundoscopy will be carried out.  
In addition to the study medication, during the whole study, patients will also be allowed to use, if 
needed, unpreserved artificial tears to improve their dry eye symptoms. Patients must be instructed 
not to use artificial tears within 30 minutes before or after use of the study medication and within 
two hours before a scheduled study visit. All other concomitant medications will be recorded on 
the electronic case report form (eCRF). A change in the use of the study treatments or any use of 
topical eye drops other than the study medication, or topical medications allowed during the study 
will be considered a protocol violation. In this clinical trial, the emergence of complications and 
the safety of study treatment will be assessed at each visit up to the exit visit (Month 15 for the 
first 130 patients who completed their Week 12 Visit and willing to participate in the 12-month 
open-label period of the study and Week 12 for the supernumerative patients). 
6.2. 
Number of Subjects 
Approximately 380 patients with Open-Angle Glaucoma (OAG), or ocular hypertension (OHT) 
(190 in DE-130A group and 190 in Xalatan® group) will be randomised in this study to obtain 
173 evaluable patients per treatment group at Week 12 (assuming a dropout rate of 10%).  


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A safety follow up of 12 months is planned for the first 130 patients who will attend the Week 12 
visit and and agree to participate in the open-label period of the study. They will then be treated 
with DE-130A in an open label fashion. 
6.3. 
Dose Adjustment Criteria 
6.3.1. 
Efficacy Criteria for Adjustment or Stopping Doses 
Not applicable. 
6.3.2. 
Safety Criteria for Adjustment or Stopping Doses 
Not applicable. 
6.3.3. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses 
Not applicable. 
6.4. 
Criteria for Study Termination 
 
The sponsor reserves the right to discontinue the study conduct for any safety, ethical or 
administrative (force majeure) reason at any time.  
If the trial is prematurely terminated or suspended, the sponsor should promptly inform the 
investigators/institutions, and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension. The IECs should also be informed promptly and 
provided the reason(s) for the termination or suspension by the sponsor or by the 
investigator/institution, as specified by the applicable regulatory requirement(s). 
 
6.5. 
End of Trial  
 
End of Trial is defined as the last visit of the last subject.  
 
 
 
 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Demographic, Baseline Characteristics, and Medical History 
At Screening visit, the information to be obtained will include demographic (age, sex, 
contraceptive status, race, ethnicity, smoking status) and baseline disease characteristics (OAG, 
OHT, and OSD history and characteristics).  
Medical history to be obtained will include whether the patient has any significant conditions or 
diseases relevant to the condition/disease under study that stopped at or prior to the signing of the 
informed consent. Ongoing conditions are considered concurrent medical conditions.  
Medication history information to be obtained includes any ophthalmic medication within 1 year 
prior to signing of the informed consent and any other medication stopped at or within 3 months 
prior to signing of the informed consent. 
 
7.2. 
Subject Inclusion Criteria 
Patient eligibility is determined according to the following inclusion criteria: 
1. Male or female, 18 years of age or older 
2. The patient has signed and dated a written informed consent form and any required 
privacy authorization prior to the conduct of any study procedures.  
3. Diagnosis of OAG (primary open angle glaucoma, pseudo exfoliative glaucoma, or 
pigmentary glaucoma), or OHT in eligible eye(s) currently on monotherapy. 
4. Unilateral OAG, or OHT are permissible as long as the physician does not anticipate 
significant IOP changes to the fellow eye that would require treatment during the 
duration of the study.   
5. Current treatment with monotherapy for OAG or OHT with a controlled IOP ≤ 18 
mmHg in each eye (pre-washout). 
6. Stable visual field (based on at least  two visual fields available within the last 18 
months prior to screening, including one in the last 6 months; A visual field test will 
be performed at screening if not already performed within the last 6 months prior to 
screening) in each eye. If historical visual fields are not available within the last 18 
months prior to screening, but at least two OCTs (optical coherence tomography) are 
available, including one in the last 6 months and are stable, the patient can be enrolled 
in the study if a visual field test is also performed at screening and shows no defect or 
only an early visual field loss in either eye (mean deviation lesser than -6 dB).  
7. Post-washout IOP ≥ 22 mmHg in at least one eye (defined at baseline visit [Day 1] by 
IOP measurement at both 9:00 am ± 1 hour and 4:00 pm ±1 hour). If IOP is <22 
mmHg, the wash-out period can be extended and the IOP should be re-assessed two 
to three days after the first measurement. If the IOP is still < 22 mmHg at the second 
measurement, a third assessment should be performed two to three days after the 


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second measurement. If the IOP is still < 22 mmHg at the third  measurement, the 
patient cannot be randomized in the study. 
8. Post-washout IOP ≤ 32 mmHg (defined at baseline visit [Day 1] by IOP measurement 
at both 9:00 am ±1 hour and 4:00 pm ±1 hour) in both eyes.  
9. Ability to discontinue their current topical IOP-lowering medication for the required 
washout period. Washout periods should be as follows;  
 Prostaglandin analogs  = 4 weeks 
 Topical beta blockers ≥ 3 weeks and ≤ 4 weeks 
 Topical carbonic anhydrase inhibitors  ≥ 5 days and ≤ 4 weeks 
 All other IOP lowering medication ≥ 2 weeks and ≤ 4 weeks 
10. Snellen best corrected visual acuity score of 20/100 or better in each eye  
11. Patient must be willing to discontinue wearing contact lenses during the study. 
12. Adequate health for study participation as determined by the investigator 
13. In the opinion of the investigator, the patient is capable of understanding and 
complying with protocol requirements  
14. Patient must be willing and able to undergo and return for scheduled study-related 
examinations.  
7.3. 
Subject Exclusion Criteria 
Any patient who meets any of the following criteria will not qualify for entry into the study: 
1. Any form of glaucoma other than primary open angle glaucoma, pseudo exfoliative 
glaucoma, and pigmentary glaucoma in either eye.  
2. IOP at any time point during the Screening or Baseline visits (Visits 1 or 2) of > 32 
mmHg in either eye.  
3. Current treatment for glaucoma with a fixed-combination therapy or more than one 
drug in either eye or with an oral drug within 6 months prior to screening. 
4. Corneal abnormalities that would interfere with accurate IOP readings with an 
applanation tonometer in either eye. 
5. Central corneal thickness  ≤ 480 µm or ≥ 600 µm in either eye (historical data or at 
the screening visit). 
6. Significant visual field loss (absolute defect in the 10° central point or mean deviation 
worse than -12 dB) or progressive field loss during the year before screening in 
either. 
7. Significant optic nerve abnormality, other than glaucomatous abnormalities in the 
opinion of the investigator as determined by ophthalmoscopy in either eye. 


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8. Significant changes of the optic neuropathy (e.g. increase cupping since the last 
examination, optic nerve hemorrhage) in either eye. 
9. Inability to visualize the patient’s optic nerve in either eye. 
10. Gonioscopy consistent with potential angle closure glaucoma in either eye. 
11. Patients with severe blepharitis and/or Meibomian Gland Disease (MGD). Patients 
enrolled with mild to moderate blepharitis and/or MGD should be treated as 
appropriate during the study in either eye. 
12. Use of oral or topical ophthalmic steroid within the past 14 days from screening date, 
or anticipated need for ocular steroid treatment during the study in either eye. 
13. Use of intravitreal or peribulbar injection of depot steroid or placement of an 
intravitreal steroid implant within the past 3 months from screening date in either eye. 
14. Known allergy or sensitivity to the study medications. 
15. Known hypersensitivity to sulfonamides, severe renal impairment or hyperchloraemic 
acidosis.  
16. Active  or expected ocular allergy during period 1. 
17. Any active ocular disease (e.g. uveitis, ocular infection, severe dry eye with CFS 
grade 4 or more on the modified Oxford scale) in either eye. Patients may have mild 
cataracts, age-related maculopathy or background diabetic retinopathy if, in the 
opinion of the Investigator, it would not interfere with the conduct of the study. 
18. Intraocular surgery within 6 months prior to screening in either eye. 
19. Past history of any filtering surgery for glaucoma in either eye. 
20. Refractive surgery of any type within 1 year prior to screening in either eye. 
21. Uncontrolled systemic disease of any type.  
22. Anticipated alteration in chronic therapy with or introduction of agents known to have 
a substantial effect on IOP  (e.g., alpha-adrenergic agonists, beta-adrenergic 
antagonists, calcium channel blockers, ACE inhibitors and/or angiotensin II receptor 
blockers), unless the subject and the medication dosage have been stable for three 
months prior to the screening visit and the dosage is not expected to change during 
the study. 
23. Anticipated change in dosage of or introduction of new medications for chronic 
cardiac, pulmonary or hypertensive conditions. 
24. Females who are pregnant or lactating and females of child-bearing potential who are 
not using a medically acceptable, highly effective method of birth control. 
25. Current enrolment in an investigational drug or device study or participation in such a 
study within 30 days prior to screening. 
26. History of drug or alcohol abuse. 


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27. Patient has any condition or situation that, in the Investigator’s opinion, might 
confound the results of the study, may put the patient at significant risk or might 
interfere with the patient’s ability to participate in the study. 
7.4. 
Screen Failure 
Investigators must account for all patients who sign informed consent. If the patient is found to be 
not eligible at screening or baseline visit, the investigator should complete the eCRF for all  
assessments they performed. 
The primary reason for screen failure should be recorded in the eCRF using the following 
categories: 
 
Did not meet inclusion criteria or did meet exclusion criteria. 
 
Adverse events 
Patient numbers assigned to patients who fail screening should not be reused. Re-screening is 
possible.  
 
7.5. 
Subject Withdrawal Criteria 
The primary reason for discontinuation or withdrawal of the patient from the study should be 
recorded in the electronic case report form (eCRF) using the following categories.  
1. Adverse event (AE). The patient has experienced a AE that requires early termination 
because continued participation imposes an unacceptable risk to the patient’s health or 
the patient is unwilling to continue because of a AE. Patients discontinued for drug –
related AE(s) will be followed-up after patient’s discontinuation until the event is 
resolved, stabilized or a final assessment can otherwise be done by the investigator. 
2. Protocol deviation. The discovery after administration of the first dose of study drug 
that the patient failed to meet protocol entry criteria or did not adhere to protocol 
requirements, and continued participation poses an unacceptable risk to the patient’s 
health. 
3. Lost to follow-up. The patient did not return to the clinic and attempts to contact the 
patient were unsuccessful. In case of a patient lost-to-follow-up, the investigator must 
do his/her best to contact the patient initially by phone, then by letter, and finally by 
certified mail. If no response is obtained from the patient, the investigator is 
encouraged to contact one of the patient’s relatives or his/her general physician. 
These attempts must be documented and associated documentation filed in the patient 
medical chart. 
4. Voluntary withdrawal. The patient (or patient’s legally acceptable representative) 
wishes to withdraw from the study. The reason for withdrawal, if provided, should be 
recorded in the eCRF. 


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Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be recorded (i.e., 
withdrawal due to an AE should not be recorded in the “voluntary withdrawal” 
category). 
5. Study termination. The Sponsor, IEC, or regulatory agency terminates the study. 
6. Lack of efficacy. the patient or the physician does not feel that the study medication 
has adequately relieved his/her symptoms. 
7. Pregnancy. The patient is found to be pregnant.  
Note: If the patient is found to be pregnant, the patient must be withdrawn immediately.  
8. Investigator decision due to non-compliance (to IMP, study visits or study related 
procedure). 
9. Other reason, specify. 
Note: All attempts should be made to determine the reason if Other is chosen (e.g. 
moving) and specific primary reason should be recorded in the “specify” field of the 
eCRF. 
 
7.6. 
Procedures for Discontinuation or Withdrawal of a Patient 
The investigator may terminate a patient’s study participation at any time during the study when 
the patient meets the study withdrawal criteria described in Section 7.5. Efforts should be made 
to perform all procedures scheduled for the Week 12/Month 15/Early Termination (ET) visit. 
Discontinued patients will not be replaced. 
 
7.7. 
Completed Enrolment 
The study enrolment will be considered as completed when the desired number of at least 380 
patients is randomised. Patients between the screening visit and the baseline visit at the time the 
desired number of 380 randomised patients is achieved, are eligible for inclusion if they fulfil the 
inclusion/exclusion criteria at the Baseline Visit (Day 1).  
 


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Study Drug  
8.1.1. 
DE-130A 
DE-130A 50 microg/ml eye drops emulsion, SD is formulated as sterile, preservative free, 
positively charged (cationic) oil-in-water ophthalmic emulsion using well-known excipients. It 
contains 50 micrograms of latanoprost per ml of emulsion. DE-130A is an oil-in-water emulsion, 
in which the oil droplets, containing latanoprost, are dispersed in the aqueous phase (see the 
Investigator’s Brochure). 
DE-130A contains the following excipients:   
- 
Medium Chain Triglycerides (MCT; w/w: 1.0%): the emulsion’s oily agent that 
constitutes the main droplet core component and solubilizes the drug. 
- 
Cetalkonium chloride (CKC; w/w: 0.005%): a cationic (positively charged) surfactant 
that ensures the emulsion stability by providing a positive charge to the oil droplets and 
consequently an electrostatic repulsion between droplets.  
- 
Polysorbate 80 (w/w: 0.050%) is a non-ionic surfactant and it is used to obtain stable 
emulsion.  
- 
Glycerol (w/w: 2.400%) is used to make the emulsion isotonic. Glycerol was selected as 
osmotic agent because it does not destabilize the emulsion. 
- 
Water for injections is added as a solvent  
Batch number and expiration dates of the investigational drug will be provided in the certificate 
of analysis. 
8.1.2. 
Xalatan® 
Xalatan® composition is described in its SmPC. Its active substance is latanoprost (50 
microg/ml) and excipients include sodium chloride, benzalkonium chloride (BAK, 0.02%), 
sodium dihydrogen phosphate monohydrate, anhydrous disodium phosphate, water for 
injections. 
 
8.2. 
Azopt® 
Azopt® will be provided to the patients for the wash out prior to the Day 1 visit.  
Patients already receiving brinzolamide prior to screening visit will have to stop their treatment 
for a 5-day washout before randomisation (6 to 7 days if over the weekend) without any need to 
receive again the brinzolamide provided by the Sponsor. At baseline, if IOP is <22 mmHg, the 
wash-out period can be extended and the IOP should be re-assessed two to three days after the 
first measurement. If the IOP is still < 22 mmHg at the second measurement, a third assessment 


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should be performed two to three days after the second measurement. If the IOP is still < 22 
mmHg at the third  measurement, the patient cannot be randomized in the study. 
Azopt® composition is described in its SmPC. Its active substance is brinzolamide (10mg/ml). 
 
8.3. 
Concomitant Medications/Therapies 
Concomitant therapies consist of any treatment or medication given concurrently with the study 
medication. The following concomitant medication(s)/treatment(s) are prohibited during study 
participation:  
- 
Use of any preserved artificial tears  
- 
Use of preservative free artificial tears over the SmPC recommended regimen  
- 
Use of Cationorm® 
- 
Use of any topical ocular treatments other than the study medication except 
preservative free artificial tears used according to the SmPC recommended regimen  
(but these artificial tears usage should remain stable during the course of the study).  
- 
Any refractive surgery (LASIK, LASEK, PRK, etc.) during the course of the study. 
The initiation or use during the course of the study of any treatments or procedures described above 
will be considered as a protocol deviation. 
8.4. 
Treatment Compliance 
Patient compliance will be assessed at each visit by pharmacist or person in charge of study 
delivery by questioning the patient and comparison to drug accountablity. All reported incidents 
of the lack of compliance will be recorded on the eCRF with the reasons. If a patient is persistently 
noncompliant with the study medication, the patient should be withdrawn from the study. All 
patients should be reinstructed about the dosing requirement during study visits. The authorized 
study personnel conducting the re-education must document the process in the patient source 
records. 
8.5. 
Randomisation and Masking  
At Baseline visit (Day 1), subjects who are eligible for the study will be randomly assigned (by 
the IWRS) in a 1:1 ratio to receive either DE-130A or Xalatan® for 12 weeks in a investigator-
masked fashion. The randomisation will be stratified according to the CFS score of the study eye 
at Baseline visit (CFS ≤ 1 vs. CFS ≥ 2, modified Oxford scale). A computer algorithm for random 
number generation will be used to generate the treatment assignments.  
Treatment assignments will be masked to Investigators. The investigator should try to avoid 
knowing the masked treatment. However, IN CASE OF EMERGENCY ONLY, (i.e. SERIOUS 
ADVERSE EVENT AND ONLY WHEN THIS INFORMATION INFLUENCES THE 
PATIENT'S MANAGEMENT), the investigator may unmask the patient by using IWRS, in 
order to obtain the study medication information (i.e. DE-130A or Xalatan®) to immediately start 


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the appropriate treatment [to be recorded in the source data and eCRF (electronic Case Report 
Form)]. A record will be made for the date, time and reason for breaking the code. The investigator 
should inform the Sponsor immediately after unmasking. The details of this unmasking procedure 
will be described in a separate document. Patients unmasked for the management of a SAE will be 
discontinued from the study.  
Treatment masking to the patients would be impossible due to the difference in the appearance of 
the DE-130A and Xalantan eye drops. But the patients shall not be explicitely told about the name 
of the study drug by the drug dispensing staff. Every effort will be made to keep all study team 
members involved in the study masked during the whole Period 1 study period, this shall include 
Santen personnel (except for drug supply personnel), CRO personnel (including CRAs except the 
ones in charge of accountability), and staffs at all clinical centers (except the drug dispensing 
person), etc. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drug 
Refer to section 8.1. 
9.2. 
Study Drug Packaging and Labeling 
9.2.1. 
Investigator-masked study treatment sequence of Period 1 
The investigational medical products will be supplied in investigator-masked sealed cardboard 
box for the 3-month Period 1: 
▪ DE-130A: polyethylene single-dose containers presented in sealed laminate aluminum pouch 
package (1 pouch contains 5 single-dose containers). 22 aluminum pouches (i.e. 110 single-
dose containers) will be placed together in a sealed cardboard box. Each single dose 
container is sufficient to treat both eyes. 
▪  Xalatan®: Three 2.5 ml dropper containers will be placed together in a sealed cardboard 
box. 
 
Investigational medicinal  products are labelled in accordance with GMP Annex 13 
requirements. 
Investigational medicinal products should not be labelled by site staff or by pharmacy with any 
additional label without written permission from the Sponsor and IEC. 
 
9.2.2. 
Open-label DE-130A of Period 2 
For the 130 patients entering for the 12-month safety follow-up (Period 2), DE-130A will be 
provided at Week 12, Month 6 and Month 9 visits.  
At Week 12 and Month 6 Visits, DE-130A will be supplied in polyethylene single-dose 
containers presented in sealed laminate aluminum pouch package (1 pouch contains 5 single-
dose containers: 
▪ 22 aluminum pouches (i.e. 110 single-dose containers) will be placed together in a sealed 
cardboard box (called one kit). 
At Month 9, DE-130A will also be supplied in polyethylene single-dose containers presented in 
sealed laminate aluminum pouch package (1 pouch contains 5 single-dose containers): 
▪ 44 aluminum pouches (i.e. 220 single-dose containers) of DE-130A will be dispensed to the 
patient i.e. two kits. 
Investigational medicinal products are labelled in accordance with GMP Annex 13 requirements. 


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9.3. 
Study Drug Storage 
All clinical trial material must be kept in an appropriate, limited-access, secure location until it is 
used or returned to the sponsor or designee for destruction. All study medication must be stored 
under the conditions specified on the label, and remain in the original container until dispensed. A 
daily temperature log of the drug storage area must be maintained every working day. Any 
temperature excursion of study drug should be notified to the sponsor and the supplies placed in 
quarantine before further instruction is received from the sponsor. The study medication will be 
delivered to the study centres by the clinical supplies distributor.  
The study medication, DE-130A must be stored below 30°C and it must not be frozen. After 
opening of the aluminium pouch, the single dose container should be kept in the original pouch in 
order to avoid evaporation.  The single dose container is to be used immediately after opening and 
the contents of one single dose container is sufficient for both eyes. The remaining content of the 
single dose container sould be discarded immediately after administration.  
The study medication Xalatan® must not be stored above 25°C and after opening of container 
used within four weeks. Keep the container in the outer carton box in order to protect from light. 
  Initially each centre will receive adequate supplies of study medication to cover the study 
treatment period for a pre-defined number of patients. Additional supplies will be dispatched after 
taking into account the recruitment rate of each study centre. The investigator or his/her designee 
will be responsible for correct handling and storage of the study medication during the course of 
the study.  
9.4. 
Study Drug Preparation 
Not applicable. 
9.5. 
Administration 
The investigational product of both Study Treatment Periods (investigator-masked study 
medication and open-label DE-130A) will be instilled one drop, once daily in the evening (9 pm 
±1 hour) in the conjunctival sac of the affected eye(s)  
The study medication is to be dispensed only by the investigator designee, and will be used in 
accordance with this protocol. Under no circumstances will the investigator allow the study 
products to be used other than directed by the protocol. All dispensations and returns of study 
medication have to be documented in the investigator’s file provided by the Sponsor. 
In order to ensure patient anonymity, patients will be identified by codes or other means of 
record identification. 
 
9.6. 
Study Drug Accountability and Destruction 
The Principal Investigator is responsible for ensuring that an inventory is conducted upon receipt 
of the clinical supplies. The receipt of clinical supplies should be completed, signed and returned 


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as directed by Santen (or designee). A copy must be maintained at the site for the Investigator’s 
records. The Principal Investigator will keep a current record of the inventory and dispensing of 
all study drugs. This record will be made available to CRO or Santen Monitor (or designee) for 
the purpose of accounting for all clinical supplies. Any discrepancy and/or deficiency must be 
recorded with an explanation. All supplies sent to investigator must be accounted for and in no 
case will study drugs be used in any unauthorized situation.  
It is a responsibility of the Principal Investigator to return any unused supplies to  Santen monitor 
(or designee) at the conclusion of the study.  
Subjects are instructed to return all unused Single Dose containers, pouches and cardboard box 
of DE-130A and all used and unused IMP bottles and cardboard box of Xalatan® at the next 
visit. The used SD containers should be discarded by the subject after daily drop(s) have been 
instilled. Subjects are instructed to return wash-out medication including outer cardboard box 
back to the site at Baseline visit (Day 1). 
Upon completion or earlier termination of the study the investigator will, unless otherwise agreed, 
return to the clinical supplies distributor any surplus quantities, unused single dose containers and 
used and unused bottles, of study medication. The investigator will record each quantity of study 
medication that has been damaged or is missing. 
Drug supplies will be counted and reconciled at the site before being returned to Santen or 
designee or being destroyed by the site after Sponsor written approval. 


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10. 
SCHEDULE OF OBSERVATIONS AND PROCEDURES 
The schedule for all study-related procedures and evaluations is shown in Table 3. Assessments 
should be completed at the designated visit/time point(s), and should be performed in both eyes. 
 


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Table 3: 
Study Design and Schedule of Assessments 
 
Screening 
Baseline 
Period 1 
Period 2 
End of Study Visit 
 
 
-5 days to 
Week -6 a 
Day 1 
Week 4 
(Day 29 ± 3 
days) 
Month 6 b 
(Day181 ±7days) 
Month 9 b 
(Day 271 ±7days) 
Period 1: Week 12 
(Day 85 ± 3 days) 
Period 2: Month 15 b 
(Day451± 7 days) 
Early Termination 
Unscheduled visit 
Signed Informed 
consent 
X 
 
 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
Review of 
Inclusion/Exclusion 
Criteria  
X 
X 
 
 
 
 
 
Ocular and systemic 
medical history 
X 
 
 
 
 
 
 
Previous and 
concomitant ocular and 
systemic medications 
(including ATs) 
X 
X† 
X† 
X† 
X† 
X† 
X† 
Urine pregnancy test 
(women of childbearing 
potential only) 
X 
 
 
 
 
X 
 
Unpreserved artificial 
tears usec 
X 
X† 
X† 
X† 
X† 
X† 
X† 
OSD symptoms d 
X 
X† 
X† 
X† 
X† 
X† 
X† 
Quality of life 
questionnaire  
(Glaucoma Quality of 
Life-15) e 
 
X† 
 
 
 
X† 
 


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Screening 
Baseline 
Period 1 
Period 2 
End of Study Visit 
 
 
-5 days to 
Week -6 a 
Day 1 
Week 4 
(Day 29 ± 3 
days) 
Month 6 b 
(Day181 ±7days) 
Month 9 b 
(Day 271 ±7days) 
Period 1: Week 12 
(Day 85 ± 3 days) 
Period 2: Month 15 b 
(Day451± 7 days) 
Early Termination 
Unscheduled visit 
Subject Global Rating 
of Treatment  
 
 
 
 
 
X† 
X 
Best corrected distance 
visual acuity (BCDVA) 
X 
X† 
X† 
X† 
X† 
X† 
X† 
Slit lamp examination 
X 
X† 
X† 
X† 
X† 
X† 
X† 
Ocular Surface Disease 
Evaluations (TFBUT, 
corneal and conjunctival 
fluorescein staining 
with modified Oxford 
scale) 
X 
X† 
X† 
X† 
X† 
X† 
X† 
Morning IOP f 
X 
 
 
X 
X 
X (only Period 2)  
X (only if during 
Period 2) 
Diurnal IOP (Peak and 
trough times) g 
 
X 
X 
 
 
X (only Period 1)  
X (only if during 
Period 1) 
Cup to disc ratio 
(undilated fundoscopy) 
  
X 
X 
X 
X 
 
X 
Dilated fundoscopy 
X 
 
 
 
 
X# 
 
Visual Field* 
X 
X 
 
 
X 
 
 
Adverse events (AEs) i 
 
X 
X 
X 
X 
X 
X 
Discontinuation of 
current IOP lowering 
medication 
X 
 
 
 
 
 
 


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Screening 
Baseline 
Period 1 
Period 2 
End of Study Visit 
 
 
-5 days to 
Week -6 a 
Day 1 
Week 4 
(Day 29 ± 3 
days) 
Month 6 b 
(Day181 ±7days) 
Month 9 b 
(Day 271 ±7days) 
Period 1: Week 12 
(Day 85 ± 3 days) 
Period 2: Month 15 b 
(Day451± 7 days) 
Early Termination 
Unscheduled visit 
Randomise qualified 
subjects to treatment 
 
X 
 
 
 
 
 
Dispensation of Wash-
out IOP lowering 
medication j 
X 
 
 
 
 
 
 
Collection of Wash-out 
IOP lowering 
medication j 
 
X 
 
 
 
 
 
Dispensation of 
investigator-masked 
study medication k 
 
X 
 
 
 
 
 
Dispensation of open-
label study 
medication l 
 
 
 
X 
X 
X 
 
Collection of unused 
study medication m 
 
 
 
X 
X 
X 
 
† To be performed/completed before the morning IOP time point (9:00 am ± 1 hour) 
‡ To be performed/completed after the afternoon IOP time point (4:00 pm ± 1 hour) 
# Period 1: To be performed/completed after the afternoon IOP time point (4:00 pm ± 1 hour 
  Period 2: To be performed/completed after the morning IOP time point (9:00 am ± 1 hour) 
a in agreement with the following conditions: 
- Prostaglandin analogs:  = 4 weeks 
- Topical beta blockers:  ≥ 3 weeks and ≤ 4 weeks 
- Topical carbonic anhydrase inhibitors: ≥ 5 days and ≤ 4 weeks 
- All other IOP lowering medication:  ≥ 2 weeks and ≤ 4 weeks 
 
 
* At screening if not already performed within the last 6 months prior to screening. At baseline and Month 9 for the first 130 patients who will be part on the period 2. 
b Months are of 30 days length. 
c Unpreserved artificial tears (AT) use :  average daily use of AT will be asked by the investigator. 


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d 3-symptom will be completed at the investigational site. 
e QoL questionnaires to be completed at the investigational site.  
f Must be performed at 9:00 am (all IOP measurements must be conducted within +/- 1 hour of the required time), using Goldmann applanation tonometry. 
g Must be performed at 9:00 am and 4:00 pm time points (all IOP measurements must be conducted within +/- 1 hour of the required time), using Goldmann 
applanation tonometry. 
i Record AEs if the unscheduled visit is after the first study drug administration. 
j Over the wash-out period: brinzolamide one drop twice daily. 
k EITHER one drop of DE-130A (latanoprost 50 microg/ml) OR one drop of Xalatan®(latanoprost 50 microg/ml) once daily in the evening (9 pm ± 1 hour), in 
the conjunctival sac of the affected eye(s).  
l one drop of DE-130A once daily (latanoprost 50 microg/ml) for 12 months. 
m In order to keep the investigator masked to the  study medication, the unused study medication of Period 1 wil only be collected at Week 12 visit. 


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10.1. 
Screening  
Patients will be screened for the study from 6 weeks to 5 days prior to the first dose of study 
medication, depending on the previous IOP lowering medication. Patients will be screened in 
accordance with predefined inclusion and exclusion criteria.  
Screening Visit: Day -5 to Week -6  
Procedures to be completed at Screening Visit include: 
 Sign Informed consent. 
 Inclusion/exclusion criteria review. 
 Demographic information. 
 Ocular and systemic medical history. 
 Urine pregnancy test (women of childbearing potential only). 
 Previous and concomitant ocular and systemic medications [including artificial tears (AT) 
usage]. 
 Unpreserved artificial tears (AT) average use over the previous week will be asked by the 
investigator. 
 Assess the severity of each of 3 OSD symptoms during the previous week (Appendix A-I). 
 BCDVA (in Snellen). 
 Slit lamp examination (Appendix A-II). 
 Tear break up time (TFBUT). 
 Corneal and conjunctival fluorescein staining (modified Oxford scale, Appendix A-III). 
 Intraocular Pressure measurement using the Goldmann applanation tonometry (Appendix A-IV).  
 Dilated fundoscopy, after the peak IOP (9:00 am) (Appendix A-VI). 
 Eligible patients will discontinue their IOP lowering medication and any prohibited ocular 
treatments. 
 Use of AT will be explained to patients. 
 Patients will be scheduled to return to the clinic in the delay established according to their 
previous IO lowering medication for the Baseline visit. 
Of note: A visual Field test will be performed at screening visit for patients who have not performed 
a visual field test in the past six months prior to this visit. 
10.2. 
Investigator-masked treatment Phase (Period 1) 
The visit time is to be established according to the IOP morning measurement (9:00 am +1 hour). 
All assessments should be done in the mentioned order to ensure that additional producedure 
doesn’t interfere with the results of other examinations. 
10.2.1. 
Baseline: Day 1 
 Inclusion/exclusion criteria review.  


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 Record of concomitant ocular and systemic medications. 
 Daily average of unpreserved AT use 
 Assess the severity of each of 3 OSD symptoms during the previous week 
 Quality of life questionnaires (Glaucoma Quality of Life-15, Appendix A-V). 
 Visual field for the first 130 patients who will be part of the period 2 
 BCDVA (in Snellen). 
 Slit lamp examination. 
 TFBUT. 
 Corneal and conjunctival fluorescein staining (modified Oxford scale). 
 Morning IOP (9:00 am +1 hour). 
 Afternoon IOP (4:00 pm +1 hour). 
 Cup to disc ratio (undilated fundoscopy) 
 Record adverse event 
 Collection of the brinzolamide container. 
 Verify inclusion and exclusion criteria based on evaluations just performed: 
o Patients fulfilling the inclusion / exclusion criteria will receive the study treatment for the 
next 3 months. 
o Patients not fulfilling the inclusion / exclusion criteria will be discontinued from the study 
and the patient becomes a screen failure.  
 The site will contact IWRS system - Medidata Balance, to obtain the investigator-masked 
treatment number. 
 Dispensation of investigator-masked study medication for the 3-month period. 
10.2.2. 
Week 4 (±3 days)  
 Record of concomitant ocular and systemic medications [other than artificial tear (AT) usage]. 
 Record adverse events (AEs). 
 Daily average of unpreserved AT use 
 Assess the severity of each of 3 OSD symptoms during the previous week 
 BCDVA (in Snellen). 
 Slit lamp examination. 
 TFBUT. 
 Corneal and conjunctival fluorescein staining (modified Oxford scale). 
 Morning IOP (9:00 am +1 hour). 
 Afternoon IOP (4:00 pm +1 hour). 
 Cup to disc ratio (undilated fundoscopy, after the trough IOP (4:00 pm)). 


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10.2.3. 
Week 12 (±3 days) - End of study visit of the other patients than the 130 first 
completers 
 Record of concomitant ocular and systemic medications [other than artificial tear (AT) usage]. 
 Urine pregnancy test (women of childbearing potential only). 
 Record adverse events (AEs). 
 Daily average of unpreserved AT use 
 Assess the severity of each of 3 OSD symptoms during the previous week 
 Quality of life questionnaires (Glaucoma Quality of Life-15). 
 Subject Global Rating of Treatment  
 BCDVA (in Snellen). 
 Slit lamp examination. 
 TFBUT. 
 Corneal and conjunctival fluorescein staining (modified Oxford scale). 
 Morning IOP (9:00 am +1 hour). 
 Afternoon IOP (4:00 pm +1 hour). 
 Dilated fundoscopy, after the trough IOP (4:00 pm) 
 Cup to disc ratio. 
 Collection of the study medication containers (not by investigator performing examinations)  
(unused). 
 Assessment of compliance to study medication. 
First 130 Period 1 completer patients - Patients will enter the 12-month safety follow-up 
 Dispensation of open-label DE-130A for the 3-month period. 
Period 1 supernumerative patients - Patients will exit the study 
 The investigator will prescribe the most appropriate therapy to the patients. 
 
10.3. 
Open-label DE-130A treatment Phase (Period 2) 
 
The visit time is to be established according to the IOP morning measurement (9:00 am +1 
hour). All assessments should be done in the mentioned order to ensure that additional 
producedure doesn’t interfere with the results of other examinations. 
10.3.1. 
Month 6 (± 7 days) and Month 9 (±7 days)  
 Record of concomitant ocular and systemic medications [other than artificial tear (AT) usage]. 
 Record adverse events (AEs). 
 Daily average of unpreserved AT use 


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 Assess the severity of each of 3 OSD symptoms during the previous week 
 Only at month 9: Visual field  
 BCDVA (in Snellen). 
 Slit lamp examination. 
 TFBUT. 
 Corneal and conjunctival fluorescein staining (modified Oxford scale). 
 Morning IOP (9:00 am +1 hour). 
 Cup to disc ratio (undilated fundoscopy, after the peak IOP (9:00 am)). 
 Collection of the study medication containers (unused). 
 Dispensation of open-label DE-130A for the 3-month period at M6 and 6-month period at M9. 
 Compliance with study medication 
10.3.2. 
Month 15 (±7 days) - End of study visit of the 130 first completers of Period 1 
 Record of concomitant ocular and systemic medications [other than artificial tear (AT) usage]. 
 Urine pregnancy test (women of childbearing potential only). 
 Record adverse events (AEs). 
 Daily average of unpreserved AT use 
 Assess the severity of each of 3 OSD symptoms during the previous week. 
 Quality of life questionnaires (Glaucoma Quality of Life-15). 
 Subject Global Rating of Treatment . 
 BCDVA (in Snellen). 
 Slit lamp examination.  
 TFBUT. 
 Corneal and conjunctival fluorescein staining (modified Oxford scale). 
 Morning IOP (9:00 am +1 hour). 
 Dilated fundoscopy, after the peak IOP (9:00 am) 
 Collection of the study medication containers (unused). 
 Assessment of compliance to study medication. 
 The investigator will prescribe the most appropriate therapy to the patients. 
 
10.3.3. 
Unscheduled Visit 
An Unscheduled visit will be performed if required between two scheduled visits (e.g: patient’s 
request, to check of medical events as needed, but not for routine care that is not related to the 
protocol) and the reason for such a visit will be recorded in the CRF. In this case, the investigator 


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may perform any of the following applicable study procedures and examinations as long as the 
chronological order defined below is followed. 
 Record of concomitant ocular and systemic medications [other than artificial tear (AT) usage]. 
 Record adverse events (AEs). 
 Daily average of unpreserved AT use 
 OSD symptom assessments 
 Subject Global Rating of Treatment  
 BCDVA (in Snellen) 
 Slit lamp examination. 
 Cup to disc ratio (undilated fundoscopy) , after the trough IOP (4:00 pm) if during Period 1. 
 Cup to disc ratio (undilated fundoscopy) , after the IOP (9:00 am) if during Period 2. 
 TFBUT. 
 Corneal and conjunctival fluorescein staining (modified Oxford scale). 
 Morning IOP (9:00 am +1 hour). 
 Afternoon IOP (4:00 pm +1 hour), ONLY if during Period 1. 
 Assessment of compliance to study medication. 
If necessary (e.g. to follow up an AE) the investigator may schedule further visits at his discretion. 
In case of patient’s premature study discontinuation:  
- the investigator will be asked to perform all the examinations and assessments scheduled for the 
End of Study Visit (Week 12/Month 15/Early Termination) .   
- the investigator will ensure that unused (SD container) and used and unused (IMP bottles) study 
medication for the study period has been collected from the patient by the appointed person at 
the study site (the used SD containers should be discarded by the patient after daily drop(s) have 
been instilled). 


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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Tonometry for measurement of Intraocular Pressure (IOP) (mmHg) 
IOP will be measured using Goldman applanation tonometry (one measurement), after instillation of 
one drop of oxybuprocaine 0.4% and fluorescein 2% solutions (both solutions provided by the 
Sponsor) (Appendix A-IV) . IOP will be assessed after completion of all other slit lamp examinations 
and dry eye assessments to avoid oxybuprocaine interference with the other examinations.  
Morning IOP must be performed at 9:00 am and afternoon IOP at 4:00 pm. all IOP measurements 
must be conducted within +/- 1 hour of the required time points. 
The patient and slit lamp should be adjusted so that the patient’s head is firmly positioned on the 
chin rest and against the forehead rest without leaning forward or straining.  Both eyes will be tested, 
with the right eye preceding the left eye. The same equipment must be used throughout the course of 
the study.  
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. 
 
11.2. 
Corneal and Conjunctival Fluorescein Staining  
Corneal and conjunctival fluorescein staining will be assessed immediately following the TFBUT.  
Reading will be performed between 1 and 4 minutes after fluorescein instillation for the TFBUT, to 
ensure that the dye does not diffuse into stroma blurring the discrete margin of any staining defects. 
The eye will then be examined at the slit lamp (16X magnification) using a yellow barrier filter and 
cobalt blue illumination to enhance visibility of staining.  
Staining using fluorescein (provided by the Sponsor) will be graded using the modified Oxford scale 
(7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) 
for cornea and conjunctiva separately, see Appendix A-III. On this modified scale, the score 0 
corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.  
A CFS grade of 0 represents complete corneal clearing. 
A negative change score from baseline (Period 1) and/or from Week 12 (Period 2) will indicate 
improvement. 
11.3. 
Tear Film Break-Up Time 
Tear film break-up time (TFBUT) will be measured by determining the time to tear break-up.   
The tear film break-up time (TFBUT) measurement is performed in conjunction with 
corneal/conjunctival fluorescein staining. 2 μl of non-preserved 2% sodium fluorescein is instilled 
onto the bulbar conjunctiva of each eye without inducing reflex tearing by using a micro-pipette. 


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To thoroughly mix the fluorescein with the tear film, the patient will be instructed to blink several 
times. In order to achieve maximum fluorescence, the examiner should wait approximately 30 
seconds after instillation before evaluating TFBUT. With the aid of a slit lamp at 10X magnification 
using cobalt blue illumination, the examiner will monitor the integrity of the tear film, noting the 
time it takes to form lacunae (clear spaces in the tear film) from the time that the eye is opened after 
the last blink. The TFBUT will be measured twice during the first minute after the instillation of the 
fluorescein, by using a stop watch. If the 2 readings differ by more than 2 seconds, then a third 
reading will be taken.  
The TFBUT value will be the average of the 2 or 3 measurements.  
A positive change from baseline (Period 1) and/or from Week 12 (Period 2) will indicate 
improvement. 
11.4. 
Slit lamp examination 
External ocular examination and undilated biomicroscopy will be performed using a slit lamp. The 
subject will be seated while being examined; grading of the Meibomian glands, lids, lashes, 
conjunctiva, tear film debris, anterior chamber and lens will be done according the scales in 
AppendixA-II. 
Slit lamp examination will also be used as a safety assessment (see 12.1.2).  
11.5. 
Dilated and undilated fundoscopy 
After the dilatation of the pupil with mydriatic eye drops, the fundus examination will be performed 
to assess the retina, optic nerve head, blood vessels. Cup-to-disc (C/D) ratio will be evaluated to 
assess the progression of glaucoma (Appendix A-VI).  At Baseline, Week 4, Month 6, and Month 9 
the fundoscopy will be done without dilatation. 
11.6. 
Use of Concomitant Artificial Tears 
The use of unpreserved artificial tears will be monitored over the course of the study for each patient. 
Patients will be asked about the average number of times per day artificial tears was used over the 
last week, and number of days they were not used during the week preceding the visits. 
11.7. 
Symptom Assessment 
Symptoms of ocular discomfort (unrelated to instillation of the study medication), including 
burning/stinging/itching, dry eye sensation, and blurred/poor vision will be done according to the 
scales in Appendix A-I.   
 
11.8. 
Subject global rating of treatment 
 
At Week 12 Visit (for subjects not participating in the open-label extension study) or at Month 15 
Visit (for subjects who participate in the open-label extension study), or at early termination visit, a 
staff member will ask the subject the following question during the office visit: “Please select one of 
the following 4 choices to rate your overall assessment of the effect of the glaucoma study medication 
you have been using once a day in the evening:” 


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1. Unsatisfactory; 
2. Not very satisfactory; 
3. Satisfactory; 
4. Very satisfactory. 
 
 


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11.9. 
Quality of Life Questionnaires 
11.9.1. 
Glaucoma Quality of Life-15 
The  Glaucoma Quality of Life-15 is a questionnaire developed to assess visual disability resulting 
from glaucoma. This questionnaire quantifies different psychophysical aspects of visual function and 
assess the relationship between objective measures of visual function and patients' perception of their 
vision-related quality of life (Nelson 2003). 
The Glaucoma Quality of Life-15 is self-administered and should be completed by the patient (see 
AppendixA-V). 
11.10. 
Exploratory investigations 
• 
Not applicable.  
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
12.1.1. 
Best Corrected Distance Visual Acuity (BCDVA) 
Best corrected distance VA will be measured with the patient’s best correction and recorded in 
Snellen.   
12.1.2. 
Slit lamp examination 
Slit lamp examination will be performed at each visit. Any clinically significant change in that 
occurred during the study will be reported as AEs. 
12.1.3. 
Adverse Events (AEs) 
Adverse events, including ocular AEs, ocular complications, and systemic AEs will be recorded in 
the eCRFs. Any clinically significant change in concomitant disease or new concomitant conditions 
that occurred between the Screening Visit and the Baseline Visit will be reported as AEs. 
12.1.4. 
Pregnancy Screen 
Women of childbearing potential cannot be included in the study if they are not using a medically 
acceptable, highly effective method of birth control (such as hormonal implants, injectable or oral 
contraceptives, intrauterine devices, sexual abstinence or vasectomized partner) from the Screening 
Visit throughout the conduct of the study treatment periods and up to 2 weeks after the study end. 
Sexual abstinence is defined as refraining from heterosexual intercourse during the entire study 
period and should be in line with the preferred and usual lifestyle of the subject. Post-menopausal 
women (two years without menstruation) do not need to use any method of birth control. For women 
of childbearing potential only, urine hCG pregnancy tests provided by the sponsor will be performed 
during the course of the study, and they will receive continued guidance with respect to the avoidance 
of pregnancy, as part of the Schedule of Study Procedures  
Patients must have a negative urine pregnancy test at Baseline and throughout the study.  
 
12.2. 
Adverse Events and Other Safety Information 
12.2.1. 
Definitions 
12.2.1.1. Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical investigation subject administered 
a study drug. An AE does not necessarily have a causal relationship with the study drug.  For this 
study, the study drugs are DE-130A (latanoprost 50 microg/ml eye drops emulsion) and Xalatan® 
(latanoprost 50 microg/ml eye dropssolution). An AE can be any unfavourable unintended sign 
(including for example an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of study drug which does not necessarily have to have a causal relationship with the 
study treatment.  
In general, changes in clinical safety variables will be recorded as AEs if clinically significant 
changes as judged by the investigator occur during the study. These may include, but are not limited 


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to, cases where a patient spontaneously reports a new symptom or when a change from baseline of 
clinical importance as judged by the investigator occurs. A clinically significant worsening in 
severity, intensity, or frequency of a pre-existing condition may indicate an AE.  
Worsening of findings e.g. in biomicroscopy from no findings to finding graded as moderate/severe, 
or change in grading from mild to severe, may be an indication of an AE. By investigator’s judgment, 
also milder changes can be recorded as AEs. 
An elective surgical procedure scheduled or planned prior to study entry 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 lack of efficacy of the study treatment for the condition being investigated is not considered an 
AE unless a clinically significant change in the patient’s condition is assessed by the investigator. 
Patients’ answers given to study questionnaires (or changes in these) are not reviewed as a basis for 
occurrence of AEs. However, the investigators will collect information on AEs at each subject 
contact by asking an open question on the subject’s general health. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious AE may occur during any study phase (ie, screening, baseline, treatment, washout, or 
follow-up) at any dose of the study drug, comparator or artificial tears.  Serious AEs are abbreviated 
as ‘SAEs’ in the protocol. SAE must  fulfil one or more of the following criteria: 
 Results in death 
 It is immediately life-threatening* 
 It requires in-patient hospitalization or prolongation of existing hospitalization 
 It results in persistent or significant disability or incapacity 
 Results in a congenital abnormality or birth defect 
 It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above (including sight-threatening** 
events and cancer or neoplasm of any type). 
*Herein ‘Life-threatening’ refers to an event in which the patient was at immediate risk of death at the time of event; it 
does not refer to an event which hypothetically might have caused death.  
**Similarly ‘Sight-threatening’ refers to an event in which the patient was at immediate risk of losing sight; it does not 
refer to an event which hypothetically might have caused losing of sight. 
Serious ocular adverse events include, but are not limited to the following adverse events which are 
considered to be sight-threatening and are to be reported as SAEs (medically important criteria): 
- 
Adverse Events that caused a decrease in visual acuity of >6 lines (compared with the last 
assessment of visual acuity at the last visit) 
- 
Adverse Events that caused a decrease in visual acuity to the level of Light Perception or 
worse 
- 
Adverse Events that required surgical intervention or laser to prevent permanent loss of sight 
- 
Adverse Events associated with severe intraocular inflammation (i.e., 3+ anterior chamber 
cell/flare or 3+ vitritis) 


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- 
Corneal perforation 
- 
Adverse Events that, in the opinion of the investigator,  may require medical intervention to 
prevent permanent loss of sight 
12.2.1.3. Case of Special Interest (CSI) 
The following cases are considered to be of special interest by the Sponsor: 
- 
Non-serious AEs requiring (24 h) reporting to the sponsor: 
 Corneal ulceration 
 Decrease in visual acuity of 3-6 lines (compared with the last assessment of visual 
acuity at the last visit) 
- 
Overdose of study drug 
 Administration of a quantity of a medicinal product exceeding the dose defined in the 
study protocol. 
- 
Misuse of study drug 
 Situations where the medicinal product is intentionally and inappropriately used not 
in accordance with the study protocol. 
- 
Medication error 
 Any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional or patient. 
- 
Abuse of study drug 
 Persistent or sporadic, intentional excessive use of medicinal product which is 
accompanied by harmful physical or psychological effects. 
12.2.1.4. Pregnancy Reports 
It is required that women of childbearing potential are using a medically acceptable, highly effective 
method of birth control during the study and up to 2 weeks after the study end. Any pregnancy 
occurring during the study or within 14 days of completing the study should be reported to Santen 
EMEA Safety Vigilance (SV) and the subject will be removed from the study. 
Pregnancies in partners of study subjects with paternal drug exposure must also be reported to Santen 
EMEA SV. 
12.2.2. 
Assessment of Adverse Events 
All AEs (non-serious and serious) spontaneously reported by the subject and/or in response to an 
open question from the study personnel or revealed by observation will be recorded and assessed 
during the study at the investigational site. 
Information about AEs will be collected from the signing of consent form until the end of the study. 
Even after completion of the study, the investigator shall notify Santen EMEA SV of any new SAEs 
that may be associated with the study drug. 
All non-serious AEs will be evaluated until recovery or until the last post-study visit/contact. The 
investigator must follow up subjects with a SAE with causal relationship to study treatment until it 


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has resolved, stabilized or a final assessment can otherwise be made. The same principle applies to 
all study drug -related AEs which can lead to early termination and AEs which are under special 
interest. 
The investigator will take appropriate and necessary therapeutic measures required for resolution of 
the AE. Any medication necessary for the treatment of a AE must be recorded. During the 
investigator-masked treatment period, the investigator should only unmask the treatment allocation 
if this is relevant to the safety of the subject. 
During the study, patients will also be allowed to use unpreserved artificial tears with the same dose 
regimen and frequency as before baseline. The events reported during the washout period with 
artificial tears are considered as AEs. After the first administration of the study drug, the events with 
causal relationship to the artificial tears are considered as AEs. The AEs with causal relationship to 
the artificial tears are also assessed, recorded and reported as described in the further section. 
12.2.2.1. Seriousness 
The seriousness of each AE must be assessed by the investigator according to the criteria set for 
SAEs in section 12.2.1.2. If the event does not meet the criteria of a SAE, it is assessed as non-
serious. 
12.2.2.2. Causality to Study Drug or Artificial Tears 
An investigator who is qualified in medicine must make the determination of causality to artificial 
tears for each AE during the washout period, and the causality assessment to the study drug and 
artificial tears, respectively, for AEs occurred during the treatment periods. The following categories 
shall be used:  
Related: There is a reasonable possibility that the AE may have been caused by the study drug 
or AT. 
Not related: There is no reasonable possibility that the AE may have been caused by the study 
drug or AT. 
The investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the study drug or artificial tears. If no valid reason 
exists for suggesting a relationship, then the AE should be classified as “unrelated.” If there is any 
valid reason, even if undetermined, for suspecting a possible cause-and-effect relationship between 
the study drug (or artificial tears) and the occurrence of the AE, then the AE should be considered 
“related”. 
The Sponsor should report serious adverse reactions with causal relationship to non-investigational 
medicinal product (artificial tears) to the MAH of the product (if not the Sponsor) or to the relevant 
competent authorities. 
12.2.3. 
Relationship to Study Procedures 
The relationship to study procedures (e.g., wash-out period) should be determined for AE using the 
following categories: 
Related: There is a reasonable possibility that an event may have been caused by a study 
procedure. 
Not Related: There is no reasonable possibility that an event may have been caused by a 
study procedure. 


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12.2.3.1. 
Severity 
Severity will be assessed according to the following scale: 
 Mild: awareness of sign or symptom, but easily tolerated 
 Moderate: discomfort sufficient to cause interference with normal activities 
 Severe: incapacitating, with inability to perform normal activities 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1.2. An AE of severe intensity may 
not be considered serious. 
12.2.4. 
Expectedness 
AEs will be evaluated as to whether they are expected or unexpected. The assessment is performed 
by the Sponsor and in this study it is based on reference safety information (Investigator’s Brochure)  
 Expected: An AE is expected when the nature or severity of which is consistent with the 
applicable product information. 
 Unexpected: An AE is unexpected when the nature or severity of which is not consistent with 
the applicable product information. 
12.2.5. 
Reporting of Safety Information 
12.2.5.1. Reporting of Adverse Events 
All serious and non-serious AEs including non-serious AEs considered to be of special interest 
(CSIs) by sponsor (in Section 12.2.1.3), must be reported on the adverse event electronic case report 
form (AE eCRF). In addition, SAEs and non-serious AEs, which have been considered to be CSI, 
must be reported expeditedly to the sponsor (Section 12.2.4.3). 
For each AE, the investigator will evaluate and report  
 the event term (verbatim),  
 the onset date,  
 severity,  
 location (e.g. right/left eye, both eyes, or not applicable if non ocular event),  
 causality to study drug (for AEs only) and artificial tears,  
 relationship to study procedures,  
 action taken for study drug (for AEs only),  
 seriousness,  
 outcome of event 
 the end date, and  
 whether or not it caused the patient to discontinue the study. 
The AE term should be reported in standard medical terminology when possible. 


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If known, the diagnosis (i.e., disease or syndrome) must be recorded rather than component signs 
and symptoms (e.g., record as "worsening of cataract" rather than "drop in vision"). However, other 
events that are considered unrelated to an encountered syndrome or disease should be recorded as 
individual AEs (e.g., if worsening of macular edema and worsening of panuveitis are observed at the 
same time and are clinically unrelated, each event should be recorded as an individual AE). 
12.2.5.2. 
Reporting of Case of Special Interest and Pregnancy 
Other CSIs (non-serious AEs covered in the Section 12.2.1.3) or spontaneously reported pregnancy 
(Section 12.2.1.4) in a patient or in a partner to the patient must be recorded in the source documents 
at the investigation site and reported expeditedly to Santen EMEA SV (Section 12.2.4.3). 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational product 
may have interfered with the effectiveness of a contraceptive medication. The pregnancy which 
occurs during the study or within 14 days of completing the study must be reported. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the patient was discontinued 
from the study presuming that the informed consent is obtained for this from the patient. The outcome 
(health of infant) must also be reported to the Santen EMEA SV. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should also 
be reported and handled as SAEs. Elective abortions without complications should not be handled 
as AEs. 
12.2.5.3. 
Expedited reporting 
All SAE, CSI and Pregnancy reports must be reported to Santen EMEA SV immediately but no 
later than within 24 hours of the first awareness of the event. The investigator must complete, sign 
and date the SAE (or CSI/Pregnancy) pages, verify the accuracy of the information recorded on the 
SAE (or CSI/Pregnancy) pages, and send a copy by e-mail or fax to Santen EMEA SV: 
 
Santen EMEA, Safety Vigilance (SV) 
Email to safetyEU@santen.com or 
 Phone +358 3 284 8625 
 
The Sponsor records all SAE, CSI and Pregnancy reports in the safety database of Santen. 
Additional follow-up information, if required or available, should all be sent by e-mail or faxed to 
Santen EMEA SV immediately but no later than within 24 hours of receipt and this should be 
completed on a follow-up SAE (or CSI/Pregnancy) form and placed with the original information 
and kept with the appropriate section of the eCRF and/or study file. 
The Sponsor is responsible for ongoing safety evaluation of the study drug. If there is at least a 
reasonable possibility that the event is related to the study drug and it is both serious and unexpected 
(SUSAR), the sponsor shall initiate expedited reporting according to applicable reporting 
requirements to all relevant parties, including regulatory authorities, ethics committees and 
investigators. Reporting responsibilities are described in the study specific safety management plan. 


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12.2.5.4. Follow-up of Adverse Events 
All reported AEs should be followed until resolution or until the scheduled exit visit. A Subject 
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 
 On-going CSIs (excluding medication errors or <other special situations(e.g. overdose)> 
not resulting in AEs) 
 Early termination and withdrawal from the study due to study drug 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, AE or CSI 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, faxed 
or reported in writting to the appropriate Email/fax numbers or personnel identified in section 
12.2.4.3.   
 
 
12.2.6. 
Documentation of Safety Information 
All AEs will be recorded during the study in the subject’s medicinal records and on the appropriate 
AE eCRF at the investigational site. CSIs and Pregnancies will be recorded in the source documents. 
The Sponsor records all SAEs, CSIs and Pregnancy reports in the safety database of Santen. 
 


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13. 
STATISTICS 
13.1. 
General Considerations 
Unless specified otherwise, for Period 1 analyses, efficacy measures will be summarized by planned 
treatment on the FAS population, and safety measures will be summarized by actual treatment 
received on the Safety population. For Period 2, and Periods 1 & 2 combined analyses, both efficacy 
and safety measures will be summarized for DE-130A group on the Open-Label population. 
Continuous variables will be summarized using descriptive statistics such as number of observations 
(n), mean, standard deviation, medium, minimum, and maximum.  Categorical variables will be 
tabulated using frequency (n) and percent (%).  For the variables recorded for both eyes, the 
descriptions will be given separately for the study eye and for the fellow eye for all ocular safety 
measures. All efficacy analyses will only be performed on the study eye. 
All data manipulations and descriptive summaries will be performed using SAS Version 9.4 or later.  
The ICH guideline on case report tabulations will be followed.  A Statistical Analysis Plan (SAP) 
will be written and finalized before the start of the analysis of the study data, which will present the 
details of how all the analyses will be performed. 
Unless otherwise specified, all statistical testing will be done with Type I error rate of 0.05 (2-sided). 
13.1.1. 
Sample Size 
For the primary efficacy endpoint of change from baseline in peak IOP and trough IOP, separately, 
at Week 12 visit, sample size calculation was based on data obtained from the phase II study 
(NVG10E118). 
Sample size was thus calculated assuming a mean difference in IOP change from baseline of 0 mmHg 
and a common standard deviation of 4.26 mmHg in the peak or trough IOPs, respectively, for the 
comparison between the DE-130A and the control (Xalatan®) groups. A total sample size of 
approximately 380 subjects (190 per treatment arm) will provide 90% power to demonstrate the non-
inferiority of the DE-130A group to the control group (one-sided α = 0.025) for non-inferiority 
margin of 1.5 mmHg, assuming 10% dropout rate. 
13.1.2. 
Study Eye 
Data collection will be done on both eyes, however, efficacy analyses will only be performed on the 
study eye. 
The study eye is defined as the eye that qualifies per inclusion / exclusion criteria at the Baseline 
Visit. If both eyes are eligible, the eye with the higher IOP at the Baseline Visit will be chosen. If 
both eyes have the same IOP value at Baseline, the eye with the higher CFS score at the Baseline 
Visit will be chosen. If both eyes have the same IOP and CFS values, then the right eye will be 
designated as the study eye. 
13.1.3. 
Multiple Comparisons/Multiplicity 
To control the overall type I error rate at 0.05 level, the three hypotheses testing in the primary and 
key sencondary endpoints will be performed sequentially according to hierarchical fixed sequence 
procedure below: 


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1. Hypothesis testing of non-inferiority of DE-130A to Xalatan® for the primary endpoint: 
change from baseline in peak (9:00 am ± 1 hour) and trough (4:00 pm ± 1 hour) IOPs, 
respectively, at Week 12. 
2. Hypothesis testing of superiority of DE-130A to Xalatan® for the first key secondary 
endpoint: change from baseline in CFS score at Week 12 in subjects with baseline CFS ≥ 1. 
3. Hypothesis testing of superiority of DE-130A to Xalatan® for the second key secondary 
endpoint: change from baseline in symptom score (average of 3 symptoms: dry eye sensation, 
blurred/poor vision and burning/stinging/itching) at Week 12 in subjects with baseline 
symptom average score >0. 
 
13.2. 
Analysis Populations 
The following analysis populations are considered: 
 The Full Analysis Set (FAS) population consists of all randomised subjects who received at 
least one dose of the study medication and provided at least one post-baseline IOP 
measurement at peak and trough timepoints, separately. The FAS population will be the 
analysis population for  all efficacy endpoints in Period 1 and will use treatment as 
randomised. 
 The Safety population consists of all subjects randomised in the study who received at least 
one dose of the study medication. The Safety population will be the analysis population for 
all safety analyses in Period 1 and will use treatment as actually received. 
 The Glaucoma/OHT Per-Protocol (PP) population will be a subset of the FAS subjects. It 
includes all FAS subjects without any of the major protocol deviations that could affect the 
primary efficacy endpoint. The PP population will be used for sensitivity analyses of the 
primary efficacy endpoints in Period 1 and will use treatment as randomised.  
 The Ocular Surface Disease Per-Protocol (PP) population will be a subset of the FAS 
subjects. It includes all FAS subjects without any of the major protocol deviations that could 
affect the key secondary endpoints. This population will be used for sensitivity analyses of 
the key secondary endpoints in Period 1 and will use treatment as randomised. 
 The Open-Label Population will be a subset of the FAS subjects whocomplete their Week 
12 Visit and agree to participate in the open-label period of the study, and received at least 
one dose of the study medication during the open-label period and provided at least one 
morning IOP measurement after the Week 12 Visit. This population will be the analysis 
population for the analyses of efficacy endpoints in Period 2 and for Periods 1 & 2 combined 
data and will use treatment as randomised. 
 The Open-Label Safety population will be a subset of the FAS subjects who complete their 
Week 12 Visit and agree to participate in the open-label period of the study, and received at 
least one dose of the study medication during the open-label period. The Open-Label Safety 
population will be the analysis population for all safety analyses in Period 2 and for Periods 
1 & 2 combined data and will use treatment as actually received. 
 
 


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13.3. 
Analysis of Demographics and Baseline Characteristics 
Descriptive summaries will be performed for demographic (including age, gender, race, ethnicity, 
female patients’ menopausal status) and baseline characteristics variables (including time since 
diagnosis and past surgery or laser treatment in the study eye, and smoking status).  
In addition, medical history (ocular and systemic), and prior and concomitant medication uses will 
be summarized by treatment groups for the overall FAS population, Safety population, Open-label 
population, separately. In addition, medical history (ocular and systemic) and prior and 
concomitant medication use will be summarized by treatment group for the overall FAS 
population. Prior medication is defined as any medication that was used by the patients that is 
discontinued before the Baseline Visit (Day 1).  
13.4. 
Efficacy analyses 
During period 1, if a patient takes any concomitant medications or undergoes any concomitant 
therapies listed in Section 8.2 of this protocol, IOP and/or CFS and OSD symptom scores after 
taking the medication/therapy will be censored for the primary and/or key secondary efficacy 
endpoints analyses. The endpoint(s) that will be censored depends on the medications or therapies 
taken, which will be determined by the Sponsor team during the masked data review before database 
lock.   
 IOP data will be censored after any IOP-lowering medication/therapy is taken.  
 CFS and symptom scores will be censored after any medication (including artificial tears 
change)/therapy that might have any effect on the OSD signs and symptoms.  
If it is determined that a medication or therapy could have an effect on both IOP and OSD endpoints, 
IOP, CFS and symptom scores will all be censored. 
 
13.4.1. 
Analysis of Primary Efficacy Endpoint 
The analysis of primary efficacy endpoint will be performed on the FAS population. 
The difference in change from baseline in peak and trough IOP between the DE-130A group 
and the Xalatan® group at the Week 12 Visit in the IOP study eye will be compared using a  
mixed-effects model for repeated measures (MMRM) on observed cases collected up to Week 
12 based on FAS population. A separate MMRM model will be used for IOP at peak and 
trough, respectively. The model will include treatment, visit, treatment-by-visit interaction and 
country as fixed effects, baseline IOP at the respective timepoint (peak or trough) as covariates.  
The 95% confidence intervals intervals and p-values will be reported.  
For the primary efficacy endpoint, the following hypotheses will be tested: 
 
H0: µT  – µC > Δ for at least one 
timepoint  
versus  
HA: µT  – µC ≤ Δ for both timepoints 
 
where µT and µC denote the mean change from baseline in peak or trough IOP in DE-130A and 
Xalatan® groups, respectively, and Δ denotes the non-inferiority margin of 1.5 mmHg. Non-
inferiority will be established if the upper limit of the one-sided 97.5% confidence interval is less 


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than or equal to the non-inferiority margin of 1.5 mmHg at both the peak and trough timepoints at 
Week 12. 
Sensitivity analysis of the primary efficacy endpoints will be done with the Glaucoma/OHT PP 
population.  
Because both the peak and trough IOP endpoints have to meet the non-inferiority criterion in order 
to claim non-inferiority of DE-130A as compared to Xalatan®, no multiplicity adjustment is needed 
for the primary efficacy endpoint. 
13.4.2. 
Analysis of Secondary Efficacy Endpoints 
13.4.2.1. Analysis of the Key Secondary Endpoints 
The key secondary endpoints are: 
 Change from baseline in CFS score in the study eye at Week 12 in patients with baseline 
CFS ≥ 1 
 Change from baseline in OSD symptom score (average of 3-symptom: dry eye sensation, 
blurred/poor vision and burning/stinging/itching) in the study eye at Week 12 in patients 
with baseline symptom average score >0 
 
If non-inferiority in the primary endpoint is achieved, the above two key secondary endpoints will 
be tested for superiority, sequentially according to hierarchical fixed procedure: 
1) Change from baseline in CFS score at Week 12 in subjects with baseline CFS ≥ 1 
 
The MMRM model with a similar model setting described for the analysis of the primary efficacy 
endpoint will be used to test the following hypotheses: 
H0S1: µTs1 – µCs1  = 0  
versus  
HAS1: µTs1– µCs1 ≠ 0 
where µTs1 and µCs1 denote the mean change from baseline in CFS in DE-130A and Xalatan® 
groups, respectively. 
If the hypothesis is rejected at 0.05 significance level, then the following key secondary endpoint 
will be tested. 
2) Change from baseline in symptom score (3-symptom average) at Week 12 in subjects with 
baseline symptom score >0 
The MMRM model with a similar model setting described for the analysis of the primary efficacy 
endpoint will be used to test the following hypotheses: 
H0S2: µTs2 – µCs2  = 0 
versus 
HAS2: µTs2 – µCs2 ≠ 0 
where µTs2 and µCs2 denote the mean change from baseline in symptom score (3-symptom average) 
in DE-130A and Xalatan® groups, respectively.  


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The Ocular Surface Disease PP population will be used for the sensitivity analysis of the two key 
secondary efficacy endpoints. 
13.4.2.2. Analysis of the Other Secondary Endpoints 
Ocular Surface Disease Assessments 
Change from baseline in conjunctival fluorescein staining, TFBUT, and each individual symptom 
score in the study eye at each analysis visit in Period 1 will be compared between treatment groups 
using MMRM on observed cases. More details on the model specifications will be provided in the 
SAP. 
Percentage of patients with conjunctival hyperemia (measured by slit lamp scored using the 
photographic scale derived from McMonnies scale [1 to 6)) in the study eye at each analysis visit in 
Period 1 will be compared between treatment groups using a Chi-squared test or Fisher’s Exact test 
wherever appropriate for the FAS population. 
CFS, corneal and conjunctival fluorescein staining, TFBUT, 3-symptom average and individual 
symptom score, and slit lamp examination in the study eye at each analysis visit will be 
summarized descriptively by treatment group. 
Artificial tears use during Period 1 will be summarised by treatment group as a continuous variable 
as well as by percentage of patients who use artificial tears at each analysis visit. 
Descriptive statistics will also be provided for ocular surface disease endpoints (corneal and 
conjunctival fluorescein staining, TFBUT, symptom scores [3-symptom average and individual 
symptom score]) and their change from baseline at each visit by analysis visit and treatment group 
in Period 1 only. 
For the patients participating to the safety follow-up, OSD endpoints and their change from 
baseline will be summarized for subjects within the Open-Label population by analysis visit for the 
whole study period (Periods 1 & 2) and change from Week 12 for Period 2. 
IOP Assessments 
Changes in peak, trough, and mean diurnal IOPs on the study eye will be summarized by treatment 
group at Week 4 and Week 12. 
Peak, trough, and mean diurnal IOP responses on the study eye (IOP 20%, 25%, 30% responses, and 
IOP < 18 mmHg response, defined in Section 5.3.3) will be summarized by treatment group at Week 
4 and Week 12. 
Quality of life Assessements 
Mean scores of quality of life (Glaucoma Quality of Life-15), and their change from baseline (Period 
1 and Periods 1 & 2) and change from Week 12 (Period 2) will be summarized by study period, 
analysis visit and by treatment group (Period 1), for the FAS population (Period 1), for the Open-
Label Population (Period 2, Periods 1 & 2). 
 
 
 
 


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Subjects Global Rating of Treatment 
Subjects global rating of treatment at Week 12/early termination will be summarized by treatment 
groups for the FAS population. Also, it will be summarized at Month 15/early termination for the 
Open-Label Population.  
 
13.5. 
Analysis of Safety and Tolerability Endpoints 
Safety and tolerability endpoints will be summarized for the following three time periods:  
 Period 1 (Day 1 to Week 12 Visit): for whole Safety population by treatment group  
 Period 2 (Week 12 Visit to Month 15 Visit/early termination): for all subjects who entered 
into the open-label period (Open-Label Safety population) 
 Entire study period (Day 1 to Month 15/early termination): for all subjects who entered into 
the open-label period (Open-Label Safety population).  
13.5.1. 
Adverse Events 
An adverse event is treatment-emergent (TEAE) if it occurs or worsens after the first dose of study 
treatment. A suspected adverse reaction (SAR) is any adverse event for which there is a reasonable 
possibility that the study drug, study procedure or artificial tears caused the adverse event. 
Adverse events will be coded using the MedDRA dictionary. Frequencies and percentages will be 
given as follows:  1) Overall summary; 2) by system organ class and preferred term, 3) by system 
organ class, preferred term and maximal severity, 4) by system organ class, preferred term and 
relationship to study medication and study procedure, respectively, and 5) by system organ class, 
preferred term, maximal severity, and relationship to study medication and study procedure, 
respectively.  
Separate analyses will be performed for AEs, SARs, SAEs, serious SARs, and for ocular and non-
ocular events. Ocular events will be summarized for the study eye and the fellow eye separately. 
13.5.2. 
Other Safety Assessments 
Other safety assessment parameters (e.g. slit lamp examination, dilated fundoscopy, BCDVA, and 
visual field) will be summarized by study period, analysis visit and treatment group (Period 1 only). 
They will be summarized for the study eye and the fellow eye separately. Pregnancy test results will 
be provided in a listing. 
13.6. 
Interim Analysis 
There is no planned interim analysis for this study. 
13.7. 
Handling of Missing Values 
Missing data will be handled within the MMRM model for all efficacy assessment analysed using 
this statistical model. 
No missing data on safety endpoints will be imputed. 


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For medical events including AEs, completely or partially missing onset and resolution dates will 
be imputed in a conservative fashion to be detailed in the Statistical Analysis Plan (SAP).  
Likewise, rules will be applied 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 the handling of missing data will be provided in the SAP. 
 
 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a patient into the clinical study, a representative of the 
Sponsor will visit the investigational study site to: 
 Determine the adequacy of the facilities. 
 Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Santen or its representatives.  This will be 
documented in a Clinical Study Agreement between Santen or its designee and the 
investigator. 
During the study, a monitor from Santen or representative will have regular contacts with the 
investigational site, for the following: 
 Provide information and support to the investigator(s). 
 Confirm that facilities remain acceptable. 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product accountability 
checks are being performed. 
 Perform source data verification.  This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records relevant 
to the study.  This will require direct access to all original records for each patient (e.g. clinic 
charts). 
 Record and report any protocol deviations not previously sent to Santen. 
 Confirm non-serious AEs and SAEs have been properly documented on eCRFs and confirm 
any safety information requiring expedited reporting to Santen EMEA SV (including SAEs, 
CSIs and Pregnancies) have been forwarded to Santen and those SAEs that met criteria for 
reporting have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs information 
or advice. 
14.2. 
Audits and Inspections 
Authorized representatives of Santen, a regulatory authority (national or foreign), an Independent 
Ethics Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification.  The purpose of an audit or inspection is to systematically and 
independently examine all study-related activities and documents to determine whether these 
activities were conducted, and data were recorded, analyzed, and accurately reported according to 
the protocol, Good Clinical Practice guidelines of the International Conference on Harmonization, 
and any applicable regulatory requirements.  The investigator should contact Santen immediately if 
contacted by a regulatory agency about an inspection. 
 


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14.3. 
Institutional Review Board (IRB)/ Independent Ethics Committee 
(IEC) 
A written favourable opinion of IRB or IEC (as appropriate) must be obtain prior starting the study. 
Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study including the 
patient consent form and recruitment materials must be maintained by the Investigator in the 
Investigational Site File and made available for inspection. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Santen may conduct a quality assurance audit.  Please see Section 14.2 for more details regarding 
the audit process. 
 


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be approved 
or given a favorable opinion in writing by an IRB or IEC as appropriate.  A copy of the letter 
indicating IRB/IEC approval or a favorable opinion must be available at the investigational site 
before the site can enroll any patient/subject into the study. 
Any amendment to the protocol must be reviewed by IRB/IEC in accordance with local 
requirements.  In addition, the IRB or IEC must approve all advertising used to recruit patients for 
the study.   
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB or 
IEC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice and applicable regulatory 
requirements. Please see Appendix B- “Responsibilities of the Investigator” and Appendix E- 
Declaration of Helsinki.  
16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the patient is given full and adequate oral 
and written information about the nature, purpose, possible risk and benefit of the study.  Patients 
must also be notified that they are free to discontinue from the study at any time.  The patient should 
be given the opportunity to ask questions and allowed time to consider the information provided. 
The patient’s signed and dated informed consent must be obtained before any protocol-directed 
procedures are performed. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy of 
the signed Informed Consent Form must be given to the patient. 
 


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17. 
DATA HANDLING AND RECORD KEEPING 
17.1. 
Inspection of Records 
Santen or Santen’s designee  will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study. The Investigator agrees to allow the monitor to 
inspect the drug storage area, study drug stocks, drug accountability records, subject charts and study 
source documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 
years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. In addition, ICH E6 Section 4.9.5 states that the 
study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Study Site Agreement between the investigator 
and Sponsor. If it becomes necessary for Santen or the Regulatory Authority to review any 
documentation relating to the study, the Investigator must permit access to such records. 
17.3. 
Source Documents 
The patient source documentation should include hospital reports, doctor’s/nurse’s notes, laboratory 
results, reports of special examinations, the signed consent forms, consultants letters. The 
Investigator is asked to report the following information in the patient’s medical file (source 
documents) according to Sources Data Agreement signed by the Principal Investigator of each 
Investigational site: 
- 
Mention of patient’s participation in the study, patient code and treatment number, date and 
process of signature of informed consent form 
- 
Demographic data  
- 
Past medical and surgery history 
- 
Past and recent treatments 
- 
Concomitant treatments at inclusion 
- 
Change in concomitant treatments throughout the study 
- 
Date of each study visit 
- 
Date of the final visit 
- 
Date and reason of premature withdrawal 
- 
All data related to study procedures 
- 
Any non-serious AEs, SAEs, and CSIs occurred during the time course of the study and 
study drug-associated SAEs which occurred after the completion of the study 
- 
Any pregnancy occurring during the study or within 14 days of completing the study 
- 
Any data that could be judged by the Investigator as relevant 
This list is not exhaustive. 


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17.4. 
 Data Collection 
The Principal Investigator must maintain detailed records on all subjects who provided informed 
consent. Data for screened and enrolled subjects will be entered into eCRFs, designed according to 
the protocol. 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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18. 
PUBLICATION POLICY 
The investigator is obliged to provide the Sponsor with complete test results and all data derived by 
the investigator from the study. During the study, only the Sponsor may make study information 
available to other study investigators or to regulatory agencies, except as required by law or 
regulation. Except as otherwise allowable in the clinical study site agreement, any public disclosure 
(including publicly accessible websites) related to the protocol or study results, other than study 
recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for any 
peer-reviewed publication will appropriately reflect contributions to the production and review of 
the document. All publications and presentations must be prepared in accordance with this section 
and the Master Services Agreement or equivalent agreement. In the event of any discrepancy between 
the protocol and the Master Services Agreement or equivalent agreement, the Master Services 
Agreement or equivalent agreement will prevail. 


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19. 
LIST OF REFERENCES 
 
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12. Baudouin C, Labbe A, Liang H, Pauly A, Brignole-Baudouin F. Preservatives in eyedrops: the 
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13. Lemij HG, Hoevenaars JG, van der Windt C, Baudouin C. Patient satisfaction with glaucoma 
therapy: reality or myth? Clin Ophthalmol. 2015;9:785-93. PubMed PMID: 25999687. 
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14. Batra R, Tailor R, Mohamed S. Ocular surface disease exacerbated glaucoma: optimizing the 
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15. Conlon R, Saheb H, Ahmed, II. Glaucoma treatment trends: a review. Can J Ophthalmol. 2017 
Feb;52(1):114-24. PubMed PMID: 28237137. 
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PMID: 8540545. Epub 1995/12/01. eng. 
17. European Glaucoma Society Terminology and Guidelines for Glaucoma, 4th Edition - Chapter 
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Jun;101(6):130-195. doi: 10.1136/bjophthalmol-2016-EGSguideline.003. 
18. Parikh RS, Parikh SR, Navin S, Arun E, Thomas R. Practical approach to medical 
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18417824. 
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23. Lallemand F, Daull P, Benita S, Buggage R, Garrigue JS. Successfully improving ocular drug 
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nanoemulsions for topical ophthalmic drug delivery. JPP. 2014;66(4):531-41. 
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disease - A randomised comparative study. J Fr Ophtalmol. 2014 Aug 12;37(8):589-98. 
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and safety of 0.1% cyclosporine A cationic emulsion in the treatment of severe dry eye 
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28. Baudouin C, de la Maza MS, Amrane M, Garrigue JS, Ismail D, Figueiredo FC, et al. One-
year efficacy and safety of 0.1% cyclosporine A cationic emulsion in the treatment of severe 
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29. Liang H, Baudouin C, Faure MO, Lambert G, Brignole-Baudouin F. Comparison of the ocular 
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19710954. 
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preservative-free Latanoprost cationic emulsion (Catioprost) and a BAK-preserved 
Latanoprost solution in animal models. JOPT. 2012;28(5):515-23. 
31. Daull P, Amrane M, Garrigue JS. Novasorb® Cationic Nanoemulsion and Latanoprost: the 
Ideal Combination for Glaucoma Management? Glauc Open Access [Internet]. 2017; 2(1). 
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of cationic nanoemulsions with human meibum films.  ARVO; May 1-5; Seattle 2016. 
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34. Cwiklik L, Melcrova A, Daull P, Garrigue J. Tear film break-up: A molecular level view by 
employing in silico approach.  ARVO; Baltimore 2017. 
35. Daull P, Feraille L, Elena PP, Garrigue JS. Comparison of the Anti-Inflammatory Effects of 
Artificial Tears in a Rat Model of Corneal Scraping. J Ocul Pharmacol Ther. 2016 Jan 
11;32(2):109-18. PubMed PMID: 26751507. 
36. Daull P, Guenin S, Garrigue J-S. Mechanism of action of cationic emulsions in the 
management of ocular surface inflammation and wound healing. .  ARVO; May 1-5; Seattle 
2016. 
37. Tamilvanan S. Oil-in-water lipid emulsions: implications for parenteral and ocular delivering 
systems. Prog Lipid Res. 2004 Nov;43(6):489-533. PubMed PMID: 15522762. 
38. Calvo P, Alonso MJ, Vila-Jato JL, Robinson JR. Improved ocular bioavailability of 
indomethacin by novel ocular drug carriers. J Pharm Pharmacol. 1996 Nov;48(11):1147-52. 
PubMed PMID: 8961163. 
39. Sahin A, Bozkurt B, Irkec M. Topical cyclosporine a in the treatment of superior limbic 
keratoconjunctivitis: a long-term follow-up. Cornea. 2008;27 (2):193-5. 
40. Tunc M, Erbilen E. Topical cyclosporine-a combined with mitomycin C for conjunctival and 
corneal squamous cell carcinoma. Am J Ophthalmol. 2006;142(4):673-5. 
41. Baudouin C, Rouland JF, Nordmann JP, Bron A, Pelen F. [Efficacy of first- or second-line 
latanoprost on intraocular pressure and ocular symptoms in patients with open-angle glaucoma 
or ocular hypertension]. J Fr Ophtalmol. 2006 Jun;29(6):615-24. PubMed PMID: 16885890. 
Efficacite du latanoprost, donne en premiere ou deuxieme intention, sur la pression intra-
oculaire et la symptomatologie oculaire chez des patients presentant un glaucome a angle 
ouvert ou une hypertension oculaire simple. 


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42. Patel SS, Spencer CM. Latanoprost. A review of its pharmacological properties, clinical 
efficacy and tolerability in the management of primary open-angle glaucoma and ocular 
hypertension. Drugs Aging. 1996 Nov;9(5):363-78. PubMed PMID: 8922563. 
43. Alm A, Schoenfelder J, McDermott J. A 5-year, multicenter, open-label, safety study of 
adjunctive latanoprost therapy for glaucoma. Arch Ophthalmol. 2004 Jul;122(7):957-65. 
PubMed PMID: 15249358. 
44. Musch D, Gillespie B. The state of being noninferior. Ophthalmology. 2006 Jan;113(1):1-2. 
45. Rouland JF, Traverso CE, Stalmans I, Fekih LE, Delval L, Renault D, et al. Efficacy and 
safety of preservative-free latanoprost eyedrops, compared with BAK-preserved latanoprost in 
patients with ocular hypertension or glaucoma. Br J Ophthalmol. 2013 Feb;97(2):196-200. 
PubMed PMID: 23203707. 
46. Mangione CM, Lee PP, Gutierrez PR, Spritzer K, Berry S, Hays RD, et al. Development of the 
25-item National Eye Institute Visual Function Questionnaire. Arch Ophthalmol. 2001 
Jul;119(7):1050-8. PubMed PMID: 11448327. 
47. Owen CG, Rudnicka AR, Smeeth L, Evans JR, Wormald RP, Fletcher AE. Is the NEI-VFQ-25 
a useful tool in identifying visual impairment in an elderly population? BMC Ophthalmol. 
2006;6:24. PubMed PMID: 16764714. Pubmed Central PMCID: 1523367. 
48. Orr P, Rentz AM, Margolis MK, Revicki DA, Dolan CM, Colman S, et al. Validation of the 
National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25) in age-related macular 
degeneration. Invest Ophthalmol Vis Sci. 2011 May;52(6):3354-9. PubMed PMID: 21282568. 
49. Brooks R. EuroQol: the current state of play. Health Policy. 1996 Jul;37(1):53-72. PubMed 
PMID: 10158943. 
50. Petroutsos G, Paschides CA, Kitsos G, Skopouli FN, Psilas K. [Sterile corneal ulcers in dry 
eye. Incidence and factors of occurrence]. J Fr Ophtalmol. 1992;15(2):103-5. PubMed PMID: 
1640062. Les ulceres corneens steriles de l'oeil sec. I. Frequence et facteurs de leur apparition. 
 


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20. 
APPENDICES 
Appendix A-I  Symptom Assessments  
The patient will be asked to assess 3 OSD symptoms regarding ocular discomfort unrelated to instillation : 
dry eye sensation, blurred/poor vision and burning/stinging/itching. The patient will grade each ocular 
symptom by its level of severity during the week before each visit : 
0 = Absent 
1 = Mild  
2 = Moderate  
3 = Severe  
4 = Very severe  


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Appendix A-II  
Slit lamp examination 
External ocular examination and undilated biomicroscopy will be performed using a slit lamp. 
The subject will be seated while being examined; grading of the Meibomian glands, lashes, lids, 
conjunctiva, tear film debris, anterior chamber and lens will be done according to the following 
scales: 
 
Meibomian Glands: 
0 = None (none are plugged). 
1 = Mild (1 to 2 glands are plugged). 
2 = Moderate (3 to 4 glands are plugged). 
3 = Severe (All glands are plugged). 
 
Lid and Lid Margin: 
- 
 Erythema: 
0 = None (normal). 
1 = Mild (redness localized to a small region of the lid(s) margin OR skin). 
2 = Moderate (redness of most or all lid margin OR skin). 
3 = Severe (redness of most or all lid margin AND skin). 
4 = Very severe (marketed diffuse redness of both lid margin AND skin). 
 
- 
Swelling: 
0 = None (normal). 
1 = Mild (localized to a small region of the lid). 
2 = Moderate (diffuse, most or all lid but not prominent/protruding). 
3 = Severe (diffuse, most or all lid AND prominent/protruding). 
4 = Very severe (diffuse AND prominent/protruding AND reversion of the lid). 
 


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Conjunctiva: 
- 
Erythema/hyperaemia will be scored using the photographic scale derived from Mac Monnies 
scale (1 to 6) : 
 
 
 
- 
Chemosis: 
0 = None (normal). 
1 = Mild (slight localized swelling). 
2 = Moderate (pink moderate/medium localized swelling or mild diffuse swelling). 
3 = Severe (severe diffuse swelling). 
4 = Very severe (very prominent/protruding diffuse swelling). 
Lashes 


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0 = Normal 
1 = Abnormal (specify) 
Tear Film Debris: 
0 = None (absence of debris). 
1 = Mild (presence of debris in inferior tear meniscus). 
2 = Moderate (presence of debris in inferior tear meniscus and in tear film overlying cornea). 
3 = Severe (presence of debris in inferior tear meniscus and in tear film overlying cornea. Presence 
of mucus strands in inferior fornix of on bulbar conjunctiva). 
4 = Very severe (presence of debris in inferior tear meniscus and in tear film overlying cornea. 
Presence of numerous AND/OR adherent mucus strands in inferior fornix and on bulbar 
conjunctiva or filamentary keratitis). 
 
Anterior Chamber Inflammation (Tyndall Effect) / (Slit beam= 0.3 mm wide, 1.0 mm long): 
0 = None (no Tyndall effect). 
1 = Mild (Tyndall effect barely discernible). 
2 = Moderate (Tyndall beam in the anterior chamber is moderately intense). 
3 = Severe (Tyndall beam in the anterior chamber is severely intense). 
 
Lens: 
0 = No opacification (normal lens). 
1 = Mild lens opacification. 
2 = Moderate lens opacification. 
3 = Severe lens opacification. 


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Appendix A-III  Corneal and Conjunctival Fluorescein Staining  
                                            
Modified Oxford scale 
                       (Grading of corneal and conjunctival fluorescein staining) 
 
 


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Appendix A-IV  Intraocular Pressure measurement  
 
Using the Goldmann applanation tonometry 
 
IOP will be performed at each visit.  
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.  
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 (oxybuprocaine 0.4%) one drop of 
fluorescein 2% may be instilled.  
 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. 


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 If corneal astigmatism is greater than 3.0 D, the prism is rotated so that the red 
line corresponds to the orientation of the longer axis of the elliptical applanated 
area. 
The above procedure is then repeated for the same eye, and that second measurement is also 
recorded in the subject’s source document. 
 If the two measurements differ by less than 3 mmHg, then the average of the two 
measurements becomes the recorded IOP. For example, if the two measurements 
are 22 and 23, then 22.5 is the final recorded IOP. 
 However, if the two measurements differ by 3 mmHg or more, then a third 
measurement is made, and the median of the three measurements becomes the 
recorded IOP (the median is the middle measurement after ordering the 
measurements from low to high). For example, if the three measurements are 15, 
19, and 16, then 16 is the final recorded IOP. 
The IOP in the left eye is then measured using the same technique. 
 
 
 


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Appendix A-V  
Glaucoma Quality of Life-15 
The Glaucoma Quality of Life-15 is self-administered and should be completed by the patient. 
Patient instruction: Please, circle the correct answer on the scale ranging from 1 to 5 where [1] stands for 
no difficulty, [2] for a little bit of difficulty, [3] for some difficulty, [4] for quite a lot of difficulty, and [5] 
for severe difficulty. If you do not perform any of the activities for other than visual reasons, please circle 
[0]. 
Does your vision give you any difficulty, even with glasses, with the following activities? 
 
None 
A little bit 
Some 
Quite a lot 
Severe 
Do not 
perform for 
nonvisual 
reasons 
Reading newspapers 
1 
2 
3 
4 
5 
0 
Walking after dark 
1 
2 
3 
4 
5 
0 
Seeing at night 
1 
2 
3 
4 
5 
0 
Walking on uneven 
ground 
1 
2 
3 
4 
5 
0 
Adjusting to bright 
lights 
1 
2 
3 
4 
5 
0 
Adjusting to dim 
lights 
1 
2 
3 
4 
5 
0 
Going from light to 
dark room or vice 
versa  
1 
2 
3 
4 
5 
0 
Tripping over 
objects 
1 
2 
3 
4 
5 
0 
Seeing objects 
coming from the 
side  
1 
2 
3 
4 
5 
0 
Crossing the road 
1 
2 
3 
4 
5 
0 
Walking on 
steps/stairs 
1 
2 
3 
4 
5 
0 
Bumping into 
objects 
1 
2 
3 
4 
5 
0 
Judging distance of 
foot to step/curb  
1 
2 
3 
4 
5 
0 
Finding dropped 
objects 
1 
2 
3 
4 
5 
0 
Recognizing faces 
1 
2 
3 
4 
5 
0 


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Appendix A-VI  Dilated fundoscopy 
The ophthalmoscopy (fundus) examination will be performed for each eye and graded as described 
below. The examination will be performed with pupil dilated at screening,  Week 12 and Month 
15 visits. 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 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 
 
 
 
 
 


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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the Sponsor are patient to ICH GCP and all the applicable 
local laws and regulations.  
The investigator agrees to assume the following responsibilities: 
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures; including study specific (non-routine/non-
standard panel) screening assessments are NOT performed on potential patients, prior 
to the receipt of written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are 
adequately informed of these obligations and that they are qualified to their roles. 
5. The Principal investigator is responsible for supervising any individual or party to 
whom the investigator  delegates study-related duties and functions conducted at the 
site   
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC, ICH, 
and local regulatory requirements. 
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research 
activity and all anticipated risks to patients. Make at least yearly reports on the progress 
of the study to the IRB/IEC, and issue a final report within 3 months of study 
completion. 
8. Ensure that requirements for informed consent, as outlined in, ICH and local 
regulations, are met. 
9. Obtain valid informed consent from each patient who participates in the study, and 
document the date of consent in the patient’s medical chart. Valid informed consent is 
the most current version approved by the IRB/IEC. Each informed consent form should 
contain a patient authorization section that describes the uses and disclosures of a 
patient’s personal information (including personal health information) that will take 
place in connection with the study. If an informed consent form does not include such 
a patient authorization, then the investigator must obtain a separate patient 
authorization form from each patient or the patient’s legally acceptable representative. 
10. Prepare and maintain adequate case histories of all persons entered into the study, 
including eCRFs, hospital records, laboratory results, etc, and maintain these data for 
a minimum of 2 years following notification by the sponsor that all investigations have 
been discontinued or that the regulatory authority has approved the marketing 
application. The investigator should contact and receive written approval from the 
Sponsor before disposing of any such documents. 


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11. Allow possible inspection and copying by the regulatory authority of GCP-specified 
essential documents. 
12. Maintain current records of the receipt, administration, and disposition of sponsor-
supplied drugs and return all unused sponsor-supplied drugs to the Sponsor.  
13. IMP destruction at site requires prior written approval from the Sponsor. 
14. Report adverse reactions to the Sponsor promptly. In the event of an SAE, notify the 
Sponsor within 24 hours. 


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Appendix CElements of the Patient Informed Consent 
In seeking informed consent, the following information shall be provided to each patient: 
 A statement that the study involves research. 
 An explanation of the purposes of the research. 
 The expected duration of the patient’s participation. 
 A description of the procedures to be followed, including invasive procedures. 
 The identification of any procedures that are experimental. 
 The estimated number of patients involved in the study. 
 A description of the patient’s responsibilities. 
 A description of the conduct of the study. 
 A statement describing the treatment(s) and the probability for random assignment to 
each treatment. 
 A description of the possible side effects of the treatment that the patient may receive. 
 A description of any reasonably foreseeable risks or discomforts to the patient and, 
when applicable, to an embryo, fetus, or nursing infant. 
 A description of any benefits to the patient or to others that reasonably may be expected 
from the research. When there is no intended clinical benefit to the patient, the patient 
should be made aware of this. 
 Disclosures of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient and their important potential risks and benefits. 
 A statement describing the extent to which confidentiality of records identifying the 
patient will be maintained, and a note of the possibility that regulatory agencies, 
auditor(s), IRB/IEC, and the monitor may inspect the records. By signing a written 
informed consent form, the patient or the patient’s legally acceptable representative is 
authorizing such access. 
 For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if 
injury occurs and, if so, what they consist of or where further information may be 
obtained. 
 The anticipated prorated payment(s), if any, to the patient for participating in the study. 
 The anticipated expenses, if any, to the patient for participating in the study. 
 An explanation of whom to contact for answers to pertinent questions about the 
research (investigator), patient’s rights, and IRB/IEC and whom to contact in the event 
of a research-related injury to the patient. 


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 A statement that participation is voluntary, that refusal to participate will involve no 
penalty or loss of benefits to which the patient otherwise is entitled, and that the patient 
may discontinue participation at any time without penalty or loss of benefits to which 
the patient is otherwise entitled. 
 The consequences of a patient’s decision to withdraw from the research and procedures 
for orderly termination of participation by the patient. 
 A statement that the patient or the patient’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to 
the patient’s willingness to continue participation in the study. 
 The foreseeable circumstances or reasons under which the patient’s participation in the 
study may be terminated. 
 A statement that significant new findings developed during the course of the research, 
which may relate to the subject’s willingness to continue participation, will be provided 
to the subject. 
 A written patient authorization (either contained within the informed consent form or 
provided as a separate document) describing to the patient the contemplated and 
permissible uses and disclosures of the patient’s personal information (including 
personal health information) for purposes of conducting the study. The patient 
authorization must contain the following statements regarding the uses and disclosures 
of the patient’s personal information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Santen, its affiliates, and 
licensing partners; (2) business partners assisting Santen, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs; 
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
patients the same level of protection as the data protection laws within this country; 
however, Santen will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law; 
c) that personal information (including personal health information) may be added to Santen’s 
research databases for purposes of developing a better understanding of the safety and 
effectiveness of the study medication(s), studying other therapies for patients, developing 
a better understanding of disease, and improving the efficiency of future clinical studies; 
d) that patients agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and 
e) that the patient’s identity will remain confidential in the event that study results are 
published. 


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Appendix DInvestigator Consent to Use of Personal Information  
Santen will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (e.g., 
the United Kingdom, United States, Japan), including the following: 
 Santen, its affiliates, and licensing partners. 
 Business partners assisting Santen, its affiliates, and licensing partners. 
 Regulatory agencies and other health authorities. 
 IRBs and IECs. 
Investigator’s personal information may be retained, processed, and transferred by Santen and 
these other parties for research purposes including the following: 
 Assessment of the suitability of investigator for the study and/or other clinical studies. 
 Management, monitoring, inspection, and audit of the study. 
 Analysis, review, and verification of the study results. 
 Safety reporting and pharmacovigilance relating to the study. 
 Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study. 
 Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication. 
 Inspections and investigations by regulatory authorities relating to the study. 
 Self-inspection and internal audit within Santen, its affiliates, and licensing partners. 
 Archiving and audit of study records. 
 Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s 
own country. 
Investigator acknowledges and consents to the use of his or her personal information by Santen 
and other parties for the purposes described above. 
 
 


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Appendix E Declaration of Helsinki  
 
WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement 
of ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. 
            The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. 
The WMA encourages others who are involved in medical research involving human subjects to adopt 
these principles.  
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6.         The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 


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8.         While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician or 
other health care professionals and never with the research subjects, even though they have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and standards. 
No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12.       Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other health 
care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14.       Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value 
and if the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of participating 
in research must be ensured. 
Risks, Burdens and Benefits  
16.       In medical practice and in medical research, most interventions involve risks and burdens. 
           Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison with 
foreseeable benefits to them and to other individuals or groups affected by the condition under 
investigation. 
           Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher.  
18.       Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
           When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.            


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Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
           All vulnerable groups and individuals should receive specifically considered protection. 
20.       Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. 
In addition, this group should stand to benefit from the knowledge, practices or interventions that result 
from the research. 
Scientific Requirements and Research Protocols  
21.       Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals 
used for research must be respected. 
22.       The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
           The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects 
and information regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. 
           In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance and approval to 
the concerned research ethics committee before the study begins. This committee must be transparent in 
its functioning, must be independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations of the country or countries 
in which the research is to be performed as well as applicable international norms and standards but these 
must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.  
           The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. No 
amendment to the protocol may be made without consideration and approval by the committee. After the 
end of the study, the researchers must submit a final report to the committee containing a summary of the 
study’s findings and conclusions.  
Privacy and Confidentiality  
24.       Every precaution must be taken to protect the privacy of research subjects and the confidentiality 
of their personal information. 
Informed Consent  


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25.       Participation by individuals capable of giving informed consent as subjects in medical research 
must be voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she freely 
agrees. 
26.       In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study 
and the discomfort it may entail, post-study provisions and any other relevant aspects of the study. The 
potential subject must be informed of the right to refuse to participate in the study or to withdraw consent 
to participate at any time without reprisal. Special attention should be given to the specific information 
needs of individual potential subjects as well as to the methods used to deliver the information. 
           After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.       
           All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
27.       When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may 
consent under duress. In such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 
28.       For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorised representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote the health of 
the group represented by the potential subject, the research cannot instead be performed with persons 
capable of providing informed consent, and the research entails only minimal risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed consent is able to 
give assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorised representative. The potential subject’s dissent should be respected. 
30.       Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research  group. In such circumstances the physician 
must seek informed consent from the legally authorised representative. If no such representative is 
available and if the research cannot be delayed, the study may proceed without informed consent provided 
that the specific reasons for involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research must be obtained as soon as possible from the subject or a 
legally authorised representative. 
31.       The physician must fully inform the patient which aspects of their care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never adversely affect the patient-physician relationship. 


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32.       For medical research using identifiable human material or data, such as research on material or 
data contained in biobanks or similar repositories, physicians must seek informed consent for its 
collection, storage and/or reuse. There may be exceptional situations where consent would be impossible 
or impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances: 
           Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
           Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the 
efficacy or safety of an intervention  
           and the patients who receive any intervention less effective than the best proven one, placebo, or 
no intervention will not be subject to additional risks of serious or irreversible harm as a result of not 
receiving the best proven intervention.  
           Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial in 
the trial. This information must also be disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to 
the publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results must be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be accepted for 
publication. 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available. 
 
 


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Appendix F - Protocol Amendment 01 Modification Summary  
Protocol 0130A01SA has been amended (Amendment 01) in order to optimize the statistical 
analyses and to harmonize the exclusion criteria throughout the study.  
A listing of protocol modifications are listed below. 
A red-lined version of Protocol 0130A01SA, Amendment 01 is on file with the Sponsor. 
Amended text is highlighted in bold italics.  
Deleted text is highlighted in bold italics and crossed out  
 
 Table 4:  Protocol 0130A01SA, Amendment 01 Modifications 
 
Page 
Section 
Number 
Section Title 
Description of Change 
 
Numerous 
Numerous 
Numerous 
Administrative changes in 
abbreviations, capitalization and formatting were 
made in the document. These individual changes 
are not listed in this table. 
3 
Table 1: 
 
 
 
Emergency Contact 
Information 
 
 
Update of Santen internal information regarding 
Safety Vigilance in the protocol synopsis, Table 
1 and in the protocol sections 3, 12 and Sponsor 
signatory personal on the last page of the 
protocol. 
4 
1. 
SYNOPSIS 
Studied period (years):  
Update of the estimated date last patient 
completed: Nov2022 
15-21 
2. 
Table of Contents 
 
Administrative changes.  
22-23 
3. 
LIST OF 
ABBREVIATIONS 
AND DEFINITIONS OF 
TERMS 
 
Removal and addition of several abbreviations 
due to statistical analysis change. 
4 
 
31 
 
1. 
 
5.2. 
SYNOPSIS 
Objectives:  
Secondary 
Protocol:   
Secondary 
The following wording has been deleted in order 
to optimize the statistical analyses:  
 
To compare the effect on improving Ocular 
Surface Disease (OSD) signs and symptoms 
between treatment groups [for the FAS 
population and by corneal fluorescein staining 


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Objectives  
 
 
CFS subgroups, baseline study eye CFS≤1 
vs.CFS ≥2, modified oxford scale] over 3 
months (Period 1). 
 
To estimate the effect of DE-130A on OSD 
signs and symptoms improvement for the Open-
Label population and by OSD sub-groups up to 
15 months (Periods 1 & 2). 
 
To compare the efficacy on IOP reduction 
between treatment groups for the FAS 
population and OSD subgroups over 3 months 
(Period 1). 
 
To estimate the effect of DE-130A on IOP 
for the Open-Label population and by OSD 
subgroups up to 15 months (Periods 1 & 2). 
 
To estimate evalutate the local ocular tolerance 
and systemic safety of the two treatments over 3 
months (Period 1, Safety population). 
To estimate the local ocular tolerance and 
systemic safety of DE-130A up to 15 months 
(Periods 1 & 2, Open-Label population). 
5 
 
 
 
 
34 
 
55 
1. 
 
 
 
 
6.1 
 
10.1. 
SYNOPSIS 
Methodology:  
Study duration: 
Protocol 
Wash Out Phase  
Study Design and 
Schedule of Assessments 
Table 3 
 
Screening 
 
Wash out period has been updated to 6-weeks 
to reflect the added wording to Criteria for 
inclusion 7.  
 
1. 
SYNOPSIS  
Protocol  
The term “enrolled” has been replaced by 
“randomized” throughout the synopsis and main 
protocol 
to clearly define the number of planned patients.  
 
5 
 
 
 
1. 
 
 
 
SYNOPSIS 
Criteria for inclusion 6.:  
Patient eligibility is 
determined according to 
The following wording was added do define that the 
imaging technique such as optical coherence 
tomography (OCT) is useful in particular for the 
follow-up of glaucoma patients. In the early stage 
glaucoma, OCT is considered as an efficient tool to 
monitor the progression of the disease. Therefore 
several glaucoma physicians use OCT instead of 


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7.2 
 
 
the following inclusion 
criteria: 
 
Protocol : 
Subject Inclusion Criteria 
6. 
 
visual field to monitor early stage glaucoma patients. 
Consequently we propose to add the OCT as an 
acceptable tool to assess the inclusion criteria #6 for 
the enrolment of  patients in the study: 
 
If historical visual fields are not available 
within the last 18 months prior to screening, 
but at least two OCTs (optical coherence 
tomography) are available, including one in the 
last 6 months and are stable, the patient can be 
enrolled in the study if a visual field test is also 
performed at screening and shows no defect or 
only an early visual field loss in either eye 
(mean deviation lesser than -6 dB). 
 
6 
 
 
39 
 
 
 
 
1. 
 
 
7.2 
 
 
SYNOPSIS 
Criteria for inclusion 7.:  
 
Protocol : 
Subject Inclusion Criteria 
 
 
The following wording was added do define that 
the washout period after discontinuation of a 
treatment may vary between individuals. The 
protocol specifies that Post-washout IOP should 
be measured 5 to 7 days after stopping 
Brinzolamide as this timeframe is considered in 
many clinical trials. However it is possible that 
for some patients, some additional days may be 
necessary before the drug is considered washed 
out. In addition the patient is not at risk when 
receiving no treatment for a few more days 
given  the IOP is in the normal range (ie. <22 
mmHg) and the patient is closely monitored. 
Therefore, the time for IOP measurement after 
Brinzolamide discontinuation can be extended 
up to 6 additional days: 
 
If IOP is <22 mmHg, the wash-out period can 
be extended and the IOP should be re-assessed 
two to three days after the first measurement. If 
the IOP is still < 22 mmHg at the second 
measurement, a third assessment should be 
performed two to three days after the second 
measurement. If the IOP is still < 22 mmHg at 
the third  measurement, the patient cannot be 
randomized in the study. 


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7 
 
 
40 
 
 
1. 
 
 
7.3. 
SYNOPSIS 
Exclusion criteria 15.: 
 
Protocol: 
Subject Exclusion 
Criteria 15. 
New exclusion criterion added to harmonize the 
exclusion criteria with the German AM1, to 
ensure the patients’ safety: 
Known hypersensitivity to sulfonamides, severe 
renal impairment or hyperchloraemic acidosis.  
8-9 
 
 
 
 
 
 
34 
 
 
 
 
44 
 
1. 
 
 
 
 
6.1 
 
 
8.2. 
SYNOPSIS 
Wash-out phase therapy: 
 
 
Protocol 
Overall Study Design 
Wash-out Phase  
 
Protocol Azopt® 
The following wording was added to reflect the 
updates made in terms of Criteria for inclusion 
7.: At baseline, if IOP is <22 mmHg, the wash-
out period can be extended and the IOP should 
be re-assessed two to three days after the first 
measurement. If the IOP is still < 22 mmHg at 
the second measurement, a third assessment 
should be performed two to three days after the 
second measurement. If the IOP is still < 22 
mmHg at the third  measurement, the patient 
cannot be randomized in the study. 
9 
 
 
 
31 
 
 
 
 
 
 
 
1. 
 
 
5.3.2. 
 
SYNOPSIS 
Efficacy: 
The key secondary 
endpoints are: 
Protocol: 
Key Secondary 
Endpoints 
The following wording was added to optimize 
the statistical analysis part: 
- Change from baseline in CFS score in the 
study eye at Week 12 in patients with baseline 
CFS ≥ 1. 
-Change from baseline in OSD symptom score 
(average of 3 symptoms: dry eye sensation, 
blurred/poor vision and burning/stinging/itching) 
in the study eye at Week 12 in patients with 
baseline symptom average score>0. 
9 
1. 
SYNOPSIS 
Efficacy: 
The key secondary 
endpoints are: 
 
The following wording was deleted to optimize 
the statistical analysis part: 
Other secondary efficacy endpoints are: over the 
3-month (Period 1), and for DE-130A up to 15 
months (Periods 1 & 2), are: 


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9 
 
 
 
 
 
 
 
 
 
33 
1. 
 
 
 
 
 
 
 
 
 
5.3.3. 
 
SYNOPSIS 
Other secondary efficacy 
endpoints are: 
 
 
 
 
 
 
 
 
 
 
Protocol :  
The other secondary 
efficacy endpoints are: 
 
Added wording due to statistical analyses 
optimization. Deletion of the use of artificial 
tears as secondary endpoint since per protocol 
this use should remain stable:  
-IOP related endpoints: 
-Change from baseline in mean diurnal IOP in 
the study eye at Week 12 
-Change from baseline in peak, trough, and 
mean diurnal IOP in the study eye at Week 4 
Morning (9:00 am ± 1 hour) IOP in the study eye 
of patients treated with DE-130A at Month 6, 
Month 9, Month 15/early termination (Period 2) 
and change from baseline at each Period 2 visit 
 
Morning (9:00 am ± 1 hour) IOP in the study eye 
of patients treated with DE-130A enrolled in 
Period 2 at Month 6, Month 9, Month 15/early 
termination (Period 2) and change from baseline 
at each Period 2 visit. 
11 
 
 
33 
 
1. 
 
 
5.3.3. 
 
SYNOPSIS 
Other secondary efficacy 
endpoints are: 
 
Protocol :  
The other secondary 
efficacy endpoints are: 
 
Deleted wording due to statistical analyses 
optimization. Deletion of the use of artificial 
tears as secondary endpoint since per protocol 
this use should remain stable:  
-Ocular surface disease assessment at Week 4, Week 
12, Month 6, Month 9 and Month 15/early 
termination:  
-Corneal and conjunctival fluorescein staining 
(modified Oxford Scale) 
-OSD symptom assessments  
-TFBUT  
-Use of artificial tears (AT) 
-Slit lamp examination (Meibomian gland 
dysfunction, conjunctiva, lids and tear film 
debris) 
11 
 
 
 
1. 
 
 
 
SYNOPSIS 
Other secondary efficacy 
endpoints are: 
 
 
 
Added and deleted wording due to statistical 
analyses optimization. Deletion of the use of 
artificial tears as secondary endpoint since per 
protocol this use should remain stable:  
-Subject global rating of treatment at Month 
15/early termination (Open-Label Population) 


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5.3.3. 
 
Protocol :  
The other secondary 
efficacy endpoints are: 
or and Week 12 (subjects not entering Period 
2) 
-Quality of life (Glaucoma Quality of Life-15) 
scores at Baseline visit, Week 12, and Month 
15/early termination visits. 
11 
 
 
33 
 
1. 
 
 
5.3.4 
SYNOPSIS 
Safety  
 
 
Protocol: Safety and 
Tolerability Endpoints 
 
Added wording to clarify that undilated  
fundoscopy is performed as safety endpoint 
(already planned but not mentioned in this 
section of the protocol): 
- Best-corrected distance visual acuity (BCDVA) 
-Dilated and undilated (for cup-to-disc ratio) 
fundoscopy 
11 
 
 
 
72 
 
 
 
1. 
 
 
 
13.2. 
SYNOPSIS 
Statistical methods: 
Analysis Populations 
 
 
Protocol 
Analysis Populations 
 
 
The following wording has been deleted or 
added in order to optimize the statistical analyses 
part:  
-The Full Analysis Set (FAS) population consists of all 
enrolled randomized subjects who received at least 
one dose of the study medication and provided at least 
one post-baseline IOP measurement at peak and 
trough timepoints, separately. The FAS population 
will be the analysis population for  all efficacy 
endpoints analyses in Period 1 and will use treatment 
as randomised. 
-The Safety population consists of all patients 
subjects enrolled randomized in the study who 
received at least one dose of the study medication and 
for whom any follow-up information is available. The 
Safety population will be the analysis population for 
all safety analyses in Period 1 and will use treatment 
as actually received. 
-The Glaucoma/OHT Per-Protocol (PP) population 
will be a subset of the FAS subjects. It includes all FAS 
subjects without any of the major protocol deviations 
that could affect the primary efficacy endpoint. The PP 
population will be used the analysis population for 
sensitivity analyses of the primary efficacy endpoints 
in Period 1 and will use treatment as randomised. 
-The Ocular Surface Disease Per-Protocol (PP) 
population will be a subset of the FAS subjects. It 
includes all FAS subjects without any of the major 
protocol deviations that could affect the key 
secondary endpoints. This population will be used for 


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sensitivity analyses of the key secondary endpoints in 
Period 1 and will use treatment as randomised. 
-The Open-Label Population will be a subset of the 
FAS subjects who are the first 130 subjects who 
complete their Week 12 Visit and enter the Period 2 
of the study agree to participate in the open-label 
period of the study, and received at least one dose of 
the study medication during the open-label period 
and provided at least one morning IOP measurement 
after the Week 12 Visit. This population will be the 
analysis population for the analyses of efficacy and 
safety endpoints in Period 2 and for Periods 1 & 2 
combined data and will use treatment as randomised. 
-The Open-Label Safety population will be a subset 
of the FAS subjects who complete their Week 12 
Visit and agree to participate in the open-label 
period of the study, and received at least one dose of 
the study medication during the open-label period. 
The Open-Label Safety population will be the 
analysis population for all safety analyses in Period 
2 and for Periods 1 & 2 combined data and will use 
treatment as actually received. 
-Efficacy analyses will also be done for the following 
subgroups in both Period 1 and Period 2 as well as 
for Periods 1 & 2 combined data: 
-CFS subgroups are defined as baseline CFS ≤ 1 vs. 
CFS ≥ 2 (modified Oxford scale) in the study eye. 
The analysis of the OSD endpoints will be 
performed on FAS and CFS subgroups. 
 
12 
 
 
73 
 
 
1. 
 
 
13.3. 
SYNOPSIS 
Analysis of 
Demographics and 
Baseline Characteristics 
Protocol 
Analysis of 
Demographics and 
Baseline Characteristics 
The following wording has been deleted or 
added in order to optimize the statistical analyses 
part: 
They will be summarized by treatment groups 
and for the overall FAS population Safety 
population, Open-label population, separately. 
for the OSD subgroups, respectively. 
12-13 
 
1. 
 
SYNOPSIS 
The following wording has been deleted or 
added in order to optimize the statistical 
analyses: 


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Analysis of Primary and 
Key Secondary Efficacy 
Endpoints 
 
The primary efficacy endpoint is the change 
from baseline in peak and trough IOP, 
respectively, between the DE-130A group and 
the Xalatan® group in the study eye at Week 12. 
Statistical analysis will be performed using a  
mixed-effects model for repeated measures 
(MMRM) on observed cases collected up to 
Week 12 based on FAS population. A separate 
MMRM model will be performed for IOP at 
peak and trough, respectively. The model will 
include treatment, visit, treatment-by-visit 
interaction and country as fixed effects, 
baseline IOP at the respective timepoint (peak 
or trough) as covariates. Non-inferiority will be 
established if the upper limit of the one-sided 
97.5% confidence interval from the 
independent-sample Student’s t-test for the 
difference between DE-130A and Xalatan® in 
change from baseline peak and trough IOP, 
respectively, at Week 12 is less than or equal to 
the non-inferiority margin of 1.5 mmHg at both 
the peak and trough timepoints at Week 12. 
Superiority is achieved with respect to this 
endpoint if the upper limit of the one-sided 
97.5% confidence interval is < 0 mmHg for 
both timepoints at Week 12.  
 If non-inferiority in the primary endpoint is 
achieved, the two key secondary endpoints will 
be tested for superiority, sequentially according 
to hierarchical fixed sequence procedure. 
MMRM models will be fitted for each key 
secondary endpoint using a similar model 
setting as described for the analysis of the 
primary efficacy endpoint  Fixed sequence 
procedure will be applied to control the overall 
Type I error rate across all hypotheses in the 
primary and key secondary endpoints at the 
0.05 level. 
-Change from baseline in CFS score at Week 
12 
-Change from baseline in symptom score (3-
symptom average) at Week 12 
13 
 
 
74 
1. 
 
 
13.4.2. 
SYNOPSIS 
Analysis of Secondary 
Efficacy Endpoints 
Protocol 
The following wording has been deleted or 
added in order to optimize the statistical analyses 
part: 
Analysis of Other Secondary Efficacy Endpoints 


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Analysis of Secondary 
Efficacy Endpoints 
 
SYNOPSIS 
 
 
 
 
The analysis of secondary efficacy endpoints 
will be performed on the FAS population and 
CFS subgroups (CFS ≤ 1 vs. CFS ≥ 2, modified 
Oxford scale). All efficacy analyses will be 
performed on the study eye.  
Analysis of Other Secondary Efficacy Endpoints 
IOP Assessments 
Changes in peak, trough, and mean diurnal 
IOPs will be summarized by treatment groups at 
Week 4 and Week 12, respectively, for the FAS 
population and CFS subgroups. 
Peak, trough, and mean diurnal IOP responses 
(IOP 20%, 25%, 30% responses, and IOP < 18 
mmHg response) will be summarized by 
treatment groups at Week 4 and Week 12, 
respectively, for the FAS population and CFS 
subgroups. 
For patients participating in the safety follow-
up, change from baseline and change from 
Week 12, respectively, in mean morning (9:00 
am ± 1 hour) IOP will be summarized for the 
Open-Label population and for CFS subgroups 
at Month 6, Month 9 and Month 15/early 
termination.  
 
Ocular surface disease Assessments 
-Change from baseline in Conjunctival 
fluorescein staining, TFBUT and each 
individual symptom score, and TFBUT at each 
analysis visit in Period 1 Week 12 will be 
compared between treatment groups using 
MMRM on observed cases. More details on the 
model specifications will be provided in the 
SAP. an independent-sample Student’s t-test 
for the FAS population and for CFS 
subgroups, respectively.   
Percentage of patients with moderate and severe 
conjunctival hyperemia (grade ≥ 3 measured by 
slit lamp scored using the photographic scale 
derived from McMonnies scale (1 to 6))  in the 
study eye at each analysis visit in Period 1 at 
Week 12 will be compared between treatment 
groups using a Chi-squared test or Fisher’s 


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Exact test wherever appropriate for the FAS 
population. 
Proportion of subjects using Artificial tears use 
during Period 1 at Week 12 will also be 
compared summarised between by treatment 
group as a continuous variable as well as by 
percentage of patients who use artificial tears 
at each analysis visit. using a Chi-squared test 
or Fisher’s Exact test wherever appropriate for 
the FAS population and for CFS subgroups, 
respectively. 
Ocular surface disease endpoints (Corneal and 
conjunctival fluorescein staining, [modified 
Oxford scale], TFBUT, symptom scores [3-
symptom average and individual symptom 
score], use of artificial tears [continuous 
variable], and slit lamp examination) and their 
change from baseline at each visit will be 
summarized for the FAS population and for 
CFS subgroups, respectively, descriptively by 
treatment group (Period 1) and by analysis visit. 
Artificial tears use during Period 1 (Day 1 to 
Week 12 Visit) will also be analyzed by 
treatment group on percentage of patients who 
use artificial tears at each visit. 
For the patients participating in the safety 
follow-up, OSD endpoints and their change 
from baseline will be summarized for the Open-
Label population and for CFS subgroups by 
analysis visit for the whole study (Periods 1 & 
2) and change from Week 12 for Period 2. 
Quality of Life Assessments 
Mean scores of quality of life (Glaucoma 
Quality of Life-15), and their change from 
baseline (Period 1 and Periods 1 & 2) and 
change from Week 12 (Period 2) will be 
summarized by analysis visit and by treatment 
group (Period 1), for the FAS population (Period 
1), for the Open-Label Population (Period 2, 
Periods 1 & 2) combined)., and for CFS 
subgroups. 
Subjects Global Rating of Treatment 
Subjects global rating of treatment at Week 
12/early termination will be summarized by 
treatment groups for the FAS population. and 


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for CFS subgroups, respectively. Also, it will be 
summarized at Month 15/early termination for 
the Open-Label Population. 
IOP Assessments 
Changes in peak, trough, and mean diurnal 
IOPs at each analysis will be summarized on the 
study eye by treatment group.  
Peak, trough, and mean diurnal IOP responses 
in the study eye (IOP 20%, 25%, 30% responses, 
and IOP < 18 mmHg response) at each analysis 
visit will be summarized by treatment group.  
For patients participating in the safety follow-
up, change from baseline and change from 
Week 12, respectively, in mean morning (9:00 
am ± 1 hour) IOP will be summarized for the 
Open-Label population and for CFS subgroups 
at Month 6, Month 9 and Month 15/early 
termination.  
 
14 
 
 
76 
1. 
 
 
13.5 
SYNOPSIS 
Analysis of Safety and 
Tolerability Endpoints 
 
Protocol  
Analysis of Safety and 
Tolerability Endpoints 
 
 
 
The following wording has been added in order 
to optimize the statistical analyses part: 
-Period 2 (Week 12 Visit to Month 15 Visit/early 
termination): for all subjects who entered into the 
open-label period (Open-Label Safety population) 
Entire study period (Day 1 to Month 15/early 
termination): for all subjects who entered into 
the open-label Safety period (Open-Label 
population). 
28-30 
4.2 
Protocol:  
Rationale for the 
Proposed Study 
 
 
The following wording has been deleted or 
added in order to optimize the statistical analyses 
part: 
In the proposed non-inferiority study, to 
approximate the peak and trough times, the IOP 
will be measured at 9:00 (±1 hour) am and 4:00 
(±1 hour) pm, and the diurnal mean will be 
used to assess the primary efficacy endpoint and 
secondary endpoints during a 3-month period 
with randomised investigator-masked 
medication. The chosen non-inferiority margin 
of 1.5 mmHg is well below (Musch, 2006 the 


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effect of the active control (−8.6±2.6 mmHg, 
Rouland, 2013 (45)). In addition to the 
comparison of peak, trough, and mean diurnal 
IOP, the rates of different responders (defined by 
a reduction in mean IOP of ≥ 20%, ≥ 25%, and ≥ 
30%, and a mean IOP < 18mm Hg) will be 
compared between treatment groups.  
Regarding the OSD, the potential positive 
impact of the cationic formulation of DE-130A 
on OSD signs (using TFBUT, slit lamp 
examination, corneal, and conjunctival 
fluorescein staining with modified Oxford scale) 
and symptoms (using 3-symptom assessment 
and artificial tears use) will be compared with 
the effect on OSD of the BAK-preserved 
Xalatan®. Furthermore the quality of life impact 
will also be compared between treatment groups. 
However in order to provide long-term 
additional data on the safety and tolerability of 
DE-130A, a 12-month follow-up with open-label 
DE-130A is to be offered up to the first 130 
patients (whatever their randomised treatment is) 
who complete their Week 12 Visit and agree to 
participate in the open-label period of the study. 
During this safety follow-up, only the peak IOP 
will be measured in order to minimize patients’ 
burden. 
31-33 
 
5.3.3 
 
Protocol: 
The other secondary 
efficacy endpoints are: 
 
New added wording to optimize the statistical 
analysis part: 
-Ocular surface disease related endpoints:  
-CFS in the study eye at Week 4 in subjects 
with baseline CFS ≥ 1 
-Tear film break-up time (TFBUT) in the 
study eye at Week 4 and Week 12 in subjects 
with baseline TFBUT ≤ 10 
-Conjunctival hyperemia (measured by slit 
lamp scored using the photographic scale 
derived from McMonnies scale [1 to 6]) in the 
study eye at Week 4, Week 12 
-Conjunctival fluorescein staining in the study 
eye at Week 4 and Week 12 in subjects with 
baseline conjunctival fluorescein staining ≥ 1 
-Dry eye sensation symptom in the study eye at 
Week 4 and Week 12 in subjects with baseline 


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dry eye sensation symptom in mild, moderate, 
or severe  
-Blurred/poor vision symptom in the study eye 
at Week 4 and Week 12 in subjects with 
baseline blurred/poor vision symptom in mild, 
moderate, or severe  
-Burning/stinging/itching symptom in the study 
eye at Week 4 and Week 12 in subjects with 
baseline burning/stinging/itching symptom in 
mild, moderate, or severe  
-Slit lamp examination (Meibomian gland 
dysfunction, conjunctiva chemosis, lids and 
tear film debris) in the study eye at Week 4 and 
Week 12 
-CFS in the study eye at Month 6, Month 9 and 
Month 15/early termination in subjects with 
baseline CFS ≥ 1 
-Tear film break-up time (TFBUT) in the study 
eye at Month 6, Month 9 and Month 15/early 
termination in subjects with baseline TFBUT ≤ 
10 
-Conjunctival hyperemia (measured by slit 
lamp scored using the photographic scale 
derived from McMonnies scale [1 to 6]) in the 
study eye at Month 6, Month 9 and Month 
15/early termination  
-Conjunctival fluorescein staining in the study 
eye at Month 6, Month 9 and Month 15/early 
termination in subjects with baseline 
conjunctival fluorescein staining ≥ 1 
-Dry eye sensation symptom in the study eye at 
Month 6, Month 9 and Month 15/early 
termination in subjects with baseline dry eye 
sensation symptom in mild, moderate, or severe  
-Blurred/poor vision symptom in the study eye 
at Month 6, Month 9 and Month 15/early 
termination in subjects with baseline 
blurred/poor vision symptom in mild, moderate, 
or severe  
-Burning/stinging/itching symptom in the study 
eye at Month 6, Month 9 and Month 15/early 
termination in subjects with baseline 
burning/stinging/itching symptom in mild, 
moderate, or severe  
-Slit lamp examination (Meibomian gland 
dysfunction, conjunctiva, lids and tear film 


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debris) in the study eye at Month 6, Month 9 
and Month 15/early termination 
34 
6.1 
Protocol :  
Overall Study Design 
The following wording has been deleted in order 
to optimize the statistical analyses:  
The Sponsor expects to enroll approximately 65% or 
more subjects with OSD in this study. For eyes to be 
considered as having an OSD, the eligible eye must 
satisfy all of the following three criteria at baseline 
(Day 1): 
-CFS score of 1, 2, or 3 (Modified Oxford scale) 
-At 
least 
one 
of 
the 
symptom 
scores 
(burning/stinging/itching, 
eye 
dryness, 
or 
blurred/poor vision) is of a severity moderate or 
worse, AND  
-TFBUT of 10 seconds or less. 
 
34 
6.1 
Protocol :  
Overall Study Design 
The study duration was updated to reflect the 
updated of the wash out period to 6-weeks. 
The study duration (including the wash-out period) 
will be up to 16 17 months, and patients will attend 
up to 6 scheduled visits after Screening visit (Table 
3). 
35 
 
Protocol  
Figure 1: 
The following wording has been added in order 
to optimize the statistical analyses part:  
*** Brinzolamide will be stopped 5 days before 
randomisation (6 to 7 days if over the weekend). At 
Day 1, if IOP is <22 mmHg, the wash-out period 
can be extended and the IOP should be re-assessed 
two to three days after the first measurement. If the 
IOP is still < 22 mmHg at the second measurement, 
a third assessment should be performed two to three 
days after the second measurement. If the IOP is 
still < 22 mmHg at the third  measurement, the 
patient cannot be randomized in the study. 
 
36 
6.1 
Protocol  
Study Treatment Period 1 
The following wording has been deleted in order 
to optimize the statistical analyses part:  
Assessement of the Subject Global Rating of 
Treatment (on the study eye), at Week 12 visit. 
 
37 
6.1 
Protocol  
Study Treatment Period 2 
The following wording has been deleted in order 
to optimize the statistical analyses part:  


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Assessement of the Subject Global Rating of 
Treatment (on the study eye), only at Month 15 
visit. 
38 
6.5 
Protocol  
End of Trial 
 
Added to harmonize with the Latvian AM1: 
End of Trial is defined as the last visit of the 
last subject 
55 
 
 
57 
 
57 
 
 
58 
 
58 
 
 
10.2. 
 
 
 
10.2.3. 
 
10.3. 
 
 
10.3.2. 
 
10.3.3. 
Protocol  
Investigator-masked 
treatment Phase Period 1 
 
Week 12  
 
Open-label DE-130A 
treatment Phase Period 2 
 
Month 15  
 
Unscheduled Visit 
The wording ”study eyes” has been deleted in 
terms of subject global rating of the treatment 
because it is expected a global rating not a 
specific one per eye:  
 
Subject Global Rating of Treatment (Study 
Eye)  
 
 
61 
11.5. 
Protocol 
Dilated fundoscopy 
 
The following wording has been added to clarify 
that the undilated  fundoscopy is performed as 
safety endpoint (already planned but not 
mentioned in this section of the protocol): 
Dilated and undilated fundoscopy 
 
61 
11.6. 
Protocol 
Use of Concomitant 
Artificial Tears 
 
The following wording has been deleted since 
per protocol this use should remain stable: 
A decrease in artificial tear use from baseline 
(Period 1) and/or from Week 12 (Period 2) will 
indicate improvement. 
64 
12.1.4. 
Protocol 
Pregnancy Screen 
 
The following wording has been added in order 
to optimize safety measures:  
Sexual abstinence is defined as refraining from 
heterosexual intercourse during the entire 
study period and should be in line with the 
preferred and usual lifestyle of the subject. 
69 
12.2.4.3. 
Expedited reporting 
 
The following wording has been deleted or 
andded to clarify the preferred choice of 
reporting: “email then phone then fax” rather 
than “email then fax then phone”.  
Santen EMEA, Safety Vigilance Pharmacovigilance 
Unit (PVU) (SV) 


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Email to safetyEU@santen.com or 
Fax to +358 3 318 1060 
Phone +358 3 284 8625 
71 
13.1.3 
Protocol  
Multiple 
Comparisons/Multiplicity 
 
The following wording has been added in order 
to optimize the statistical analyses part:  
To control the overall type I error rate at 0.05 level, 
the three hypotheses testing in the primary and key 
sencondary endpoints will be performed sequentially 
according to hierarchical fixed sequence procedure 
below: 
4. Hypothesis testing of non-inferiority of DE-
130A to Xalatan® for the primary endpoint: 
change from baseline in peak (9:00 am ± 1 
hour) and trough (4:00 pm ± 1 hour) IOPs, 
respectively, at Week 12. 
5. Hypothesis testing of superiority of DE-
130A to Xalatan® for the first key secondary 
endpoint: change from baseline in CFS 
score at Week 12 in subjects with baseline 
CFS ≥ 1. 
6. Hypothesis testing of superiority of DE-
130A to Xalatan® for the second key 
secondary endpoint: change from baseline 
in symptom score (average of 3 symptoms: 
dry eye sensation, blurred/poor vision and 
burning/stinging/itching) at Week 12 in 
subjects with baseline symptom average 
score >0. 
 
73 
13.4 
Protocol 
Efficacy analyses 
 
 
The following wording has been added to 
change the statistical method for the primary 
analysis of the efficacy endpoints so that (1) will 
be able to adjust for baseline variables to 
improve the precision of estimates on treatment 
effect ; (2) handle missing data with a newer 
approach:  
During period 1, if a patient takes any concomitant 
medications 
or 
undergoes 
any 
concomitant 
therapies listed in Section 8.2 of this protocol, IOP 
and/or CFS and OSD symptom scores after taking 
the medication/therapy will be censored for the 


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primary and/or key secondary efficacy endpoints 
analyses. The endpoint(s) that will be censored 
depends on the medications or therapies taken, 
which will be determined by the Sponsor team 
during the masked data review before database lock.  
-IOP data will be censored after any IOP-lowering 
medication/therapy is taken.  
-CFS and symptom scores will be censored after any 
medication 
(including 
artificial 
tears 
change)/therapy that might have any effect on the 
OSD signs and symptoms.  
If it is determined that a medication or therapy could 
have an effect on both IOP and OSD endpoints, IOP, 
CFS and symptom scores will all be censored. 
 
 
73 
 
13.4.1. 
Protocol 
Analysis of Primary 
Efficacy Endpoint 
 
The following wording has been added or 
deleted to change the statistical method for the 
primary analysis of the efficacy endpoints so that 
(1) will be able to adjust for baseline variables to 
improve the precision of estimates on treatment 
effect ; (2) handle missing data with a newer 
approach:  
 
The difference in change from baseline in 
peak and trough IOP between the DE-130A 
group and the Xalatan® group at the Week 
12 Visit in the IOP study eye will be 
compared using a  mixed-effects model for 
repeated measures (MMRM) on observed 
cases collected up to Week 12 based on 
FAS population. A separate MMRM model 
will be used for IOP at peak and trough, 
respectively. The model will include 
treatment, visit, treatment-by-visit 
interaction and country as fixed effects, 
baseline IOP at the respective timepoint 
(peak or trough) as covariates.  an 
independent-sample Student’s t-test and 
reported along with its The 95% confidence 
intervals intervals and p-values will be 
reported., respectively. For the primary 
efficacy endpoint, the following hypotheses 
will be tested: 


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H0: µT  – µC > Δ or at least one timepoint 
versus 
HA: µT  – µC ≤ Δ for both timepoints 
 
where µT and µC denote the mean change from 
baseline in peak or trough IOP in DE-130A and 
Xalatan® groups, respectively, and Δ denotes the non-
inferiority margin of 1.5 mmHg.  Non-inferiority will 
be established if the upper limit of the one-sided 97.5% 
confidence interval is less than or equal to the non-
inferiority margin of 1.5 mmHg at both the peak and 
trough timepoints at Week 12. 
Sensitivity analysis of the primary efficacy endpoints 
will be done with the Glaucoma/OHT PP population 
and with the observed cases only.  
Because both the peak and trough IOP endpoints have 
to meet the non-inferiority criterion in order to claim 
non-inferiority of DE-130A as compared to Xalatan®, 
no multiplicity adjustment is needed for the primary 
efficacy endpoint. 
During period 1, if a patient takes any concomitant 
medications 
or 
undergoes 
any 
concomitant 
therapies listed in Section 8.2 of this protocol, IOP 
and/or CFS and OSD symptom scores after taking 
the medication/therapy will be censored for the 
primary and/or key secondary efficacy endpoints 
analyses.  The variable(s) that will be censored 
depends on the medications or therapies taken, 
which will be determined by the Sponsor team 
during the masked data review before database lock.  
IOP data will censored after any IOP-lowering 
medication/therapy is taken; CFS and symptom 
scores will be censored after any medication 
(including artificial tears)/therapy that might have 
any effect on the OSD signs and symptoms. If it is 
determined that a medication or therapy could have 
an effect on both IOP and OSD endpoints, IOP, CFS 
and symptom scores will all be censored. 


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74 
13.4.2.1. 
Protocol  
Analysis of Key 
Secondary Endpoints 
 
 
The following wording has been added or 
deleted to change the statistical method for the 
primary analysis of the efficacy endpoints so that 
(1) will be able to adjust for baseline variables to 
improve the precision of estimates on treatment 
effect ; (2) handle missing data with a newer 
approach:  
The key secondary endpoints are: 
-Change from baseline in CFS score at Week 12 
in subjects with baseline CFS ≥ 1 
-Change from baseline in symptom score (3-
symptom average: dry eye sensation, 
blurred/poor vision and 
burning/stinging/itching) at Week 12 in 
subjects with baseline symptom score >0 
If non-inferiority in the primary endpoint is 
achieved, the above two key secondary 
endpoints will be tested sequentially according 
to hierarchical fixed sequence procedure: 
3) Change from baseline in CFS score at 
Week 12 in subjects with baseline CFS 
≥ 1 
The MMRM model with a similar model setting 
described for the analysis of the primary 
efficacy endpoint An independent-sample 
Student’s t-test will be used to test the following 
hypotheses: 
H0S1: µTs1 – µCs1  = 0  
versus  
HAS1: µTs1– µCs1 ≠ 0 
where µTs1 and µCs1 denote the mean change 
from baseline in CFS in DE-130A and Xalatan® 
groups, respectively. 
If the hypothesis is rejected at 0.05 significance 
level, then the following key secondary endpoint 
will be tested. 
4) Change from baseline in symptom score 
(3-symptom average) at Week 12 in 
subjects with baseline symptom score 
>0 


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The MMRM model with a similar model setting 
described for the analysis of the primary 
efficacy endpoint An independent-sample 
Student’s t-test will be used to test the following 
hypotheses: 
H0S2: µTs2 – µCs2  = 0 
versus 
HAS2: µTs2 – µCs2 ≠ 0 
where µTs2 and µCs2 denote the mean change 
from baseline in symptom score (3-symptom 
average) in DE-130A and Xalatan® groups, 
respectively.  
As a The Ocular Surface Disease PP 
population will be used for the sensitivity 
analysis of the two key secondary efficacy 
endpoints sensitivity analysis of these key 
secondary endpoints, a subject will be excluded 
from these analyses if his/her artificial tears 
use status has changed prior to the Week 12 
visit. The artificial tears use status change is 
defined as meeting one of the following 
criteria: 
-For patients who do not use artificial tears 
before the Screening Visit, if they start to use 
artificial tears at any time in between Baseline 
and the Week 12 visits. 
-For patients who already use artificial tears 
before the Screening Visit, if at any time in 
between Baseline and the Week 12 visits: 
o The dosing frequency increased 
≥ 2 drops/day 
Add a new or change to another artificial tears. 
75 
13.4.2.2. 
Protocol  
Analysis of Other 
Secondary Endpoints 
Ocular Surface Disease 
Assessments 
 
The following wording has been deleted or 
added in order to optimize the statistical analyses 
part: 
IOP Assessments 
Change from baseline in conjunctival fluorescein 
staining, TFBUT, and each individual symptom 
score in the study eye at each analysis visit in Period 
1 will be compared between treatment groups using 


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MMRM on observed cases. More details on the 
model specifications will be provided in the SAP. 
Percentage of patients with conjunctival 
hyperemia (measured by slit lamp scored using 
the photographic scale derived from 
McMonnies scale [1 to 6)) in the study eye at 
each analysis visit in Period 1 will be compared 
between treatment groups using a Chi-squared 
test or Fisher’s Exact test wherever appropriate 
for the FAS population. 
CFS, conjunctival fluorescein staining, 
TFBUT, 3-symptom average and individual 
symptom score, and slit lamp examination in 
the study eye at each analysis visit will be 
summarized descriptively by treatment group. 
Artificial tears use during Period 1 will be 
summarised by treatment group as a 
continuous variable as well as by percentage of 
patients who use artificial tears at each analysis 
visit. 
Descriptive statistics will also be provided for 
ocular surface disease endpoints (corneal and 
conjunctival fluorescein staining, TFBUT, 
symptom scores [3-symptom average and 
individual symptom score]) and their change 
from baseline at each visit by analysis visit and 
treatment group in Period 1 only. 
For the patients participating to the safety 
follow-up, OSD endpoints and their change 
from baseline will be summarized for subjects 
within the Open-Label population by analysis 
visit for the whole study period (Periods 1 & 2) 
and change from Week 12 for Period 2. 
IOP Assessments 
Changes in peak, trough, and mean diurnal 
IOPs on the study eye will be summarized by 
treatment group at Week 4 and Week 12. 
Peak, trough, and mean diurnal IOP responses 
on the study eye (IOP 20%, 25%, 30% responses, 
and IOP < 18 mmHg response, defined in 
Section 5.3.3) will be summarized by treatment 
group at Week 4 and Week 12. 
Changes in peak, trough, and mean diurnal 
IOPs will be summarized by treatment groups at 


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Week 4 and Week 12, respectively, for the FAS 
population and CFS subgroups. 
Peak, trough, and mean diurnal IOP responses 
(IOP 20%, 25%, 30% responses, and IOP < 18 
mmHg response, defined in Section 5.3.3) will 
be summarized by treatment groups at Week 4 
and Week 12, respectively, for the FAS 
population and CFS subgroups. 
For patients participating to the safety follow-
up, change from baseline and change from 
Week 12, respectively, in mean morning (9:00 
am ± 1 hour) IOP will be summarized for the 
Open-Label population and for CFS subgroups 
at Month 6, Month 9 and Month 15/early 
termination. 
Ocular surface disease Assessments 
 
Change from baseline in each 
individual symptom score, and TFBUT 
at Week 12 will be compared between 
treatment groups using an 
independent-sample Student’s t-test for 
the FAS population and for CFS 
subgroups, respectively.   
 
Percentage of patients with moderate 
and severe conjunctival hyperemia 
(grade ≥ 3 measured by slit lamp scored 
using the photographic scale derived 
from McMonnies scale (1 to 6)) at 
Week 12 will be compared between 
treatment groups.  
 
Proportion of subjects using artificial 
tears at Week 12 will also be compared 
between treatment group using a Chi-
squared test or Fisher’s Exact test 
wherever appropriate for the FAS 
population and for CFS subgroups, 
respectively. 
Ocular surface disease endpoints (corneal and 
conjunctival fluorescein staining [modified 
Oxford scale], TFBUT, symptom scores [3-
symptom average and individual symptom 
score], use of artificial tears [continuous 
variable], and slit lamp examination) and their 
change from baseline at each visit will be 
summarized for the FAS population and for 


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CFS subgroups, respectively, by treatment 
group (Period 1) and by analysis visit. 
Artificial tears use during Period 1 (Day 1 to 
Week 12 Visit) will also be analyzed by 
treatment group on percentage of patients who 
use artificial tears at each visit. 
For the patients participating to the safety 
follow-up, OSD endpoints and their change 
from baseline will be summarized for the Open-
Label population and for CFS subgroups by 
analysis visit for the whole study (Periods 1 & 
2) and change from Week 12 for Period 2. 
Quality of life Assessments 
Mean scores of quality of life (Glaucoma Quality of 
Life-15), and their change from baseline (Period 1 and 
Periods 1 & 2) and change from Week 12 (Period 2) 
will be summarized by study period,  analysis visit and 
by treatment group (Period 1), for the FAS population 
(Period 1), for the Open-Label Population (Period 2, 
Periods 1 & 2)., and for CFS subgroups. 
Subjects Global Rating of Treatment 
Subjects global rating of treatment at Week 12/early 
termination will be summarized by treatment groups 
for the FAS population and for CFS subgroups, 
respectively. Also, it will be summarized at Month 
15/early termination for the Open-Label Population. 
 
76 
13.5.1. 
Protocol  
Adverse Events 
 
 
The following wording has been deleted or 
added in order to optimize the statistical analyses 
part: 
A suspected adverse reaction (SAR) is any adverse 
event for which there is a reasonable possibility that 
the study drug or study procedure or artificial tears 
caused the adverse event. 
76 
13.5.2. 
Protocol  
Other Safety 
Assessments 
 
The following wording has been added in order 
to optimize the statistical analyses part: 
Other safety assessment parameters (e.g. slit lamp 
examination, dilated fundoscopy, BCDVA, and visual 
field) will be summarized by study period, analysis 
visit and treatment group (Period 1 only).  


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76 
13.7. 
Protocol  
Handling of Missing 
Values 
 
 
The following wording has been deleted or 
added in order to optimize the statistical analyses 
part: 
 
Missing data will be handled within the 
MMRM model for all efficacy assessment 
analysed using this statistical model. 
No missing data on safety endpoints will be 
imputed. 
subjects whose IOP, or CFS/symptom score 
data got censored due to the usage of 
prohibited medications/therapies, their 
censored data after being rescued will be 
imputed using a last-observation-carried-
forward approach (LOCF). For missing IOP 
measures, IOP values taken at the same time 
point (peak or trough) at the last visit prior to 
being rescued will be used for the imputation. 
If during Period 1, a subject has missing data 
but not taking any concomitant medications or 
therapies that has IOP-lowering or OSD sign 
and/or symptom improving effect, the LOCF 
approach will be used to impute the missing 
data on IOP, CFS, or symptom scores (3-
symptom average).  For peak or trough IOP, 
the last observation at peak or trough, 
respectively, will be carried forward. Missing 
data will be only imputed for the primary and 
key secondary efficacy endpoints analyses. 
For medical events including AEs, completely or 
partially missing onset and resolution dates will be 
imputed in a conservative fashion to be detailed in the 
Statistical Analysis Plan (SAP).  Same Likewise 
rules will be applied followed to impute the 
completely or partially missing start and end dates of 
non-study medications.  
 
NAP 
COMPANY/SPONSOR 
APPROVERS 
Replace the name of the clinical operation leader 
due to 
new organisation inside Santen company. 
 
 
 


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SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:   
A Phase III, Multinational, Multicenter, Investigator-Masked, 
Randomized, ActiveControlled Trial, comparing the efficacy and 
safety of DE-130A with Xalatan® in Patients with Open-Angle 
Glaucoma or Ocular Hypertension over a 3-Month period, followed 
by a 12-Month Follow-Up with Open-Label DE-130A Treatment. 
 
 
NCT Number:  
 NCT04133311 
 
Date of the document: 
 11 March 2022 
 
 
 


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STATISTICAL ANALYSIS PLAN 
 
 
 
 
Protocol 
Title: 
A Phase III, Multinational, Multicenter, Investigator-Masked, Randomized, Active-
Controlled Trial, comparing the efficacy and safety of DE-130A with Xalatan® in 
Patients with Open-Angle Glaucoma or Ocular Hypertension over a 3-Month period, 
followed by a 12-Month Follow-Up with Open-Label DE-130A Treatment  
 
 
Product: 
DE-130A (latanoprost 50 microg/ml eye drops emulsion, SD) 
 
 
Protocol 
Number:  
0130A01SA 
 
 
Sponsor: 
Santen Inc. 
 
6401 Hollis Street, Suite 125 
Emeryville, CA  94608 
U.S.A. 
 
 
Date:  
March 11th, 2022 
 
 
Status:  
Version 1.0 
 
CONFIDENTIAL 
 
The information in this document is considered privileged and confidential by Santen Inc. and may not be disclosed to others 
except to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by Federal 
and State Laws.  Persons to whom this information is disclosed must be informed that this information is privileged and 
confidential and that it should not be further disclosed. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
ABBREVIATIONS .........................................................................................................................7 
1. 
INTRODUCTION ........................................................................................................8 
2. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .....................................................9 
2.1. 
Objectives .....................................................................................................................9 
2.2. 
Estimands ......................................................................................................................9 
2.3. 
Endpoints ....................................................................................................................10 
2.3.1. 
Primary Endpoint ........................................................................................................10 
2.3.2. 
Secondary Endpoints ..................................................................................................10 
2.2.2.1. 
Key Secondary Endpoints ...........................................................................................10 
2.2.2.2. 
Other Secondary Endpoints ........................................................................................10 
2.3.3. 
Safety and Tolerability Endpoints ..............................................................................12 
3. 
STUDY DESIGN .......................................................................................................13 
3.1. 
General Study Design .................................................................................................13 
3.2. 
Randomization and Masking ......................................................................................14 
3.3. 
Sample Size Planning .................................................................................................14 
3.4. 
Visits and Assessments ...............................................................................................14 
4. 
TIME-RELATED TERMS .........................................................................................17 
4.1.1. 
Baseline Visit (Day 1) ................................................................................................17 
4.1.2. 
Treatment Start Date and Treatment End Date ...........................................................17 
4.1.3. 
Study Day ...................................................................................................................18 
4.1.4. 
Out-of-Window Measurements and Analysis Window ..............................................18 
4.1.5. 
Extent of Exposure .....................................................................................................19 
5. 
GENERAL CONSIDERATIONS ..............................................................................20 
5.1. 
Handling of Missing Data ...........................................................................................20 
5.1.1. 
Efficacy Measures ......................................................................................................20 
5.1.2. 
Safety Measures ..........................................................................................................21 
5.1.3. 
Dates for Medical Events and Medications ................................................................21 
5.2. 
Multi-Center Studies ...................................................................................................22 


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5.3. 
Multiple Comparisons / Multiplicity ..........................................................................22 
5.4. 
Interim Analysis and Data Monitoring Committee ....................................................22 
6. 
ANALYSIS POPULATION ......................................................................................24 
6.1. 
Randomized Subject Population .................................................................................24 
6.2. 
Full Analysis Set (FAS) Population ...........................................................................24 
6.3. 
Safety Population ........................................................................................................24 
6.4. 
Per-Protocol Population ..............................................................................................24 
6.4.1. 
Glaucoma Per-Protocol Population ............................................................................24 
6.4.2. 
Ocular Surface Disease Per-Protocol Population .......................................................24 
6.5. 
Enrolled Population to Open-Label Period .................................................................24 
6.6. 
Open-Label Population ...............................................................................................25 
6.7. 
Open-Label Safety Population ....................................................................................25 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................26 
7.1. 
Subject Disposition .....................................................................................................26 
7.2. 
Demographics and Baseline Characteristics ...............................................................26 
7.2.1. 
Demographics .............................................................................................................26 
7.2.2. 
Baseline Characteristics ..............................................................................................26 
7.3. 
Medical and Surgical History .....................................................................................27 
7.4. 
Protocol Deviations ....................................................................................................28 
7.5. 
Prior and Concomitant Medications ...........................................................................28 
7.6. 
Treatment Compliance ................................................................................................28 
7.7. 
Treatment Exposure ....................................................................................................29 
8. 
EFFICACY ANALYSES ...........................................................................................30 
8.1. 
Endpoint-Related Definitions .....................................................................................30 
8.1.1. 
Study Eye and Fellow Eye ..........................................................................................30 
8.1.2. 
Baseline Score ............................................................................................................30 
8.1.3. 
Change from Baseline .................................................................................................30 
8.1.4. 
Efficacy Measures ......................................................................................................30 
8.1.4.1. 
Intraocular Pressure ....................................................................................................30 
8.1.4.2. 
Corneal and Conjunctival Fluorescein Staining .........................................................31 
8.1.4.3. 
Ocular Surface Disease (OSD) Symptom Scores .......................................................31 
8.1.4.4. 
Tear Film Break-Up Time ..........................................................................................31 
8.1.4.5. 
Use of Concomitant Artificial Tears (AT) ..................................................................31 


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8.1.4.6. 
Slit Lamp Examination ...............................................................................................31 
8.1.4.7. 
Subjects Global Rating of Treatment .........................................................................32 
8.1.4.8. 
Glaucoma Quality of Life-15 (GQL-15) Questionnaire .............................................32 
8.2. 
Analysis of Primary Efficacy Endpoints ....................................................................33 
8.2.1. 
Primary Analysis of the Primary Efficacy Endpoints.................................................33 
8.2.2. 
Sensitivity Analyses of the Primary Efficacy Endpoints ............................................34 
8.3. 
Analysis of Secondary Endpoints ...............................................................................36 
8.3.1. 
Analysis of the Key Secondary Efficacy Endpoints ...................................................36 
8.3.1.1. 
Primary Analysis of the Key Secondary Efficacy Endpoints .....................................36 
8.2.1.2. 
Sensitivity Analysis of the Key Secondary Efficacy Endpoints .................................37 
8.3.2. 
Analysis of Other Secondary Efficacy Endpoints ......................................................37 
8.3.2.1 
IOP Assessments ........................................................................................................37 
8.2.2.2 
Ocular Surface Disease (OSD) Assessments ..............................................................38 
8.2.2.3 
Quality of Life Assessments .......................................................................................39 
8.2.2.4 
Subject Global Rating of Treatment ...........................................................................39 
8.4. 
Subgroup Analyses .....................................................................................................39 
9. 
SAFETY ANALYSES ...............................................................................................41 
9.1. 
Safety-Related Definitions ..........................................................................................41 
9.1.1. 
Adverse Event (AE) ....................................................................................................41 
9.1.1.1. 
Ocular Adverse Event .................................................................................................41 
9.1.1.2. 
Suspected Adverse Reaction .......................................................................................41 
9.1.1.3. 
Serious Adverse Event (SAE) ....................................................................................42 
9.1.1.4. 
Sight-Threatening Adverse Event...............................................................................42 
9.1.1.5. 
Adverse Event Leading to Discontinuation ................................................................43 
9.1.1.6. 
Case of Special Interest ..............................................................................................43 
9.1.2. 
Other Safety Measures ................................................................................................43 
9.1.2.1. 
Slit Lamp Examination ...............................................................................................43 
9.1.2.2. 
Best-Corrected Distance Visual Acuity (BCDVA) ....................................................43 
9.1.2.3. 
Dilated and Undilated Fundoscopy ............................................................................44 
9.1.2.4. 
Visual Field .................................................................................................................44 
9.2. 
Adverse Event .............................................................................................................44 
9.3. 
Slit-lamp Examination ................................................................................................45 
9.4. 
Dilated and Undilated Fundoscopy ............................................................................46 


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9.5. 
Best Corrected Distance Visual Acuity (BCDVA) ....................................................46 
9.6. 
Visual Field .................................................................................................................46 
10. 
CHANGES FROM THE PROTOCOL ......................................................................47 
10.1 
Analysis Population ....................................................................................................47 
10.2 
Secondary Efficacy Endpoint .....................................................................................47 
11. 
REFERENCES ...........................................................................................................49 
12. 
APPENDICES ............................................................................................................50 
 
LIST OF TABLES 
Table 1: 
Study Design and Schedule of Assessments ..............................................................15 
Table 2: 
Definitions for Treatment Start and End Dates by Treatment Period ........................17 
 
LIST OF FIGURES 
Figure 1: Study Design and Schedule of Assessments............................................................13 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AT 
Artificial Tears 
BCDVA 
Best Corrected Distance Visual Acuity 
CSI 
Case of Special Interest 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
DED 
Dry Eye Disease 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GQL-15 
Glaucoma Quality of Life-15 Questionnaire 
IOP 
Intraocular pressure 
IOP-L drug 
Intraocular Pressure Lowering drug 
IWRS 
Interactive Web Response System 
LOCF 
last-observation-carried-forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
OAG 
Open-Angle Glaucoma 
OHT 
Ocular Hypertension 
OSD 
Ocular Surface Disease 
PP 
Per-Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Classification 
TFBUT 
Tear Film Breakup Time 
TEAE 
Treatment Emergent Adverse Event 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the statistical methods to be implemented for the 
analysis of data collected from DE-130A within the scope of Santen’s Protocol 0130A01SA , “A 
Phase III, Multinational, Multicenter, Investigator-Masked, Randomized, Active-Controlled 
Trial, comparing the efficacy and safety of DE-130A with Xalatan® in Subjects with Open-
Angle Glaucoma or Ocular Hypertension over a 3-Month period, followed by a 12-Month 
Follow-Up with Open-Label DE-130A Treatment ”. It applies to the study protocol dated 26 
February 2021 and provides detailed instructions as to how each analysis will be performed.    
Results obtained from the analyses specified in the final approved version of the SAP will 
become the basis of the clinical study report (CSR) for this protocol.  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, ENDPOINTS AND ESTIMANDS 
2.1. 
Objectives 
The primary objective is to demonstrate that the intraocular pressure (IOP) reducing effect of 
DE-130A (latanoprost 50 microg/ml preservative-free eye drops emulsion) is non-inferior to that 
of Xalatan® (latanoprost 50 microg/ml BAK-preserved eye drops solution), in subjects with 
Open-Angle Glaucoma (OAG) or Ocular Hypertension (OHT) at Week 12 without using any 
rescue medication(s).  
 
The secondary objectives are: 
• To compare the effect on improving Ocular Surface Disease (OSD) signs and symptoms 
between treatment groups over 3 months (Period 1). 
• To estimate the effect of DE-130A on OSD signs and symptoms up to 15 months 
(Periods 1 & 2). 
• To compare the efficacy on IOP reduction between treatment group over 3 months 
(Period 1). 
• To estimate the effect of DE-130A on IOP to 15 months (Periods 1 & 2). 
• To estimate the local ocular tolerance and systemic safety of the two treatments over 3 
months (Period 1). 
• To estimate the local ocular tolerance and systemic safety of DE-130A up to 15 months 
(Periods 1 & 2). 
 
2.2. 
Estimands  
Primary estimands of the primary objective is;  
- 
The difference between the mean change from baseline IOP (peak and trough) after 
Week 12 in subjects with OAG or OHT treated with DE-130A versus Xalatan.  For 
subjects who had received IOP rescue medication before Week 12 or who discontinued 
due to any reason during double masked period, the data of IOP will be censored (treated 
as missing value), then primary model will be applied.       
 
Supplementally, estimand for key-secondary endpoint are also described.  This will be used 
when statistical testing strategy (step down approach) is applied (See Section 8.2 and 8.3).    
- 
The difference between the mean change from baseline CFS score after Week 12 in 
subjects with OAG or OHT and with baseline CFS score ≥ 1 treated with DE-130A 
versus Xalatan.  For subjects who had received rescue medication before Week 12 or 
who discontinued due to any reason during double masked period, the data will be 
censored (treated as missing value), then primary model will be applied.  
- 
The difference between the mean change from baseline OSD symptom score after Week 
12 in subjects with OAG or OHT and with baseline OSD symptom average score>0 
treated with DE-130A versus Xalatan.  For subjects who had received rescue medication 


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before Week 12 or who discontinued due to any reason during double masked period, the 
data will be censored (treated as missing value), then primary model will be applied.  
 
 
2.3. 
Endpoints  
2.3.1. 
Primary Endpoint 
The primary efficacy endpoint is the change from baseline in peak (9:00 am ± 1 hour) and trough 
(4:00 pm ± 1 hour) IOPs, respectively, at Week 12 between the two treatment groups in the study 
eye. 
2.3.2. 
Secondary Endpoints 
2.2.2.1. 
Key Secondary Endpoints 
The key secondary endpoints are: 
• 
Change from baseline in CFS score in the study eye at Week 12 in patients with baseline 
CFS ≥ 1 
• 
Change from baseline in OSD symptom score (average of 3 symptoms: dry eye sensation, 
blurred/poor vision and burning/stinging/itching) in the study eye at Week 12 in patients 
with baseline symptom average score>0. 
2.2.2.2. 
Other Secondary Endpoints 
Other secondary efficacy endpoints are: 
• 
Ocular surface disease related endpoints:  
o CFS in the study eye at Week 4 in subjects with baseline CFS ≥ 1 
o Tear film break-up time (TFBUT) in the study eye at Week 4 and Week 12 in 
subjects with baseline TFBUT ≤ 10 
o Conjunctival hyperemia (measured by slit lamp scored using the photographic 
scale derived from McMonnies scale [1 to 6]) in the study eye at Week 4, Week 
12 
o Conjunctival fluorescein staining in the study eye at Week 4 and Week 12 in 
subjects with baseline conjunctival fluorescein staining ≥ 1 
o Dry eye sensation symptom in the study eye at Week 4 and Week 12  
o Blurred/poor vision symptom in the study eye at Week 4 and Week 12  
o Burning/stinging/itching symptom in the study eye at Week 4 and Week 12  
o Slit lamp examination (Meibomian gland dysfunction, conjunctiva chemosis, lids 
and tear film debris) in the study eye at Week 4 and Week 12 
o CFS in the study eye at Month 6, Month 9 and Month 15/early termination in 
subjects with baseline CFS ≥ 1 


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o Tear film break-up time (TFBUT) in the study eye at Month 6, Month 9 and 
Month 15/early termination in subjects with baseline TFBUT ≤ 10 
o Conjunctival hyperemia (measured by slit lamp scored using the photographic 
scale derived from McMonnies scale [1 to 6]) in the study eye at Month 6, Month 
9 and Month 15/early termination  
o Conjunctival fluorescein staining in the study eye at Month 6, Month 9 and Month 
15/early termination in subjects with baseline conjunctival fluorescein staining ≥ 
1 
o Dry eye sensation symptom in the study eye at Month 6, Month 9 and Month 
15/early termination  
o Blurred/poor vision symptom in the study eye at Month 6, Month 9 and Month 
15/early termination  
o Burning/stinging/itching symptom in the study eye at Month 6, Month 9 and 
Month 15/early termination  
o Slit lamp examination (Meibomian gland dysfunction, conjunctiva, lids and tear 
film debris) in the study eye at Month 6, Month 9 and Month 15/early termination 
 
• 
IOP related endpoints: 
o Change from baseline in mean diurnal IOP in the study eye at Week 12 
o Change from baseline in peak, trough, and mean diurnal IOP in the study eye at 
Week 4 
o Peak, trough, and mean diurnal IOP response in the study eye at Week 4 and 
Week 12: 
▪ IOP 20% response (reduction in mean IOP of ≥ 20% from Baseline 
at the specified follow-up visit)  
▪ IOP 25% response (reduction in mean IOP of ≥ 25% from Baseline 
at the specified follow-up visit)  
▪ IOP 30% response (reduction in mean IOP of ≥ 30% from Baseline 
at the specified follow-up visit)  
▪ IOP < 18 mmHg response (mean IOP < 18 mmHg at the specified 
follow-up visit) 
o Morning (9:00 am ± 1 hour) IOP in the study eye of patients treated with DE-130A 
at Month 6, Month 9, Month 15/early termination (Period 2) and change from 
baseline at each Period 2 visit 
• 
Subject global rating of treatment at Month 15/early termination) and Week 12. 
• 
Quality of life (Glaucoma Quality of Life-15) scores at Baseline visit, Week 12, and 
Month 15/early termination visits. 


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2.3.3. 
Safety and Tolerability Endpoints   
For Safety Population, at all visits and for each treatment (Period 1) and for the Open-Label 
Population for DE-130A at all visits (Period 2 and Periods 1 & 2 combined), safety and 
tolerability endpoints are: 
• The incidence and severity of ocular and systemic adverse events  
• Best-corrected distance visual acuity (BCDVA) 
• Slit lamp examination (lashes, anterior chamber and lens) 
• Dilated and undilated (for cup-to-disc ratio) fundoscopy  
 


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3. 
STUDY DESIGN 
3.1. 
General Study Design 
The proposed 3-month phase III study is a prospective, interventional, multinational, multicenter 
investigator-masked, randomized, active-controlled trial to demonstrate the non-inferior IOP 
reducing effect of DE-130A (latanoprost 50 microg/ml preservative-free eye drops emulsion) 
compared to Xalatan® (latanoprost 50 microg/ml BAK-preserved eye drops emulsion) over a 12 
weeks treatment period (Period 1) in subjects with OAG or OHT. In addition, after Week 12, a 
12-month follow-up with open-label DE-130A in a subgroup of subjects (n=130 and some 
Belgium subjects) will estimate the long-term safety and tolerance and explore the long-term 
efficacy of DE-130A (Period 2).  Period 2 will be open in some countries only. 
After a wash-out phase (5 days to 5 weeks) depending on previous IOP lowering medications, 
approximately 380 subjects are randomized in a 1:1 ratio to receive either: 
• 
Test regimen - DE-130A (latanoprost 50 microg/ml preservative-free eye drops 
emulsion) once daily (QD) at 9 PM for 12-week duration of the double-masked treatment 
period. 
 
• 
Control regimen - Xalatan® groups (latanoprost 50 microg/ml BAK-preserved eye 
drops emulsion) QD at 9 PM for 12-week duration of the double-masked treatment 
period. 
At the end of the double-masked period, the first 130 subjects and some Belgium subjects who 
complete the Week 12 visit and agree to participate in the safety follow-up will enter the open-
label period and receive DE-130A QD for additional 12 months (Figure 1). 
The study duration (including the wash-out period) will be up to 16 months, and subjects will 
attend up to 6 scheduled visits after Screening visit (Table 1). 
The study design is illustrated by Figure 1. 
Figure 1: 
Study Design and Schedule of Assessments  
 


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IOP-L drug: intraocular pressure-lowering drug   
Notes:   
* Start of the open-label DE-130A 12-month safety follow-up for the first 130 subjects and some Belgium who complete their 
Week 12 visit and agree to participate in the open-label period of the study.  
** End of study for subjects who do not participate in the open-label period of the study. 
 
3.2. 
Randomization and Masking 
At the Baseline Visit (Day 1), subjects who are eligible for the study will be randomly assigned 
(by the IWRS) in a 1:1 ratio to receive either DE-130A or Xalatan® for 12 weeks.  The 
randomization will be stratified according to the CFS score of the study eye at the Baseline Visit 
(CFS ≤ 1 vs. CFS ≥ 2, modified Oxford scale). 
This study is investigator-masked because the appearance of the two eye drops are totally 
different and it would be impossible to mask the subjects. But subjects shall not be explicitly told 
about the name of the study drug by the drug dispensing staff. Every effort will be made to keep 
all study team members involved in the study masked during the whole Period 1 study period, 
this shall include Santen personnel (except for drug supply personnel), CRO personnel 
(including CRAs except the ones in charge of accountability), and staffs at all clinical centers 
(except the drug dispensing person), etc. 
3.3. 
Sample Size Planning 
For the primary efficacy endpoint of change from baseline in peak IOP and trough IOP, 
separately, at Week 12 visit, sample size calculation was based on data obtained from the phase 
II study (NVG10E118). Sample size was thus calculated assuming a mean difference in IOP 
change from baseline of 0 mmHg and a common standard deviation of 4.26 mmHg in the peak or 
trough IOPs, respectively, for the comparison between the DE-130A and the control (Xalatan®) 
groups. A total sample size of approximately 380 subjects (190 per treatment arm) will provide 
90% power to demonstrate the non-inferiority of the DE-130A group to the control group (one-
sided α = 0.025) for non-inferiority margin of 1.5 mmHg, assuming 10% dropout rate. 
3.4. 
Visits and Assessments 
The schedule for all study-related procedures and evaluations are shown in Table 1: 
Study 
Design and Schedule of Assessments. Assessments should be completed at the designated visit/time 
point(s) and should be performed in both eyes. 


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Table 1: 
Study Design and Schedule of Assessments  
 
Screening 
Baseline 
Period 1 
Period 2 
End of Study Visit 
 
 
-5 days to 
Week -5 a  
Day 1 
Week 4 
(Day 29 
± 3 days) 
Month 6 b 
(Day181 
±7days) 
Month 9 
b (Day 
271 
±7days) 
Period 1: Week 12 
(Day 85 ± 3 days) 
Period 2: Month 15 
b (Day451± 7 days)  
Early Termination 
Unscheduled visit 
Signed Informed consent 
X 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Review of Inclusion/Exclusion Criteria  
X 
X 
 
 
 
 
 
Ocular and systemic medical history 
X 
 
 
 
 
 
 
Previous and concomitant ocular and systemic medications 
(including ATs)  
X 
X† 
X† 
X† 
X† 
X† 
X† 
Urine pregnancy test (women of childbearing potential only)  
X 
 
 
 
 
X  
 
Unpreserved artificial tears use c 
X 
X† 
X† 
X† 
X† 
X† 
X† 
OSD symptoms d 
X 
X† 
X† 
X† 
X† 
X† 
X† 
Quality of life questionnaire (Glaucoma Quality of Life-15) e 
 
X† 
 
 
 
X† 
 
Subject Global Rating of Treatment  
 
 
 
 
 
X† 
X† 
Best corrected distance visual acuity (BCDVA) 
X 
X† 
X† 
X† 
X† 
X† 
X† 
Slit lamp examination 
X 
X† 
X† 
X† 
X† 
X† 
X† 
Ocular Surface Disease Evaluations (TFBUT, corneal and 
conjunctival fluorescein staining with modified Oxford scale) 
X 
X† 
X† 
X† 
X† 
X† 
X† 
Morning IOP f 
X 
 
 
X 
X 
X (only Period 2) 
X (only if during 
Period 2) 
Diurnal IOP (Peak and trough times) g 
 
X 
X 
 
 
X (only Period 1) 
X (only if during 
Period 1) 
Cup to disc ratio (undilated fundoscopy) 
 
X 
X 
X 
X 
 
X 
Dilated fundoscopy 
X 
 
 
 
 
X# 
 
Visual Field* 
         X 
X 
 
 
X 
 
 
Adverse events (AEs) i 
 
X 
X 
X 
X 
X 
X 
Discontinuation of current IOP lowering medication 
         X 
 
 
 
 
 
 
Randomise qualified subjects to treatment 
 
X 
 
 
 
 
 
Dispensation of Washout IOP lowering medication j 
X 
 
 
 
 
 
 
Collection of Wash-out IOP lowering medication j 
 
X 
 
 
 
 
 
Dispensation of investigator-masked study medication k 
 
X 
 
 
 
 
 
Dispensation of open-label study medication l 
 
 
 
X 
X 
X 
 
Collection of unused study medication m 
 
 
 
X 
X 
X 
 


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† To be performed/completed before the morning IOP time point (9:00 am ± 1 hour)  
‡ To be performed/completed after the afternoon IOP time point (4:00 pm ± 1 hour)  
# Period 1: To be performed/completed after the afternoon IOP time point (4:00 pm ± 1 hour)     
    Period 2: To be performed/completed after the morning IOP time point (9:00 am ± 1 hour) 
a in agreement with the following conditions: - Prostaglandin analogs:  = 4 weeks - Topical beta blockers:  ≥ 3 weeks and ≤ 4 weeks - Topical carbonic anhydrase inhibitors: ≥ 5 
days and ≤ 4 weeks - All other IOP lowering medication:  ≥ 2 weeks and ≤ 4 weeks    
* At screening if not already performed within the last 6 months prior to screening. At baseline and Month 9 for the first 130 subjects who will be part on the period 2. 
b Months are of 30 days length. 
c Unpreserved artificial tears (AT) use :  average daily use of AT will be asked by the investigator.  
d 3-symptom will be completed at the investigational site. 
e QoL questionnaires to be completed at the investigational site.  
f Must be performed at 9:00 am (all IOP measurements must be conducted within +/- 1 hour of the required time), using Goldmann applanation tonometry.  
g Must be performed at 9:00 am and 4:00 pm time points (all IOP measurements must be conducted within +/- 1 hour of the required time), using Goldmann applanation 
tonometry.  
i Record AEs if the unscheduled visit is after the first study drug administration.  
j Over the wash-out period: brinzolamide one drop twice daily.  
k EITHER one drop of DE-130A (latanoprost 50 microg/ml) OR one drop of Xalatan®(latanoprost 50 microg/ml) once daily in the evening (9 pm ± 1 hour), in the conjunctival 
sac of the affected eye(s).  
 l one drop of DE-130A once daily (latanoprost 50 microg/ml) for 12 months. 
 m In order to keep the investigator masked to the study medication, the unused study medication of Period 1 will only be collected at Week 12 visit.


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4. 
TIME-RELATED TERMS 
4.1.1. 
Baseline Visit (Day 1) 
The Baseline Visit is Day 1 when the subject is randomized.   
 
NOTE: If an endpoint is not measured at Day 1 Baseline visit, the nearest data prior to first 
dosing day will be defined as the baseline.   
4.1.2. 
Treatment Start Date and Treatment End Date 
Treatment start date and treatment end date for each treatment period are defined as follows in 
Table 2. 
Table 2: 
Definitions for Treatment Start and End Dates by Treatment Period  
Treatment 
Period 
Treatment Start Date 
Treatment End Date 
Double-Masked 
(DM) Treatment 
Period 
The date at which a 
randomized subject 
takes the first dose of 
the DM study drug 
The date at which a randomized subject takes the 
last dose of the DM study drug.  If the date of 
the last dose is missing and the subject does not 
receive any OL study drug:  
• The day before the Week 12 date will be 
considered the treatment end date for subjects 
who completed the Week 12 Visit 
• The day before the Exit Visit date will be used 
for subjects who prematurely discontinued 
from the study before Week 12 visit.  If the 
Exit Visit date of a non-completer is not 
available, then the day before the last available 
visit date will be considered the treatment end 
date 
Open-Label 
(OL) Treatment 
Period 
The date at which a 
randomized subject 
takes the first dose of 
the OL study drug 
The date at which a randomized subject takes the 
last dose of the OL study drug.  If the date of the 
last dose is missing: 
• The day before the Month 15 date will be 
considered the treatment end date for subjects 
who completed the Month 15 Visit 
• The day before the Exit Visit date will be used 
for subjects who prematurely discontinued 
from the study during OL period.  If the Exit 
Visit date of a non-completer is not available, 


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then the day before the last available visit date 
will be considered the treatment end date 
Entire Study 
The date at which a 
randomized subject 
takes the first dose of 
the DM study drug 
The date at which a randomized subject takes the 
last dose of the study drug. 
Missing last dose date will be handled the same 
way as mentioned above. 
Notes:  
1) For each treatment period, the treatment end date will be set to missing if the treatment start date is missing. 
2) OL Treatment Period and Entire Period only apply to the first 130 subjects and some Belgium subjects who 
complete their week 12 visit and agree to participate in the OL period. 
4.1.3. 
Study Day 
The study day variable describes the relative day of the observation starting with the reference 
date.  For this study, the treatment start date is the reference date, which is the Baseline Visit 
(Day 1) date. The study day will be calculated as: 
• For days prior to the Baseline Visit, Study Day = Date – Treatment Start Date  
• For days on/after the Baseline Visit, Study Day = Date – Treatment Start Date + 1 
Note that there is no Day 0 and the Baseline Visit date is Day 1. 
4.1.4. 
Out-of-Window Measurements and Analysis Window 
For this study, a measurement collected at a visit is an out-of-window measurement if the study 
day of the visit falls outside of a visit window specified in the protocol (Table 1), or it is a 
within-window measurement otherwise. 
Analysis visit is a timing variable to be used for analyses involving visits.  For each analysis visit, 
an analysis window is set up to determine the analysis visit to which a measurement should be 
mapped. The analysis window, which is wider than the visit window, will be employed to 
minimize the impact of missing data due to out-of-window measurements for analysis.  The 
analysis windows for all post-baseline visits will be specified in the ADaM specifications 
document.  The table below shows the analysis windows for post-baseline visits up to Month 15. 
Analysis Visit Name  
(Target Assessment Date) 
Protocol-defined 
Visit Window 
Analysis Window 
Analysis Window 
(QOL ONLY) 
Week 4 (Day 29) 
[26, 32] 
 [2, 57] 
 
Week 12 (Day 85) 
[82, 88] 
 [58, 133] 
[2, 268] 
Month 6 (Day 181) 
[174, 188] 
[134, 226] 
 
Month 9 (Day 271) 
[264, 278] 
[227, 361] 
 
Month 15 (Day 451) 
[444, 458] 
[362 -  
[269 - 


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For analyses involving post-baseline visits, if there are two or more measurements that fall into 
the same analysis window of a post-baseline visit, then the measurement closest to the target 
assessment day will be selected for that visit for analysis while the other measurement will be 
excluded from analysis.  In the case when the two closest measurements are of the same distance 
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 and used for analysis while the other measurement will be 
excluded from analysis. 
For analyses of IOP involving post-baseline visits in Period 1, 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 (peak and trough) will be selected for that analysis visit 
first, before applying the above rule. 
4.1.5. 
Extent of Exposure 
The extent of exposure to study medication will be assessed by duration of treatment exposure, 
which will be derived using the following formula: 
Duration of treatment exposure = (Treatment end date – Treatment start date) + 1 
Treatment exposure will also be categorized into the following categories:  
• 
For subjects who only enter Period 1:  
o < 31 days 
o 31 – 60 days 
o 61 – 90 days 
o > 90 days 
• 
Additional categories for subjects who enter Period 2:  
o < 151 days 
o 151 – 240 days 
o 241 – 330 days 
o 331 – 420 days 
o 421 – 481 days 
o > 481 days 


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5. 
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 (%). 
Unless otherwise specified, the following conventions will be followed in reporting the decimal 
places. 
Variables 
Decimal Places 
Range (low value, high value) 
Recorded decimal places 
Mean, median 
Recorded value + 1 decimal places 
Confidence interval, standard deviation, 
standard error 
Recorded value + 2 decimal places 
p-Value 
4 Decimal places 
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 SAS® Version 9.4 or later. 
Additional analyses not specified in this SAP may be conducted if deemed necessary and will be 
documented in the CSR. 
5.1. 
Handling of Missing Data 
5.1.1. 
Efficacy Measures 
If a subject takes any concomitant medications or undergoes any concomitant therapies listed in 
Section 8.3 of the protocol, IOP and/or CFS and OSD symptom scores after taking the 
medication/therapy will be censored (treated as missing) for the primary and/or key secondary 
efficacy endpoints analyses in double-masked period. The endpoint(s) that will be censored 
depends on the medications or therapies taken, which will be determined by the Sponsor team 
during the masked data review before database lock.   
Different lists of medications will be applied to IOP and CFS/Symptom endpoints.  
• IOP data will be censored after any IOP-lowering medication/therapy is taken.  
• CFS and symptom scores will be censored after any medication (including artificial tears 
change)/therapy that might have any effect on the OSD signs and symptoms. 
 
 


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For OSD symptom score (average of 3 symptoms) calculation: 
• If one out of the three individual symptom scores is missing, use the average of two non-
missing symptom scores; 
• If two out of the three individual symptom scores are missing, use the one non-missing 
score.  
 
For primary and key secondary endpoints: the below imputation approach are applied.   
• No imputation is needed for the analysis on observed cases using the Mixed-effects 
Model for Repeated Measures (MMRM).  
• Pattern mixture model will be applied to evaluate robustness of primary analysis 
depending on the reasons of discontinuation or rescue medication  
 
For mean diurnal IOP calculation: if there is a missing IOP measurement at a scheduled 
timepoint, the mean diurnal IOP will not be calculated. 
 
5.1.2. 
Safety Measures 
Descriptive summaries of safety measures will be based on observed data.  No imputation of 
missing scores will be implemented. 
5.1.3. 
Dates for Medical Events and Medications 
The completely or partially missing onset and resolution dates of medical events, i.e., medical 
history events and AEs, will be imputed in a conservative fashion as follows: 
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 day of YYYY to impute the missing 
month and date parts of the onset date 
YYYY and MM are 
available but DD is missing 
Use the first day of MM to impute the missing date 
part of the onset date 
 


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Date 
Type of Missing Date 
Handling of Missing 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 Study 
Exit date. 
Only YYYY is available 
Use the last day of YYYY to impute the missing 
month and date parts of the resolution date  
YYYY and MM are 
available but DD is missing 
Use the last day of MM to impute the missing date 
part of the resolution date 
Same rules will be followed to impute the completely or partially missing start and end dates of 
non-study medications. 
5.2. 
Multi-Center Studies 
This study is a multinational and multi-center study.  Since there are many small investigational 
sites, site will not be included as a covariate in statistical models.  Instead, country will be used 
as a covariate in statistical models. 
5.3. 
Multiple Comparisons / Multiplicity 
To control for the overall Type I error rate associated with the multiple comparisons on the 
primary and the key secondary endpoints at the 0.05 level (two-sided), the following hierarchical 
testing strategy will be employed: 
1. Conduct the statistical testing for the primary comparison between DE-130A and Xalatan 
on the primary endpoint. Difference between the two treatment groups in change from 
baseline in both the peak and trough IOP at Week 12, separately, have to meet the non-
inferiority criterion that the upper limit of the one-sided 97.5% confidence interval is less 
than or equal to the non-inferiority margin of 1.5 mmHg.  
2. If non-inferiority in the primary efficacy endpoints is achieved, conduct the statistical 
testing for the comparison between DE-130A and Xalatan on the following key 
secondary endpoints sequentially according to hierarchical fixed sequence procedure: 
1) Change from baseline in CFS score at Week 12 in subjects with baseline CFS ≥ 1. If 
the hypothesis is rejected at the 0.05 significance level (two-sided), then the following 
key secondary endpoint will be tested.  
2) Change from baseline in OSD symptom score (average of 3 symptoms: dry eye 
sensation, blurred/poor vision and burning/stinging/itching) in the study eye at Week 
12 in subjects with baseline symptom average score >0.  
5.4. 
Interim Analysis and Data Monitoring Committee 
There is no planned interim analysis and no data monitoring committee for this study. 
At the end of Period 1, when all subjects have completed their Week 12 Visit, database will be 
“soft” locked and be used to analyze all Period 1 endpoints per this SAP.  The data cut plan of 


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this study is prepared as a separate document, and it details how data collected during period 2 
will be cut for this “snapshot”.  


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6. 
ANALYSIS POPULATION 
6.1. 
Randomized Subject Population  
This population consists of all subjects who randomized in the study.   
6.2. 
Full Analysis Set (FAS) Population 
The FAS population consists of all randomized subjects who received at least one dose of study 
medication and provided at least one post-baseline IOP measurement at peak and trough 
timepoints, separately. Unless specified otherwise, the FAS population will be the analysis 
population for efficacy endpoints analyses in Period 1 and will use treatment as randomized.  
6.3. 
Safety Population 
The Safety population consists of all subjects randomized in the study who received at least one 
dose of the study medication. The Safety population will be the analysis population for all safety 
analyses in Period 1 and will use treatment as actually received. 
6.4. 
Per-Protocol Population 
Per-Protocol (PP) population is a subset of the FAS and is defined as two separate definitions 
depending on endpoints, primary efficacy (Glaucoma PP population) and key secondary 
endpoints (Ocular Surface PP population).   
Before the unmasking of treatment assignment, Santen’s study team will review all protocol 
deviations, identify subjects with any protocol deviation that could affect the efficacy outcome, 
and determine whether or not to exclude the subject from these PP population.   
6.4.1. 
Glaucoma Per-Protocol Population 
The Glaucoma Per-Protocol (PP) population will be a subset of the FAS subjects. It includes all 
FAS subjects without any of the major protocol deviations that could affect the primary efficacy 
endpoint. The Glaucoma PP population will be used for sensitivity analyses of the primary 
efficacy endpoints in Period 1 and will use treatment as randomized.  
6.4.2. 
Ocular Surface Disease Per-Protocol Population 
The Ocular Surface Disease Per-Protocol (OSD-PP) population will be a subset of the FAS 
subjects. It includes all FAS subjects without any of the major protocol deviations that could 
affect the key secondary efficacy endpoint.  The OSD - PP population will be used for sensitivity 
analyses of the key secondary efficacy endpoints in Period 1 and will use treatment as 
randomized.  
6.5. 
Enrolled Population to Open-Label Period 
The enrolled population to open-label period will be the first 130 and some Belgium subjects 
who had informed consent to enroll in period 2.  


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6.6. 
Open-Label Population 
The Open-Label population will be subjects who are the first 130 subjects and some Belgium 
subjects who complete their Week 12 Visit and agree to participate in the open-label period of 
the study and received at least one dose of the study medication during the open-label period and 
provided at least one morning IOP measurement after the Week 12 Visit. This population will be 
the analysis population for the analyses of efficacy endpoints in Period 2 and for Periods 1 & 2 
combined data and will use treatment as randomized. 
6.7. 
Open-Label Safety Population 
The Open-Label Safety population will be subjects who are the first 130 subjects and some 
Belgium subjects who complete their Week 12 Visit and agree to participate in the open-label 
period of the study and received at least one dose of the study medication during the open-label 
period. The Open-Label Safety population will be the analysis population for all safety analyses 
in Period 2 and for Periods 1 & 2 combined data and will use treatment as actually received. 
 
 


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7. 
SUMMARY OF STUDY POPULATION DATA 
7.1. 
Subject Disposition 
The subject disposition will be summarized based on all screened subjects for Period 1 (double 
masked period) and based on all enrolled subjects to Period 2 (enrolled population to open label 
period) for Period 2 separately.   
For the period 1, it will be summarized by planned treatment group (and overall) and include the 
number of screened subjects, the number (n) and percentage (%) of Safety, FAS and PP subjects 
(on randomized subjects).  This disposition summary will also include the n and % of subjects 
who completed or discontinued.  For discontinued subjects, the summary (n and %) will also be 
summarized by each reason.    
For the period 2, it will be summarized by planned treatment group (and overall) and include the 
number of enrolled subjects in period 2, the number (n) and percentage (%) of open-label safety 
population and open label population subjects (on all enrolled subject in period 2 (signed 
informed consent for this period)).  This disposition summary will also include the n and % of 
subjects who completed, subjects who are still on the study at the time of data cut (interim data 
only), or subjects who discontinued during period 2.  For discontinued subjects, the summary (n 
and %) will also be summarized by each reason. 
 
In addition, the subject enrollment will be summarized by region (EU, and non-EU), country and 
primary investigator name. 
7.2. 
Demographics and Baseline Characteristics 
Subject demographic characteristics and baseline characteristics will be summarized by planned 
treatment group on FAS and Open-label population, separately.  
7.2.1. 
Demographics 
The following subject demographics variables will be summarized: 
• Age on consent date (continuous and categorical: < 65 years and ≥ 65 years) 
• Sex (categorical: male and female) 
• Race (categorical: American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, Other, and Unknown) 
7.2.2. 
 Baseline Characteristics 
The following baseline characteristics variables will be summarized for study eye and fellow eye 
separately.  In addition, this table will be summarized by planned treatment group and by CFS 
subgroups on FAS: 
• Primary diagnosis (categorical):  
o Primary open angle glaucoma 


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o Pseudo exfoliative glaucoma 
o Pigmentary glaucoma 
o Ocular hypertension 
• Time since diagnosis (continuous) 
• Baseline IOP-lowering medication(s) (categorical: prostaglandin analogues, beta 
blocking agents, carbonic anhydrase inhibitors, each combination of medications, 
other) 
− For “each combination of medications”, all combinations of this study will be 
included in the table.  
• Baseline peak (9 am), trough (4 pm), and mean diurnal IOP (continuous) 
• Baseline CFS score (continuous and categorical) 
− Categorical (Grade): 0.5, 1, 2, 3, 4, 5  
− This is not included for CFS subgroup tables because CFS is considered as 
subgroup factor. 
 
In addition, the following variables at baseline will be summarized.  
• Alcohol use [yes or no; if yes, ≤ 30 g per day (women) or ≤ 40 g per day (men), > 30 g 
per day (women) or > 40 g per day (men)] 
• Illicit or recreational drug use (yes or no) 
• Tobacco use 
o Yes 
▪ Ex-smoker (number of packets per year and duration of smoking) 
▪ Current smoker (number of packets per year and duration of smoking) 
o No 
▪ Passive tobacco use (yes, no)  
 
 
7.3. 
Medical and Surgical History 
The medical history events will be coded using the MedDRA Version 23.1 and summarized 
based on FAS for period 1 and based on open-label population for period 2.   
Subjects reporting any medical history events will be tabulated by SOC and preferred term.  In 
addition, subjects reporting any medical history events ongoing at baseline will also be tabulated.  
Any subject with more than one medical and/or surgical term within the same SOC (or mapped 
to the same preferred term) will be counted only once for that SOC (or preferred term). 
This study also collects data on the surgical procedures/therapies that are performed during the 
study. Those data will be listed. 


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7.4. 
Protocol Deviations 
In this study, protocol deviations are categorized as follows: 
• Consent Issues 
• Enrollment Issues 
• Protocol Implementation Issues 
• Safety Issues 
• Investigational and Non-Investigational Product  
• 
Others  
 
A protocol deviation is considered major if it may affect the subject’s rights, safety, or well-
being and/or the completeness, accuracy, and reliability of the study data.  Santen’s study team 
will review all protocol deviations and determine the major protocol deviations prior to database 
lock.   
FAS subjects or open label population to open label period subjects with any major protocol 
deviations will be tabulated by deviation category for period 1and 2.  In addition, two types 
protocol deviation list will be prepared, all significant (major) protocol deviation and subjects 
who excluded from per protocol population (Period 1 only).   
7.5. 
Prior and Concomitant Medications 
Non-study medications will be categorized into prior medications and concomitant medications.  
Specifically, prior medications are non-study medications started and ended prior to the 
treatment start date (Day 1). Concomitant medications are defined as any non-study medications 
taken concurrently while on the study medication.  
All prior and concomitant medications will be classified using the Anatomical-Therapeutic-
Chemical (ATC) classification system, mapped to a World Health Organization Drug Dictionary, 
Version Enhanced (WHO-DDE, September 2018) format B3 preferred drug name, and 
summarized on the FAS subjects for Period 1, and open label population for Period 2, separately.  
A subject will be counted at most once for each prior or concomitant medication, separately, 
even if the subject might take the same prior or concomitant medication on multiple occasions. 
7.6. 
Treatment Compliance 
Treatment compliance will be summarized (continuously and categorically) on the FAS 
population for Period 1, and on open-label population for Period 2 and the entire study period 
separately.  
Treatment compliance will be assessed at each scheduled visit and unscheduled visit.  Dose(s) 
missed since the previous visit will be asked.  For the purpose of treatment compliance 
calculation, there will be five study intervals: 
• Baseline Visit (Day 1) to Week 4 Visit 
• Week 4 Visit to Week 12 Visit 


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• Week 12 Visit to Month 6 Visit 
• Month 6 Visit to Month 9 Visit 
• Month 9 Visit to Month 15 Visit 
For a given study interval, compliance rate will be calculated using the following formula: 
Compliance = Number of days of the followup interval − Number of missed doses
Number of days of the followup interval
 x 100 
Compliance rate of ≥ 80% will be treated as compliant. 
 
7.7. 
Treatment Exposure 
The duration of exposure to a study medication is measured by days on treatment as derived in 
Section 4.1.5.  The duration of exposure will be summarized using descriptive statistics, and 
frequency and percentage of subjects will be tabulated by actual treatment received for period 1 
(Safety population), period 2 (Open-label safety population), and the entire study (Safety 
population) separately. For the entire study period, the duration of exposure to overall DE-130A 
treatment will also be provided, which will combine exposure to DE-130A from both period 1 
arms. For subjects who were in the Xalatan arm during period 1, their duration of exposure to 
DE-130A will be the total duration on the study minus the number of days they were exposed to 
Xalatan treatment. 


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8. 
EFFICACY ANALYSES 
All efficacy analyses will use treatment as randomized, and, unless specified otherwise:  
8.1. 
Endpoint-Related Definitions 
8.1.1. 
Study Eye and Fellow Eye 
The study eye is defined as the eye that qualifies based on protocol-defined inclusion/exclusion 
criteria at the Baseline Visit. If both eyes are eligible, the eye with the higher morning IOP at the 
Baseline Visit will be chosen. If both eyes have the same morning IOP value at Baseline, the eye 
with the higher CFS score at the Baseline Visit will be chosen. If both eyes have the same IOP 
and CFS values, then the right eye will be designated as the study eye. The fellow eye is the non 
study eye.  
NOTE: If there is any reason by a investigator site to identify study eye, the team will discuss it 
to define the eye. 
Study eyes and fellow eyes that are designated by this definition will be used for all efficacy 
endpoints analyses. All safety endpoints and baseline characteristics summaries will be based on 
study eyes and fellow eyes. 
8.1.2. 
Baseline Score 
For any measure, the baseline score is the last observed measurement prior to instillation of the 
first drop of the study drug.  If any variable is missing a value on Day 1, values from the 
Screening Visit will be used to impute the baseline score, i.e., the last observation carried 
forward (LOCF) approach will be used to impute the baseline score and used for the purpose of 
calculating change from baseline scores. 
8.1.3. 
Change from Baseline 
For any measure, the change from baseline at a post-baseline visit will be derived as:  
Change from baseline at a post-baseline visit =  
(Score at the post-baseline visit) – (Baseline score). 
8.1.4. 
Efficacy Measures 
8.1.4.1. 
Intraocular Pressure 
IOP will be measured using Goldman applanation tonometry.  Morning IOP (9:00 am ± 1 hour) 
as well as afternoon IOP (4:00 pm ± 1 hour) will be measured at the Baseline (Day 1) Visit, 
Week 4 Visit, Week 12 Visit, and unscheduled visits during Period 1. IOP will be measured only 
in the morning (9:00 am ± 1 hour) at the Screening Visit, Month 6, Month 9 Visit, Month 15 
Visit, and unscheduled visits during Period 2.  
At each time point, IOP will be measured twice on each eye. If the two measurements differ by 
less than 3 mmHg, then the average of the two measurements becomes the recorded IOP. 
However, if the two measurements differ by 3 mmHg or more, then a third measurement is 
made, and the median of the three measurements becomes the recorded IOP. 


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A decrease in IOP at follow-up visits will indicate improvement. 
8.1.4.2. 
Corneal and Conjunctival Fluorescein Staining  
Corneal and conjunctival fluorescein staining will be performed at each scheduled and 
unscheduled visit and will be graded using the modified Oxford scale (7-point ordinal scale, 
score 0, 0.5, and 1 to 5) for cornea and conjunctiva (nasal and temporal conjunctiva) separately 
on each eye.  
A CFS grade of 0 represents complete corneal clearing. A decrease in CFS and/or conjunctival 
fluorescein staining score at follow-up visits will indicate improvement. 
8.1.4.3. 
Ocular Surface Disease (OSD) Symptom Scores 
Three OSD symptoms regarding ocular discomfort unrelated to instillation of the study drug will 
be assessed at each scheduled visit and unscheduled visit:  
• Dry eye sensation 
• Blurred/poor vision 
• Burning/stinging/itching 
The subject will grade each ocular symptom for the week before each visit by its level of severity 
on a 5-point scale (0 = Absent, 1 = Mild, 2 = Moderate, 3 = Severe, and 4 = Very severe). 
A decrease in OSD symptom scores at follow-up visits will indicate improvement. 
8.1.4.4. 
Tear Film Break-Up Time  
Tear film break-up time (TFBUT) will be measured by determining the time to tear break-up. At 
each visit, the TFBUT will be measured twice on each eye separately. If the 2 readings differ by 
more than 2 seconds, then a third reading will be taken. The TFBUT value will be the average of 
the 2 or 3 measurements.  
An increase in TFBUT at follow-up visits will indicate improvement.  
8.1.4.5. 
Use of Concomitant Artificial Tears (AT) 
The use of protocol-authorized, unpreserved artificial tears will be monitored over the course of 
the study for each subject. Subjects will be asked about the average number of times per day 
artificial tears was used over the last week, and number of days they were not used during the 
week preceding the visits at each scheduled and unscheduled visit. Artificial tear usage in the 
past 7 days will be derived using the following equation: 
AT usage = Average number of times per day used AT × (7 – number of days without AT use) 
A decrease in AT usage at follow-up visits will indicate improvement. 
8.1.4.6. 
Slit Lamp Examination 
External ocular examination and undilated biomicroscopy will be performed using a slit lamp at 
each scheduled visit and unscheduled visit. Grading of the Meibomian glands, conjunctival 
erythema/ hyperaemia, anterior chamber inflammation, and lens will be on a 0 to 3 scale; 0 


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indicates normal and 3 indicates the most severe state. Lid erythema, lid swelling, conjunctival 
chemosis, and tear film debris will be graded on a 0 to 4 scale; 0 indicates normal and 4 indicates 
the most severe state. Lashes will be graded as normal or abnormal. 
A decrease in slit lamp grading at follow-up visits will indicate an improvement. 
8.1.4.7. 
Subjects Global Rating of Treatment 
At Week 12 Visit and Month 15 Visit (open-label population only) or early termination visit, 
subjects will be asked to rate their overall assessment of the effect of the glaucoma study 
medication: 
1 = Unsatisfactory 
2 = Not very satisfactory 
3 = Satisfactory 
4 = Very satisfactory. 
Higher score indicates higher satisfaction from the subjects. 
8.1.4.8. 
Glaucoma Quality of Life-15 (GQL-15) Questionnaire 
The Glaucoma Quality of Life-15 (GQL-15) is a questionnaire developed to assess visual 
disability resulting from glaucoma. Subjects will be asked to complete the questionnaire at the 
Baseline Visit, Week 12 Visit, and Month 15 Visit (open-label population only). 
Subjects will be asked to rate the level of difficulty in terms of their vision (with glasses on) on 
15 activities: 
Does your vision give you any difficulty, even with glasses, with the following activities? 
 
None 
A little bit 
Some 
Quite a lot 
Severe 
Do not 
perform for 
nonvisual 
reasons 
Reading newspapers 
1 
2 
3 
4 
5 
0 
Walking after dark 
1 
2 
3 
4 
5 
0 
Seeing at night 
1 
2 
3 
4 
5 
0 
Walking on uneven 
ground 
1 
2 
3 
4 
5 
0 
Adjusting to bright 
lights 
1 
2 
3 
4 
5 
0 
Adjusting to dim 
lights 
1 
2 
3 
4 
5 
0 
Going from light to 
dark room or vice 
versa  
1 
2 
3 
4 
5 
0 


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Tripping over 
objects 
1 
2 
3 
4 
5 
0 
Seeing objects 
coming from the 
side  
1 
2 
3 
4 
5 
0 
Crossing the road 
1 
2 
3 
4 
5 
0 
Walking on 
steps/stairs 
1 
2 
3 
4 
5 
0 
Bumping into 
objects 
1 
2 
3 
4 
5 
0 
Judging distance of 
foot to step/curb  
1 
2 
3 
4 
5 
0 
Finding dropped 
objects 
1 
2 
3 
4 
5 
0 
Recognizing faces 
1 
2 
3 
4 
5 
0 
Sum of individual scores, other than those 0s, will be calculated. For questions that are answered 
as 0s, they will be set as missing and not be used in the analysis. 
Decrease in the sum score at the follow-up visits will indicate improvement. 
8.2. 
Analysis of Primary Efficacy Endpoints 
The primary efficacy endpoints are the change from baseline in peak (9:00 am ± 1 hour) and trough 
(4:00 pm ± 1 hour) IOPs, respectively, at Week 12 between the DE-130A and Xalatan® groups in 
the study eye. 
 
Several endpoint definitions were updated from protocol version 5.0, and only subjects who meet 
the criterion are included in each endpoint analysis.  The below is the lists of criteria.  Please refer 
to each endpoint definition for the detail.   
o Subjects with baseline CFS ≥ 1 
o Subjects with baseline OSD symptom average score >0.  
o Subjects with baseline TFBUT ≤ 10 
o Subjects with baseline conjunctival fluorescein staining ≥ 1 
 
8.2.1. 
Primary Analysis of the Primary Efficacy Endpoints 
For the primary efficacy endpoint, the following hypotheses will be tested: 
H0: µT  – µC > Δ, for at least one timepoint 
vs. 


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HA: µT  – µC ≤ Δ at both timepoints 
where µT and µC denote the mean change from baseline in peak or trough IOP in DE-130A and 
Xalatan® groups, respectively, and Δ denotes the non-inferiority margin of 1.5 mmHg. 
Noninferiority will be established if the upper limit of the one-sided 97.5% confidence interval is 
less than or equal to the non-inferiority margin of 1.5 mmHg at both the peak and rough timepoints.  
Superiority is achieved with respect to this endpoint if the upper limit of the one-sided 97.5% 
confidence interval is ≤ 0 mmHg for both timepoints. 
The analysis of primary efficacy endpoint will be performed on the FAS population using a  
mixed-effects model for repeated measures (MMRM) on observed cases collected up to Week 12 
(Laird & Ware, 1982; Lindstrom & Bates, 1988).  No imputation of missing data will be needed.  
A separate MMRM model will be used for IOP at each timepoint (peak and trough). The model 
will include treatment, visit, and treatment-by-visit interaction as fixed effects, baseline IOP at 
the respective timepoint (peak or trough) and country as covariates. Within-subject errors will be 
modeled using an unstructured (UN) covariance matrix.  
If the UN model fails to converge, then the first-order auto-regression [AR(1)] model and the 
variance components (VC) model will be fitted sequentially until the convergence criteria are 
met.  
 
NOTE: The two-visit data, change from baseline to week 4 or 12, will be used as response values 
to fit a MMRM model, and a two by two matrix will be considered as variance-covariance 
matrix.  Several structures (e.g. TOEPH, TOEP, ARH (1), CS) are same structure as AR(1).   
 
From the MMRM, estimates of treatment effects at Week 12 and the pair wise treatment 
comparison will be based on least square means (LS mean) and the corresponding 95% 
confidence intervals (CI) will be provided.   
 
8.2.2. 
Sensitivity Analyses of the Primary Efficacy Endpoints 
To assess the robustness of the primary analysis results, the following sensitivity analyses will be 
performed on the primary efficacy endpoints: 
• The primary analysis will be repeated on the PP population. 
• The primary analysis will be repeated with multiple imputation using pattern mixture 
model.  See the below for the detail.   
 
 
 
 
 


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Pattern Mixture Model:  
This analysis applies pattern mixture model with two different multiple imputation approach 
depending on the reason to evaluate the robustness of primary analysis under different missing 
mechanism of missing not at random (MNAR) (Ratitch et al. (2013)).   
Glaucoma is a chronic disease, and this scenario assumes that IOP would return to baseline value 
in short term (within 3 month) when a subjects stopped to take the treatment due to the reasons 
(AE and Lack of efficacy) or the censoring after IOP medication, while all other reason of DC is 
assumed to IOP change as other subjects.  The below table shows overall strategy of multiple 
imputation by different type of missing data.    
 
Type of Missing Data 
Imputation Method 
#1 
- 
For subjects who discontinued due to AE 
(Including SAE, Death), or Lack of 
efficacy, the data after the discontinuation.   
- 
For subjects how had any rescue 
medication, data after rescue medication 
(This is assumed to be equivalent to lack of 
efficacy discontinuation).  
 
Baseline value is used as the response value to 
generate multiple imputed data of post-baseline 
IOP values based on the below equation (about 
monotone regression).   
 
Baseline IOP* = Age + Sex + Primary 
Diagnosis (Study Eye) + Time since diagnosis 
(Study Eye).  
#2 
- 
For subjects who discontinued due to all 
other reasons, the data after the 
discontinuation.    
 
Treatment and all post-baseline IOP are used to 
impute post-baseline IOP data based on the 
“monotone regression” under MAR 
assumptions.    
* For key secondary endpoints, this will be replaced to baseline CFS or baseline OSD score.   
 
PMM depending on the reasons will be applied, as follows: 
• Use Markov chain Monte Carlo (MCMC) to create monotone missingness first.  The 
missing data are filled in and 50 complete datasets are created. The seed that will be used 
in the SAS program is 1234.   
• 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, BOCF type multiple imputation will be 
applied based on the model in the above table (#1).  The seed that will be used in the SAS 
program is 2345.  
• For each IOP value that had been missing because of other reasons from the above bullet, 
monotone regression with treatment and all post-baseline data will be applied to impute 
to the rest of missing data (#2).  The seed that will be used in the SAS program is 3456. 
• Each of the complete datasets will be analyzed separately using the same MMRM as used 
for the primary analysis.  


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• The estimates obtained from the MMRM analysis of each complete dataset are combined 
for inference purposes.  
• NOTE: Similar analysis will be applied to key-secondary endpoints as well.   
 
8.3. 
Analysis of Secondary Endpoints 
8.3.1. 
Analysis of the Key Secondary Efficacy Endpoints 
8.3.1.1. 
Primary Analysis of the Key Secondary Efficacy Endpoints 
The following key secondary endpoints will be analyzed using the same MMRM model as 
specified for the primary efficacy endpoint using the observed data: 
• Change from baseline in CFS score in the study eye at Week 12 in subjects with 
baseline CFS ≥ 1. 
• Change from baseline in OSD symptom score (average of 3 symptoms: dry eye 
sensation, blurred/poor vision and burning/stinging/itching) in the study eye at Week 
12 in subjects with baseline symptom average score >0. 
 
The hierarchical testing strategy described in Section 5.3 will be applied to control the overall 
type I error rate associated with the multiple comparisons on the primary and key secondary 
endpoints at the 0.05 level (two-sided). 
 
If non-inferiority in the primary endpoint is achieved, the above two key secondary endpoints 
will be tested sequentially according to hierarchical fixed sequence procedure: 
• Change from baseline in CFS score in the study eye at Week 12 in subjects with baseline 
CFS ≥ 1 
The MMRM model (with observed data) will be used to test the following hypotheses: 
H0S1: µTs1 – µCs1  = 0  
versus  
HAS1: µTs1– µCs1 ≠ 0 
where µTs1 and µCs1 denote the mean change from baseline in CFS in DE-130A and Xalatan® 
groups, respectively. 
If the hypothesis is rejected at 0.05 significance level, then the following key secondary endpoint 
will be tested. 
• Change from baseline in symptom score (3-symptom average) at Week 12 in patients 
with baseline symptom average score>0 


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The MMRM model (with observed data) will be used to test the following hypotheses: 
H0S2: µTs2 – µCs2  = 0 
versus 
HAS2: µTs2 – µCs2 ≠ 0 
where µTs2 and µCs2 denote the mean change from baseline in symptom score (3-symptom 
average) in DE-130A and Xalatan® groups, respectively.  
8.2.1.2. 
Sensitivity Analysis of the Key Secondary Efficacy Endpoints 
The following sensitivity analyses will be conducted on the two key secondary endpoints: 
• The primary analysis will be repeated on the PP population. 
• The primary analysis will be repeated with multiple imputation using pattern mixture 
model.  .   
 
Additionally, for the CFS score (NOT to change from baseline), shift table with n and the 
proportion (%) will be generated by planned treatment group to evaluate from baseline CFS 
score to each visit (Week 4 or 12) of period 1.  This table includes all available data of subjects 
who meet FAS criteria regardless of baseline CFS score.   
 
8.3.2. 
Analysis of Other Secondary Efficacy Endpoints  
8.3.2.1 
IOP Assessments 
For the following IOP secondary endpoints, summary statistics (n, mean, SD, SE, median, min, 
and max) by treatment group will provided for period 1, period 2 and entire study period.  In 
addition, the mean difference between two groups and the corresponding 95% confidence 
interval will be also provided. 
For continuous endpoint (mean diurnal IOP), a similar MMRM to primary endpoint analysis  
will be performed for period 1, and the model includes treatment, visit, and treatment-by-visit 
interaction as fixed effects, baseline diurnal IOP and country as covariates.  Estimates of 
treatment effects will be based on least square means (LS mean).  The LS mean, difference of the 
LS mean between two groups, and the corresponding 95% confidence intervals (CI) will be 
provided at each visit.    
For the binary endpoints, number of subjects who achieved the criteria, response rate (%), risk 
difference and the corresponding 95% confidence interval, and p-value (Chi-squared test)  will 
be provided.  
 
• Period 1, for FAS Population by treatment group, respectively: 
o Changes from baseline in peak, trough, and mean diurnal IOPs at Week 4 and 
Week 12, respectively 


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▪ NOTE: Change from baseline in peak and trough IOP a Week 4 is 
included in the MMRM of primary efficacy endpoint at Week 12.  
o Peak, trough and mean diurnal IOP response, separately, at Week 4 and Week 12: 
✓ IOP 20% response (reduction in mean IOP of ≥ 20% from Baseline at the 
specified follow-up visit)  
✓ IOP 25% response (reduction in mean IOP of ≥ 25% from Baseline at the 
specified follow-up visit)  
✓ IOP 30% response (reduction in mean IOP of ≥ 30% from Baseline at the 
specified follow-up visit)  
✓ IOP < 18 mmHg response (mean IOP < 18 mmHg at the specified follow-
up visit) 
• Period 2 for Open-Label Population: 
o Change from Week 12, respectively, in mean morning (9:00 am ± 1 hour) IOP at 
Month 6, Month 9 and Month 15. 
• Entire Study period for Open-Label Population: 
o Change from baseline in mean morning (9:00 am ± 1 hour) IOP at Week 4, Week 
12, Month 6, Month 9 and Month 15. 
 
For IOP (Peak, trough, mean diurnal IOP), the score (raw value) will also be summarized as a 
supportive information. 
8.2.2.2 
Ocular Surface Disease (OSD) Assessments 
The below is the list of OSD endpoints.  For continuous endpoint, summary statistics (n, mean, 
SD, SE, median, min, and max) by planed treatment group will provided for period 1 (FAS), 
period 2 (Open-Label Population) and entire study period (Open-Label Population) depending on 
each endpoint.  In addition, the mean difference between two groups and the corresponding 95% 
confidence interval will be also provided.   For the binary endpoints, number of subjects who 
achieved the criteria, response rate (%), risk difference and the corresponding 95% confidence 
interval will be provided.   
• OSD endpoints: 
o Score and change from baseline: Each individual symptom score,  
o Time: Tear film break-up time (TFBUT) in the study eye in subjects with baseline 
TFBUT ≤ 10, 
o Score and change from baseline: Conjunctival hyperemia (measured by slit lamp 
scored using the photographic scale derived from McMonnies scale [1 to 6]),  
▪ In addition, proportion of subjects with moderate and severe conjunctival 
hyperemia (grade ≥ 3 measured by slit lamp) is considered, 


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o Score and change from baseline: Conjunctival fluorescein staining in the study 
eye in subjects with baseline conjunctival fluorescein staining ≥ 1,  
o Score and change from baseline: Dry eye sensation symptom in the study eye,  
o Score and change from baseline: Blurred/poor vision symptom in the study eye,  
o Score and change from baseline: Burning/stinging/itching symptom in the study 
eye,  
o Score and change from baseline: Slit lamp examination (Meibomian gland 
dysfunction, conjunctiva chemosis, lids and tear film debris),  
8.2.2.3 
Quality of Life Assessments 
Glaucoma Quality of Life-15 (GQL-15) data will be summarized as follows: 
• Period 1, for FAS Population by treatment group, respectively: 
 
o Score and change from baseline in GQL-15 at Week 12 
• Period 2, for Open-Label Population: 
o Score and change from baseline and change from Week 12, respectively, in GQL-
15 at Month 15. 
Summary statistics (n, mean, SD, SE, median, min, and max) of each individual score and the 
sum of them will be provided by treatment group at each visit for period 1 (FAS), period 2 
(Open-label population).  In addition, the number of subjects in each category and the percentage 
(%) will be provided by treatment group. 
8.2.2.4 
Subject Global Rating of Treatment 
Subject global rating of treatment will be assessed at the Week 12 Visit and Month 15 Visit (for 
Open-Label Population only), or Study Exit Visit. The number of subjects in each category 
(Unsatisfactory, Not very satisfactory, Satisfactory, Very satisfactory) and the percentage (%) 
will be provided by treatment group.   
8.4. 
Subgroup Analyses 
To assess the homogeneity of treatment effects among subgroups, the primary efficacy endpoints 
will be summarized for the following subgroups on the FAS.  The primary analysis (MMRM) for 
primary endpoint will be conducted by each subgroup when total sample size of each subgroup is 
equal or more than 10: 
• Age group (< 65 or ≥ 65 years)  
• Sex (male or female) 
• Primary ocular diagnosis (open angle glaucoma or ocular hypertension) 
• Baseline use of IOP lowering medication (prostaglandin analogues, beta blocking 
agents, carbonic anhydrase inhibitors, other) 
• Baseline lens status (phakic, or pseudophakic/aphakic)  


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• CFS scores at Baseline (CFS ≤ 1 or CFS ≥2)   
In addition to table of these subgroups, forest plots will be prepared. 


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9. 
SAFETY ANALYSES 
Safety measures collected in this study include AEs, slit-lamp examination, BCDVA, dilated and 
undilated fundoscopy, and visual field. 
All the safety endpoints will be summarized by treatment arm using actual treatment received 
based on safety population for the following three study periods separately: 
• Period 1 (Day 1 to Week 12 Visit): for Safety Population by treatment group   
• Period 2 (Week 12 Visit to Month 15 Visit): for Open-Label Safety Population  
• Entire Study period (Day 1 to Month 15): for Open-Label Safety Population. 
 
9.1. 
Safety-Related Definitions 
9.1.1. 
Adverse Event (AE) 
An AE can be any unfavorable unintended sign (including for example an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug which does not 
necessarily have to have a causal relationship with the study treatment.  
Each AE will be graded by the Clinical Investigator as Mild (aware or unaware of event, but 
easily tolerated), Moderate (discomfort enough to cause interference with usual activity), or 
Severe (incapacitating; unable to work or perform usual activity).  AEs will also be rated by the 
Investigator as to their causality/relationship to the study medication, to artificial tears, as well as 
to the study procedures (related vs. not related). 
For tabulations of AEs during this study, only the treatment-emergent AEs, i.e., AEs that 
occurred on or after the treatment start date and before or on the treatment end date of the 
analysis period or worsened relative to pre-treatment state will be included.  Note that events that 
occurred before the first drop of DE-130A or Xalatan are considered medical history and will be 
tabulated separately. 
Each AE will be classified into a System Organ Classification (SOC) and coded to a preferred 
term and a lowest level term using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.1. 
 
9.1.1.1. 
Ocular Adverse Event 
An AE will be counted as an ocular AE if the Clinical Investigator selected ‘OD’, ‘OS’, or ‘OU’ 
for the AE eCRF field “Event Location”. 
 
9.1.1.2. 
Suspected Adverse Reaction 
Suspected adverse reactions are defined as any AEs that are deemed related to study drug, or 
study procedure, or artificial tears by the Investigators. Any ocular AE that occurred 
simultaneously to both eyes will be counted once for both the study eye and the fellow eye. 


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9.1.1.3. 
Serious Adverse Event (SAE) 
A serious AE may occur during any study phase (i.e., screening, washout, treatment) with study 
drug (Test or Control) or artificial tears.  AEs will be classified as SAEs if it meets one or more 
of the following criteria:  
• 
Results in death  
• 
It is immediately life-threatening*  
• 
It requires in-subject hospitalization or prolongation of existing hospitalization  
• 
It results in persistent or significant disability or incapacity  
• 
Results in a congenital abnormality or birth defect  
• 
It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above (including sight-threatening** 
events and cancer or neoplasm of any type). 
*Herein ‘Life-threatening’ refers to an event in which the subject was at immediate risk of death at the 
time of event; it does not refer to an event which hypothetically might have caused death.   
**Similarly, ‘Sight-threatening’ refers to an event in which the subject was at immediate risk of losing 
sight; it does not refer to an event which hypothetically might have caused losing of sight, refer to 
definitions in Section 9.1.1.4.   
 
9.1.1.4. 
Sight-Threatening Adverse Event 
A sight-threatening AE is any SAE that places the subject at immediate risk of permanently 
losing vision in either eye as a direct result of the event.   In this study, the following serious 
ocular AEs will be reported as sight-threatening AEs if it meets one or more of the following 
criteria: 
• 
Adverse Events that caused a decrease in visual acuity of > 6 lines (compared with the 
last assessment of visual acuity at the last visit) 
• 
Adverse Events that caused a decrease in visual acuity to the level of Light Perception or 
worse 
• 
Adverse Events that required surgical intervention or laser to prevent permanent loss of 
sight 
• 
Adverse Events associated with severe intraocular inflammation (i.e., 3+ anterior 
chamber cell/flare or 3+ vitritis)  
• 
Corneal perforation 
• 
Adverse Events that, in the opinion of the investigator, may require medical intervention 
to prevent permanent loss of sight 


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9.1.1.5. 
Adverse Event Leading to Discontinuation 
An AE will be counted as an AE leading to Discontinuation if the Clinical Investigator selected 
“Adverse event” in the “Primary reason for discontinuation” checklist under the Study Exit 
eCRF and checked “Drug withdrawn” in the “Action taken with study drug as related to adverse 
event” checklist under the AE eCRF. 
 
9.1.1.6. 
Case of Special Interest 
In this study, cases of special interest (CSIs) include, but are not limited to,  
• AEs requiring (24 h) reporting to the Sponsor:  
o Corneal ulceration 
o Decrease in visual acuity of 3-6 lines (compared with the last assessment of visual 
acuity at the last visit)  
• Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional 
or subject. 
o Overdose of study drug: Administration of a quantity of a medicinal product 
exceeding the dose defined in the study protocol.  
o Misuse of study drug: Situations where the medicinal product is intentionally and 
inappropriately used not in accordance with the study protocol.  
o Abuse of study drug: Persistent or sporadic, intentional excessive use of medicinal 
product which is accompanied by harmful physical or psychological effects. 
o Other  
 
9.1.2. 
Other Safety Measures  
9.1.2.1. 
Slit Lamp Examination 
Slit lamp examination is described in Section 8.1.4.6.  It is an efficacy measure as well as a 
safety measure.   
 
9.1.2.2. 
Best-Corrected Distance Visual Acuity (BCDVA) 
 
BCDVA will be measured with the subject’s best correction and recorded in Snellen notation. 
An increase in BCDVA (i.e., decrease in Snellen denominator) indicates improvement in the 
best-corrected distance visual acuity.   


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9.1.2.3. 
Dilated and Undilated Fundoscopy 
At the Screening, Week 12, and Month 15 visits, dilated fundoscopy will be performed. 
Glaucomatous optic nerve finding will be graded as 0 = none, 1 = mild, 2 = moderate, and 3 = 
severe.  Retina, macula, choroid, and vitreous will be graded as 0 = normal, 1 = abnormal, and 2 
= unable to assess. 
Cup-to-disc (C/D) ratio will be evaluated to assess the progression of glaucoma. It will be 
assessed via dilated fundoscopy together with other parameters.  Also, it will be assessed using 
undilated fundoscopy at the Baseline (Day 1), Week 4, Month 6, Month 9, and unscheduled 
visits.  
9.1.2.4. 
Visual Field 
A visual field test is an eye examination that can detect dysfunction in central and peripheral 
vision which may be caused by medical conditions like glaucoma.  A visual field test will be 
performed in each eye at the Screening Visit if the subject has not performed the test within the 6 
months prior to the Screening Visit.  For subjects who will be entering Period 2 (the first 130 
subjects), visual field will be assessed at the Baseline and Month 6 visits. 
 
9.2. 
Adverse Event 
AEs are defined in Section 9.1. Only TEAEs will be included in the tabulations. All the AEs 
collected during this study, including those non-TEAEs, will be provided in a listing. 
 
In the overall AE summaries, subjects with any AE(s) will be tabulated by the following types of 
AEs:  
• AEs 
• SAEs 
• Non-Serious AEs (including number of events) 
• Suspected adverse reactions (SARs) 
o AEs related to the study medication 
o AEs related to study procedures 
o AEs related to artificial tears 
• Serious SARs (Serious SARs) 
• AEs leading to premature discontinuation 
• Sight threatening AEs 
• Case of special interest 


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• Death 
The above summaries will be repeated for ocular AEs, and non-ocular AEs, respectively. 
Besides the overall summary of AEs, subjects with any AE(s) will be tabulated by system organ 
class (SOC) and preferred term (PT) coded in MedDRA Version 23.1 by study period and 
treatment. For AE summaries, a subject who experienced multiple AEs within a SOC and/or PT 
will be counted only once at the maximum severity for that SOC and/or PT.   
AEs will be summarized for the following categories by SOC and PT: 
• All AEs 
• Ocular AEs (for study eye and fellow eye separately) 
• Non-ocular AEs 
• Suspected adverse reactions (SARs) 
o AEs related to study drug 
o AEs related to study procedure 
o AEs related to artificial tears 
o Please note that SAR will be summarized by each category for ocular AE and will 
be summarized for non-ocular SAR (AEs related to study drug).  
SAEs and serious SARs will be repeated for all of the above AE and SAR summaries. A separate 
table will be generated that will include number of events for SAEs. 
Non-serious AEs, with number of events, will be summarized by SOC and PT. 
In addition, AEs will be tabulated by the following categories: 
• SOC, PT, and maximal severity  
• SOC, PT, and relationship (related to study medication, study procedure, or artificial 
tears)  
• SOC, PT, maximal severity, and relationship (related to study medication, study 
procedure, or artificial tears)  
Sight-threatening AEs and cases of special interest will be summarized by type of events 
specified in Section 9.1.1.4 and Section 9.1.1.6. 
AEs, AEs leading to discontinuation, SAEs, sight-threatening AEs, case of special interest, and 
death, if any, will be listed separately.   
9.3. 
Slit-lamp Examination 
The lashes, anterior chamber, cataract severity, and lens are defined as safety endpoint of slit-
lamp examination.   
For each slit lamp parameter rated on a 0-3 scale (0=None, 1=Mild, 2=Moderate, or 3=Severe) or 
0-4 scale (0=None, 1=Mild, 2=Moderate, 3=Severe, and 4=Very severe), the number of subjects 
in each scale and the percentage (%) will be provided by treatment group by study period, 


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treatment, and analysis visit.  In addition, any worsening (increase) of ≥ 2 units from baseline 
will be listed. 
For lashes, which are collected as Normal or Abnormal, rating scores and shift from baseline in 
status will be summarized by study period, treatment, and analysis visit.   
For lens, shift from baseline in status will be summarized by study period, treatment, and 
analysis visit. 
 
9.4. 
Dilated and Undilated Fundoscopy 
Frequency and percentage of ratings on glaucomatous optic nerve findings, retina, macula, 
choroid, and vitreous will be summarized by treatment (for Period 1 only) and analysis visit and 
shift from baseline in status will be summarized by study period, treatment (Period 1 only), and 
analysis visit.  In addition, any worsening (increase) of ≥ 2 units from baseline on glaucomatous 
optic nerve findings, or any change from Normal at baseline to Abnormal on retina, macula, 
choroid, and vitreous will be listed by ophthalmoscopic parameter. 
For cup/disc ratio, score and change-from-baseline score will be summarized by study period, 
treatment, and analysis visit (combined the dilated and undilated readings).  Subjects with any 
worsening (increase) of 0.2 units or more from baseline in cup/disc ratio will be listed for dilated 
and undilated readings. 
 
9.5. 
Best Corrected Distance Visual Acuity (BCDVA) 
BCDVA scores and changes from baseline in BCDVA will be summarized by study period, 
treatment, and analysis visit.  This endpoint is converted to log MAR scale, then the data will be 
summarized.  
 
9.6. 
Visual Field 
Visual field scores and changes from baseline in Visual field score will be summarized device 
type, treatment, and analysis visit.  
 
 
 


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10. 
CHANGES FROM THE PROTOCOL 
10.1 Analysis Population  
A subject was only measured peak IOP (Not measured trough IOP) during the double mask 
period, then was entered into the open label period.  Original definition of Open-Label 
Population and Open-Label Safety population were a subset of FAS subjects in Section 6.6 and 
6.7.  Because no IOP trough measurement is not impacted to efficacy in open label period 
evaluation, “a subset of FAS subjects” was removed from these definitions.   
In this SAP, the below underlines were removed from the definition in the protocol.     
Open Label Population  
The Open-Label population will be a subset of the FAS subjects who are the first 130 subjects 
and some Belgium who complete their Week 12 Visit and agree to participate in the open-label 
period of the study, and received at least one dose of the study medication during the open-label 
period and provided at least one morning IOP measurement after the Week 12 Visit. This 
population will be the analysis population for the analyses of efficacy endpoints in Period 2 and 
for Periods 1 & 2 combined data and will use treatment as randomized. 
 
Open-Label Safety Population 
The Open-Label Safety population will be a subset of the FAS subjects who are the first 130 
subjects and some Belgium who complete their Week 12 Visit and agree to participate in the 
open-label period of the study, and received at least one dose of the study medication during the 
open-label period. The Open-Label Safety population will be the analysis population for all 
safety analyses in Period 2 and for Periods 1 & 2 combined data and will use treatment as 
actually received. 
 
10.2 Secondary Efficacy Endpoint 
Endpoints of OSD each symptom scores (dry eye sensation symptom, blurred/poor vision 
symptom, and burning/stinging/itching symptom) is limited for subjects with baseline severity of 
mild, moderate, or severe in the protocol (ver 5.0).  However, clinical science colleagues 
suggested to summarize regardless of baseline status in the second TFL review meeting in 
February 8th 2022.     
 
Protocol (Ver 5.0):  
o Dry eye sensation symptom in the study eye at Week 4 and Week 12 in subjects 
with baseline dry eye sensation symptom in mild, moderate, or severe  
o Blurred/poor vision symptom in the study eye at Week 4 and Week 12 in subjects 
with baseline blurred/poor vision symptom in mild, moderate, or severe  


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o Burning/stinging/itching symptom in the study eye at Week 4 and Week 12 in 
subjects with baseline burning/stinging/itching symptom in mild, moderate, or 
severe  
o Dry eye sensation symptom in the study eye at Month 6, Month 9 and Month 
15/early termination in subjects with baseline dry eye sensation symptom in mild, 
moderate, or severe  
o Blurred/poor vision symptom in the study eye at Month 6, Month 9 and Month 
15/early termination in subjects with baseline blurred/poor vision symptom in 
mild, moderate, or severe  
o Burning/stinging/itching symptom in the study eye at Month 6, Month 9 and 
Month 15/early termination in subjects with baseline burning/stinging/itching 
symptom in mild, moderate, or severe  
 
SAP:  
o Dry eye sensation symptom in the study eye at Week 4 and Week 12  
o Blurred/poor vision symptom in the study eye at Week 4 and Week 12  
o Burning/stinging/itching symptom in the study eye at Week 4 and Week 12  
o Dry eye sensation symptom in the study eye at Month 6, Month 9 and Month 
15/early termination  
o Blurred/poor vision symptom in the study eye at Month 6, Month 9 and Month 
15/early termination  
o Burning/stinging/itching symptom in the study eye at Month 6, Month 9 and 
Month 15/early termination  
 


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11. 
REFERENCES 
1. Laird, Nan M.; Ware, James H. (1982). Random-Effects Models for Longitudinal Data. 
Biometrics, 38 (4): 963–974. 
2. Lindstrom, ML; Bates, DM (1988). Newton-Raphson and EM algorithms for linear 
mixed-effects models for repeated-measures data. JASA, 83 (404): 1014–1021.  
3. Ratitch, Bohdana, Michael O'Kelly, and Robert Tosiello. "Missing data in clinical trials: from 
clinical assumptions to statistical analysis using pattern mixture models." Pharmaceutical 
statistics 12.6 (2013): 337-347.  
 
 


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12. 
APPENDICES 
 
 
 
 
 


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