Clinical trial NCT04445519
Conditions: Open Angle Glaucoma Ocular Hypertension
Sponsor: Nicox Ophthalmics, Inc.
Start date: 2020-06-01; Completion date: 2022-09-16
Enrollment: 691 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this clinical study is to evaluate the safety and efficacy of NCX 470 Ophthalmic Solution in lowering intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma. In the adaptive dose selection phase of the trial, subjects will be randomized in a 1:1:1 ratio to one of two doses of NCX 470 (0.065% or 0.1%) or to latanoprost 0.005%. Following the selection of one dose of NCX 470, subjects will be randomized in a 1:1 ratio to the chosen dose of NCX 470 or to latanoprost 0.005%.

Detailed description:

Arms: arm 1: NCX 470 Ophthalmic Solution, 0.065% dosed once daily to both eyes (initial phase of trial) arm 2: NCX 470 Ophthalmic Solution, 0.1% dosed once daily to both eyes (initial phase of trial) arm 3: Latanoprost Ophthalmic Solution, 0.005% dosed once daily to both eyes (initial phase of trial) arm 4: NCX 470 Ophthalmic Solution, 0.1% dosed once daily to both eyes (chosen dose of NCX 470 to continue in remainder of trial) arm 5: Latanoprost Ophthalmic Solution, 0.005% dosed once daily to both eyes (active comparator for remainder of trial)
Interventions: intervention 1: NCX 470 0.065% (initial phase of trial) intervention 2: Latanoprost 0.005% (initial phase of trial) intervention 3: NCX 470 0.1% (initial phase of trial) intervention 4: NCX 470 0.1% (remainder of trial) intervention 5: Latanoprost 0.005% (remainder of trial)
Intervention descriptions: intervention 1: NCX 470 Ophthalmic Solution, 0.065% (initial phase of trial) intervention 2: Latanoprost Ophthalmic Solution, 0.005% intervention 3: NCX 470 Ophthalmic Solution, 0.1% intervention 4: NCX 470 Ophthalmic Solution, 0.1% intervention 5: Latanoprost Ophthalmic Solution, 0.005%

Protocol documents:
Prot_000.pdf: 
 
Phase 3 Trial of NCX 470 vs Latanoprost in Subjects with Open-Angle Glauocma or Ocular 
Hypertension (Mont Blanc) 
 
NCT#04445519 
 
08-July-2020 


NCX-470-02 version 2.0; 08-July-2020 
Page 1 of 78 
Nicox Ophthalmics, Inc. 
4721 Emperor Blvd., Suite 260, Durham, North Carolina 27703 - USA 
Compound 
NCX 470 
Study Number 
NCX-470-02 
Study Title 
A Phase 3, Randomized, Adaptive Dose-Selection, Multi-Regional, Double-
Masked, Parallel-Group, 3–Month Trial Evaluating the Safety and Efficacy of 
NCX 470 vs. Latanoprost 0.005% in Subjects with Open-Angle Glaucoma or 
Ocular Hypertension (Mont Blanc) 
PROTOCOL 
Version # 2.0 
Released on 08-July-2020 
Clinical Development Phase: 
3 
Sponsor: 
Nicox Ophthalmics, Inc. 
4721 Emperor Blvd., Suite 260,  
Durham, North Carolina 27703 - USA 
CONFIDENTIAL 
This document contains confidential information, which is not to be divulged in any way 
unless previously authorized by Nicox Ophthalmics, Inc. 


NCX-470-02 version 2.0; 08-July-2020 
 
Page 2 of 78 
PROTOCOL SIGNATURE PAGE  
 
Study No.: 
NCX-470-02 
Title:  
A Phase 3, Randomized, Adaptive Dose-Selection, Multi-Regional, Double-Masked, 
Parallel-Group, 3–Month Trial Evaluating the Safety and Efficacy of NCX 470 vs. 
Latanoprost 0.005% in Subjects with Open-Angle Glaucoma or Ocular Hypertension (Mont 
Blanc) 
 
APPROVAL OF STUDY PROTOCOL 
Version: 
 
Version 2.0 
Release Date:  
08-July-2020 
 
Site Details (Address and Telephone Number): 
 
 
 
 
 
The undersigned confirms that: 
• 
This protocol has been read in its entirety and agreed to all aspects. 
• 
This study will be implemented and conducted diligently and in strict compliance with the protocol, 
Good Clinical Practices, and all applicable laws and regulations. 
• 
All information supplied by Nicox or its legal representatives will be maintained in confidence and, 
when this information is submitted to an Institutional Review Board (IRB) it will be submitted with a 
designation that the material is confidential. 
 
Principal Investigator: 
 
 
 
 
 
(Printed Name) 
 
Date 
 
Signature 
 
 
Sponsor: 
Nicox Ophthalmics, Inc. 
 
4721 Emperor Blvd., Suite 260, Durham, North Carolina 27703 - USA 
 
On behalf of the Sponsor:  


NCX-470-02 version 2.0; 08-July-2020 
 
Page 3 of 78 
CONTACT INFORMATION 
 
Protocol Identification 
A Phase 3, Randomized, Adaptive Dose-Selection, Multi-Regional, Double-Masked, Parallel-Group,  
3–Month Trial Evaluating the Safety and Efficacy of NCX 470 vs. Latanoprost 0.005% in Subjects with 
Open-Angle Glaucoma or Ocular Hypertension (Mont Blanc) 
 
Version #2.0 released on 08-July-2020 
 
Sponsor  
Nicox Ophthalmics, Inc. 
4721 Emperor Blvd., Suite 260,  
Durham, North Carolina 27703 - USA 
 
Sponsor Contact 
  
 
 
 
 
 
 
 
 
Company Representing the Sponsor: 
  
 
 
 
 
Primary Contact for SAEs: 
 
  
 
Medical Monitor: 
 
 
 
 


NCX-470-02 version 2.0; 08-July-2020 
 
Page 4 of 78 
PROTOCOL HISTORY TABLE 
 
REASONS FOR CHANGES  
DETAILS OF CHANGES 
Version 2.0, dated 08-July-2020; Amendment 1 
Limit the number of 
subjects randomized to 
treatment arm to be 
discontinued beyond the 
30 randomized subjects 
target; describe handling 
of subjects and visits 
during Adaptive Dose 
Selection Period; 
describe study 
participation of 
discontinued subjects 
• Added detail regarding the design of the dose-ranging phase of the 
trial,
 
 
  
• Clarified that the adaptive dose selection would be based on data from 
at least 30 subjects randomized into each of the three treatment arms 
 
 
• Revised overall number of subjects 
 
(Synopsis; Sections 1.2, 3.1, 4.1, 6.7) 
• Added guidance regarding handling of completed and new Eligibility 1 
and Eligibility 2 Visit data based on Adaptive Dose Selection Period 
(new Section 3.3, Sections 7.2, 7.3) 
• Revised Section 3.2
 
 
 
 
• Corrected the duration of treatment (6 weeks to 3 months) for subjects 
in the treatment arm to be discontinued 
 
• Clarified the overall study duration of the trial, 
 
 
 
) 
• Specified that following the adaptive dose selection, ongoing subjects 
who were randomized to the discontinued arm should be discontinued 
at their next regularly scheduled visit 
 
 
Ensure adequate 
washout of investigational  
IOP-lowering medications 
• Revised exclusion criteria #26
 


NCX-470-02 version 2.0; 08-July-2020 
 
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REASONS FOR CHANGES  
DETAILS OF CHANGES 
Consistency with 
exclusion criteria in 
Phase 2 trial  
NCX-470-17001 
• Revised exclusion criteria #13
 
 
Ensure capture of all prior 
ophthalmic medications 
• Added requirement to capture investigational ophthalmic products used 
in prior 12 months (Section 5.1) 
Reduce burden on 
subjects and increase 
flexibility for sites 
• Allowed prior visual field
 
 
 
 
 
Support consistency of 
methodology within and 
across sites  
• Added light meter (if required) to list of other study supplies provided to 
sites (Section 6.13) 
• Indicated that a replacement bulb with fenestrated sleeve (diffuser) was 
only required if applicable (Appendix 2) 
Ensure earlier eligibility of 
screened subjects 
• Removed allowance for pachymetry or gonioscopy
 
Covid-19 precaution 
• Specified that monitoring visits could include remote visits (Section 
13.1) 
Clarification 
 
• Revised exclusion #16 
 
• Clarified that Exclusion Criteria #1, #4, #13 and #24 applied to either 
eye (Synopsis; Section 4.4)  
• Revised area of application for prohibited steroid medications for 
consistency with Exclusion Criterion #21 (Section 5.2) 
• Provided more detail regarding actual labeling of study medication 
(Section 6.4) 
• Revised terminology regarding packaging of study medication to “kit(s)” 
vs “box(es)” and include a description of kit (Sections 6.3, 6.4, 6.5, 6.6, 
6.8, 7.3, 7.5, 7.6 and 13.1) 
• Clarified that the outer kit includes a storage temperature sticker 
(Section 6.4 and 6.5) 
• Specified that the unmasked site designee instructs subjects on proper 
storage and handling of study medication (Section 6.5) 
• Clarified that the maximum time of 
days between Screening Visit 
and Eligibility 1 Visit 
 
 
 
• Clarified that decision rules for selecting the NCX 470 dose would be 
detailed in the Adaptive Decision Committee charter, as well as in the 
SAP (Synopsis; Section 11.5.1) 


NCX-470-02 version 2.0; 08-July-2020 
 
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REASONS FOR CHANGES  
DETAILS OF CHANGES 
Clarification 
 
• Clarified that in Study NCX-470-17001, NCX 470 resulted in up to 
1.4 mmHg greater IOP-lowering efficacy than latanoprost based on 
reduction from baseline in time-matched IOP over the Week 1, 2 and 4 
Visits (Section 1.2) 
• Clarified that pachymetry 
 
• Clarified that baseline IOP analyses will be based
 
• 
 
• Other minor clerical corrections or clarification of terminology 
(Synopsis; Section 2.3, 3.1, 4.3, 4.4, 6.3, 6.4, 6.6, 6.7, 6.8, 6.12, 8.6, 
11.5.1, 11.5.3; 13.3, Appendix 2; Appendix 3) 
Administrative 
 
• Added a section to identify the Coordinating Investigator for the trial 
(Section 14.7) 
• Updated List of Abbreviations; added change history for Amendment 1 
Version 1.0, dated 20-Feb-2020; Original Protocol 
Original version 
Not Applicable  
 
 
 
 
 


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TABLE OF CONTENTS 
Page 
STUDY TITLE .................................................................................................................................. 1 
PROTOCOL HISTORY TABLE ...................................................................................................... 4 
TABLE OF CONTENTS ................................................................................................................... 7 
LIST OF FIGURES ........................................................................................................................ 10 
LIST OF TABLES ........................................................................................................................... 10 
LIST OF ABBREVIATIONS .......................................................................................................... 11 
STUDY OUTLINE / PROTOCOL SYNOPSIS ............................................................................... 13 
1.
INTRODUCTION ........................................................................................................... 23 
1.1 
Background and Rationale .................................................................................. 23 
1.2 
Study Background................................................................................................ 24 
1.3 
Potential Risks and Benefits to Human Subjects ................................................ 26 
2.
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 28 
2.1 
Study Objectives .................................................................................................. 28 
2.2 
Study Endpoints ................................................................................................... 28 
2.3 
Efficacy Evaluations ............................................................................................. 28 
2.4 
Safety Evaluations ............................................................................................... 28 
3.
STUDY DESIGN ............................................................................................................ 30 
3.1 
Overall Study Design ........................................................................................... 30 
3.2 
Washout Period for Majority of the Study Subjects ............................................. 31 
3.3 
Washout Period and Handling of Eligibility 1 and Eligibility 2 Study Visits for the Study 
Subjects during Adaptive Dose Selection Period ................................................ 32 
4.
SUBJECT SELECTION ................................................................................................. 35 
4.1 
Number of Subjects and Sites ............................................................................. 35 
4.2 
Subject Population Characteristics ...................................................................... 35 
4.3 
Inclusion Criteria .................................................................................................. 35 
4.4 
Exclusion Criteria ................................................................................................. 36 
5.
CONCOMITANT MEDICATION(S) ............................................................................... 39 
5.1 
Previous and Concomitant Medication(s) ............................................................ 39 
5.2 
Prohibited Medication(s) ...................................................................................... 39 
6.
STUDY SUPPLIES ........................................................................................................ 40 
6.1 
Description of Study Medication .......................................................................... 40 
6.2 
Description of Active Comparator ........................................................................ 40 


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6.3 
Packaging of the Study Medication ..................................................................... 40 
6.4 
Labeling of the Study Medication ......................................................................... 40 
6.5 
Storage of the Study Medication .......................................................................... 42 
6.6 
Accountability of Study Medication ...................................................................... 42 
6.7 
Assigning Subjects to Treatment and Study Masking ......................................... 42 
6.8 
Study Medication Dispensing and Collection ...................................................... 43 
6.9 
Instructions for Use and Administration ............................................................... 43 
6.10 
Emergency Subject Unmasking ........................................................................... 44 
6.11 
Study Medication Compliance ............................................................................. 44 
6.12 
Return of Study Medication by the Clinical Sites ................................................. 44 
6.13 
Other Study Supply .............................................................................................. 44 
7. 
STUDY PROCEDURES BY VISIT ................................................................................ 45 
7.1 
Screening Visit ..................................................................................................... 45 
7.2 
Eligibility 1 Visit (Day 
 .............................................................................. 46 
7.3 
Eligibility 2 Visit (Day 
 ....................................................................................... 47 
7.4 
Week 2 Visit (Day 14
 .................................................................................... 47 
7.5 
Week 6 Visit (Day 42 
 .................................................................................... 48 
7.6 
Month 3 Visit (Day 90 
/Exit Visit .................................................................... 48 
7.7 
Unscheduled Visits .............................................................................................. 49 
8. 
SCREEN FAILURES, COMPLETION AND DISCONTINUATION ................................ 50 
8.1 
Subject Screen or Eligibility Failures ................................................................... 50 
8.2 
Subject Completion .............................................................................................. 50 
8.3 
Subject Early Discontinuation .............................................................................. 50 
8.4 
Subject Lost to Follow-up .................................................................................... 51 
8.5 
Study Termination ................................................................................................ 51 
8.6 
Subjects Discontinued Per Protocol Following Adaptive Evaluation ................... 51 
9. 
PROTOCOL COMPLIANCE .......................................................................................... 52 
10. 
ADVERSE EVENTS ...................................................................................................... 53 
10.1 
Adverse Event Definition ..................................................................................... 53 
10.2 
Severity of Adverse Event ................................................................................... 53 
10.3 
Causal Relationship with Study Medication ......................................................... 53 
10.4 
Serious Adverse Events ...................................................................................... 54 
10.5 
Adverse Event Reporting ..................................................................................... 54 
10.6 
Serious Adverse Event Reporting ........................................................................ 55 
11. 
STATISTICAL CONSIDERATIONS AND METHODS OF ANALYSIS .......................... 56 


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11.1 
Determination of Sample Size and Power Calculations ...................................... 56 
11.2 
Analysis Population.............................................................................................. 56 
11.3 
Data Display ......................................................................................................... 57 
11.4 
Collection and Derivation of Primary Efficacy Assessments ............................... 57 
11.5 
Hypothesis and Methods of Analysis ................................................................... 57 
11.5.1 Primary Efficacy Analysis .................................................................................... 57 
11.5.2 Secondary Efficacy Analyses .............................................................................. 59 
11.5.3 Safety Analysis .................................................................................................... 60 
12. 
EMERGENCY PROCEDURES ..................................................................................... 61 
12.1 
Emergency Contact Procedure ............................................................................ 61 
12.2 
Procedure in Case of Pregnancy ......................................................................... 61 
13. 
STUDY MANAGEMENT ................................................................................................ 62 
13.1 
Monitoring ............................................................................................................ 62 
13.2 
Source Documents .............................................................................................. 62 
13.3 
Source Data Verification ...................................................................................... 63 
13.4 
Completion of Electronic Case Report Forms ..................................................... 63 
13.5 
Data Management ............................................................................................... 63 
13.6 
Audits and Inspections ......................................................................................... 63 
13.7 
Access to Source Data ........................................................................................ 63 
13.8 
Training of Staff .................................................................................................... 64 
13.9 
Changes to the Protocol ...................................................................................... 64 
14. 
ADMINISTRATIVE, LEGAL, AND ETHICAL ASPECTS ............................................... 65 
14.1 
Conduct of the Trial.............................................................................................. 65 
14.2 
Ethical Principles.................................................................................................. 65 
14.3 
Health Authorities and Institutional Review Board (IRB) ..................................... 65 
14.4 
Subject Information and Consent ........................................................................ 65 
14.5 
Confidentiality Regarding Trial Subjects Data ..................................................... 66 
14.6 
Archiving at the End of the Study ........................................................................ 66 
14.7 
Coordinating Investigator ..................................................................................... 66 
15. 
PUBLICATION POLICY ................................................................................................ 67 
16. 
REFERENCES .............................................................................................................. 68 
APPENDIX 1: TIME AND EVENTS TABLE ................................................................................... 70 
APPENDIX 2: METHODS OF CLINICAL EVALUATION .............................................................. 72 
APPENDIX 3: GENERAL INSTRUCTIONS FOR COMPLETION OF SAE FORMS .................... 77 


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LIST OF FIGURES 
 
FIGURE 1: NCX-470-02 STUDY DESIGN ................................................................................................................ 31 
 
 
LIST OF TABLES 
 
TABLE 1: MINIMUM WASHOUT PERIOD(S) FOR IOP-LOWERING MEDICATIONS ............................................... 32 
TABLE 2:  HANDLING OF NON-RANDOMIZED SUBJECTS DURING THE ADAPTIVE DOSE SELECTION PERIOD ...... 33 
TABLE 3: TIMES AND EVENTS SCHEDULE ..................................................................................................... 70 
 
 
 
 
 


NCX-470-02 version 2.0; 08-July-2020 
 
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LIST OF ABBREVIATIONS  
ACE 
Angiotensin-converting Enzyme 
ADC 
Adaptive Decision Committee 
AE 
Adverse Event 
ALT 
Argon Laser Trabeculoplasty 
AM 
Ante Meridiem (before midday) 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ASA 
Advanced Surface Ablation 
BCVA 
Best Corrected Visual Acuity 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
COV 
Close Out Visit 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CTA 
Clinical Trial Agreement 
DMP 
Data Management Plan 
EDC 
Electronic Data Capture 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRT  
Interactive Response Technology 
 
 
LASIK 
Laser-Assisted in situ Keratomileusis 
LDPE 
Low Density Polyethylene 
 
 
logMAR 
Logarithm of Minimum Angle Resolution 


NCX-470-02 version 2.0; 08-July-2020 
 
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LS 
Least Square 
MCMC 
Monte Carlo Markov Chain 
MI 
Multiple Imputations 
MIGS 
Minimally Invasive Glaucoma Surgery 
MP 
Monitoring Plan 
mmHg 
Millimeters of Mercury 
NCS 
Not Clinically Significant 
NDA 
New Drug Application 
NO 
Nitric Oxide 
OAG 
Open-Angle Glaucoma 
OHT 
Ocular Hypertension 
PGA 
Prostaglandin Analog 
PGF2α 
Prostaglandin F2α 
PI 
Principal Investigator 
PM 
Post Meridiem (after midday) 
POAG 
Primary Open-Angle Glaucoma 
PP 
Per Protocol 
PRK 
Photorefractive Keratectomy 
QD 
Quaque Die (once daily) 
R&D 
Research and Development 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDV 
Source Data Verification 
SLT 
Selective Laser Trabeculoplasty 
SMP 
Safety Management Plan 
TM 
Trabecular Meshwork 
TEAE 
Treatment Emergent Adverse Event 
US 
United States 
VA 
Visual Acuity 
WHO 
World Health Organization 
 
Note: the first occurrence of some abbreviations is not spelled out in the document (e.g., units of 
measure). 
 


NCX-470-02 version 2.0; 08-July-2020 
 
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STUDY OUTLINE / PROTOCOL SYNOPSIS 
 
Title 
A Phase 3, Randomized, Adaptive Dose-Selection, Multi-Regional, Double-
Masked, Parallel-Group, 3–Month Trial Evaluating the Safety and Efficacy of 
NCX 470 vs. Latanoprost 0.005% in Subjects with Open-Angle Glaucoma or Ocular 
Hypertension (Mont Blanc) 
Study No. 
NCX-470-02 
Sponsor 
Nicox Ophthalmics, Inc. 
Background 
and Rationale  
Glaucoma is a leading cause of blindness worldwide (Jonas, 2017).  Intraocular 
pressure (IOP) is the primary risk factor for glaucoma, and lowering IOP to prevent 
optic nerve injury is currently the only proven effective treatment (Jonas, 2017).  
Topical prostaglandin analogs (PGAs), such as latanoprost, bimatoprost, and 
travoprost, are the most common first-line therapies used to lower IOP in glaucoma 
patients (Daka, 2014). 
Nicox is developing NCX 470, a nitric oxide (NO)-donating bimatoprost 
prostaglandin analog, as a new therapy for lowering of IOP in patients with open-
angle glaucoma (OAG) or ocular hypertension (OHT). When exposed to esterases 
in the eye, NCX 470 is cleaved into the prostamide bimatoprost, which in turn is 
converted to bimatoprost acid, a prostaglandin F2α receptor agonist, and into 6-
(nitrooxy)-hexanoic acid, a NO-donating moiety.   
Nitric oxide relaxes the trabecular meshwork (TM) and increases outflow of the 
aqueous humor through the primary outflow mechanism from the anterior chamber 
(Gabelt, 2011; Heyne, 2013; Cavet, 2014).  In an additive manner, bimatoprost acts 
by increasing the outflow of aqueous humor primarily through the uveoscleral 
pathway (Krauss, 2004).   
The additive effect of a NO-donor and a prostaglandin F2α receptor agonist has 
been established in clinical trials with latanoprostene bunod, a dual-acting single 
molecular entity with NO-donating moiety linked to latanoprost. Latanoprostene 
bunod ophthalmic solution, 0.024% (VYZULTA®) was developed for the reduction 
of IOP in patients with OAG or OHT (Medeiros, 2016; Weinreb, 2016). In addition 
to the clinical validation of this approach, extensive nonclinical studies for both 
NCX 470 and latanoprostene bunod support this dual mechanism of action of NO-
donating PGAs for increased outflow via TM and uveoscleral pathways. 
The results of the Phase 2 trial “Dolomites”, NCX-470-17001 demonstrated that all 
tested concentrations of NCX 470 (0.021%, 0.042%, and 0.065%) once daily (QD) 
met the primary efficacy endpoint of non-inferiority to latanoprost 0.005% QD for 
reduction from baseline in mean diurnal IOP at Day 28. In pre-specified secondary 
efficacy analyses, NCX 470 0.065% was superior to latanoprost for mean IOP 
reduction from baseline at all 3 time points (8AM, 10AM and 4PM) on Day 28, with 
the difference reaching up to 1.4 mmHg. Mean IOP reduction from baseline at the 
3 time points across Days 7, 14 and 28 ranged from 7.6 to 9.8 mmHg for 
NCX 470 0.065% compared with 6.3 to 8.8 mmHg for latanoprost. Additionally, all 
three concentrations of NCX 470 were well tolerated. The most frequent adverse 
event was conjunctival hyperemia. There were no treatment-related serious 
adverse events, and no evidence of treatment-related systemic side effects. 
NCX 470 showed increased IOP-lowering efficacy with each incremental 
concentration of NCX 470, with a conjunctival hyperemia dose-response which 
plateaued at the middle dose (0.042%). The separation of the dose-response 


NCX-470-02 version 2.0; 08-July-2020 
 
Page 14 of 78 
curves in IOP lowering vs. conjunctival hyperemia showed a favorable therapeutic 
index thereby allowing for a higher concentration of NCX 470 (i.e., 0.1%) to be 
evaluated in this trial alongside the highest dose tested (0.065% NCX 470) in the 
Phase 2 Dolomites trial. An adaptive design will be utilized wherein one of the 
NCX 470 doses will be discontinued during the adaptive evaluation, which will occur 
after at least 30 randomized subjects in each arm complete their Week 2 Visit. 
Study Period 
Q2 2020-Q2 2021 
Study Phase  
Phase 3 
Study Design 
Randomized, multi-regional, double-masked, parallel groups, active comparator-
controlled clinical trial with adaptive dose selection. 
Number of 
Subjects  
This trial will be conducted at approximately 50 sites in the United States and 
 in China.
 
   
Approximately 
670 randomized. 
 
 
 
 
 
Objectives  
The primary objective is to demonstrate that NCX 470 (0.065% or 0.1%) QD is non-
inferior to latanoprost 0.005% QD based on mean IOP reduction from time-matched 
baseline at the 8AM and 4PM time points at the Week 2, Week 6 and Month 3 Visits. 
A secondary objective is to demonstrate that NCX 470 QD is superior to latanoprost 
0.005% QD based on mean IOP reduction from time-matched baseline at the 8AM 
and 4PM time points at the Week 2, Week 6 and Month 3 Visits. 
Another secondary objective is to demonstrate that NCX 470 (0.065% or 0.1%) QD 
is safe and well tolerated when administered to subjects for 3 months.  
Selection of 
Target 
Subject 
Population 
Adult men and women with a diagnosis of OAG or OHT in both eyes. 


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Study 
Medication, 
Comparator, 
Dosage and 
Mode of 
Administration 
During the initial adaptive design dose-ranging phase, at least 30 subjects will be 
randomized in each arm in a 1:1:1 ratio to receive NCX 470 ophthalmic solution 
(0.065% or 0.1%), or latanoprost ophthalmic solution, 0.005% QD in the evening, 
one drop in each eye. 
• NCX 470 ophthalmic solution, 0.065% (minimum 30 subjects randomized)
• NCX 470 ophthalmic solution, 0.1% (minimum 30 subjects randomized)
• Latanoprost ophthalmic solution, 0.005% (minimum 30 subjects randomized)


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Trial Conduct 
and Duration 
of Treatment 
Subjects will be evaluated over 6 clinical visits. Subjects who meet 
inclusion/exclusion criteria at the Screening Visit will be withdrawn from their pre-
study IOP-lowering medications, 
 
. 
IOP-Lowering Medication 
Minimum Washout 
Period 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After the 
adaptive dose selection of one dose of NCX 470 to be studied further and 
discontinuation of the other dose of NCX 470, subjects will be randomized in a 1:1 
ratio to receive the selected dose of the NCX 470 ophthalmic solution or latanoprost 
ophthalmic solution, 0.005% QD in the evening, one drop in each eye for 3 months. 
Inclusion 
Criteria 
1) Subjects 
 years old. Subject must be of legal age (at least 18 years 
of age) on the date the informed consent form (ICF) is signed and must be able 
to provide a written informed consent to participate in the study, in accordance 
with the International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines and local regulations, before initiating any study-related 
procedures. 
2) Subjects will have a diagnosis of OAG or OHT in both eyes 
 
 
 
3) If treated for OAG or OHT, treatment nature and dose regimen must have been 
stable for both eyes for 
 prior to the Screening Visit. 
4) Subjects will meet the following IOP requirements at the Eligibility 1 (Days 
 
) and Eligibility 2 (Day ) Visits: 
• 
 
 
 
 


NCX-470-02 version 2.0; 08-July-2020 
 
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• 
 
 
5) Subjects who are on a PGA or NO-donating PGA therapy at Screening Visit 
must have a time-matched IOP increase of 
 in the study eye after the 
washout period at the Eligibility 1 and Eligibility 2 Visits.  
6) Subjects with best-corrected visual acuity (BCVA), using Early Treatment of 
Diabetic Retinopathy Study (ETDRS) chart, of 
logMAR units (Snellen 
equivalent 
 or better in each eye. 
7) If female, subjects must either be incapable of pregnancy because of bilateral 
oophorectomy, hysterectomy, bilateral tubal ligation, or be post-menopausal 
(have been amenorrheic for at least 2 years) or must use an effective (e.g., 
double barrier) method of birth control for the duration of the study.  Female 
subjects of childbearing potential must have a negative pregnancy test and not 
be nursing. 
8) Subjects who are able and willing to comply with all study procedures. 
Exclusion 
Criteria  
Ocular 
1) Subjects with advanced glaucoma or subjects with a cup/disc ratio greater than 
 
Subjects who are unable to reliably perform perimetry in either eye 
(see Appendix 2 for reliability criteria). 
2) Subjects unwilling or unable to discontinue their current IOP-lowering 
medication(s). (An IOP-lowering medication with a shorter washout period is 
permitted between the Screening Visit and Eligibility 1 Visit) – see Table 1. 
Refer also to Table 2 for use of an IOP-lowering medication with a short 
washout period in non-randomized subjects during the Adaptive Dose Selection 
Period. 
3) Subjects with narrow angles 
 according to 
Shaffer anterior chamber angle grading system) and subjects with angle 
closure, clinically significant peripheral anterior synechiae, congenital glaucoma, 
or a history of angle closure in either eye. 
4) Subjects with an iris or pupil anomaly (e.g., synechiae, coloboma) preventing 
reliable assessment of pupil diameter in either eye. 
5) Subjects whose central corneal thickness is less than 
 or greater than 
 in either eye. 
6) Subjects with any condition that prevents reliable applanation tonometry in 
either eye (e.g., significant corneal surface abnormalities, scars, keratoconus).  
7) Subjects with 
 conjunctival hyperemia in either eye at the 8AM 
assessment at the Eligibility 1 or Eligibility 2 Visits graded on high resolution, 
color photography scale. 
8) Subjects with previous or currently active clinically significant corneal disease in 
either eye that could affect study outcome per Investigator’s judgment.  
9) Subjects with a history of 
. 
10) Subjects with any active or recurrent 
 
.  


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11) Subjects with a diagnosis of a clinically significant 
 
 
 
12) Subjects unwilling or unable to discontinue
 
 
 
. 
Ocular Surgery 
13) Subjects with history of previous glaucoma
 
 
 
14) 
 
 
15) 
 
  
16) 
 
 
 
 
17) 
 
 
 
Medication 
18) Subjects with a known hypersensitivity or contraindications to PGA(s) or any of 
the ingredients in the study medications. 
19) Subjects with known contraindications to NO treatments (e.g., 
 
 
20) Subjects whose concomitant use of medications may interact with the safety or 
efficacy of a NO-donating compound 
 
21) Subjects who currently require treatment or are expected to require treatment 
with ocular or systemic corticosteroids during the study period
 
 
22) Subjects with an anticipated need to initiate or modify medication 
 
 
 
 
23) Subjects who currently require treatment or are expected to require treatment 
with any ocular medications, 
 
 
 


NCX-470-02 version 2.0; 08-July-2020 
 
Page 19 of 78 
24) 
 
 
Other 
25) Subjects with a history or presence of uncontrolled systemic disease 
 
 
26) 
 
 
27) Subjects who were randomized in the 
 
Study 
Endpoints  
Efficacy Measures 
Primary Endpoint: The primary efficacy endpoint for this trial is mean IOP reduction 
from time-matched baseline (based on Eligibility 1 and Eligibility 2 Visits) at the 8AM 
and 4PM time-points at the Week 2, 6 and Month 3 Visits in the study eye.  
The primary efficacy analysis is the non-inferiority comparison of the mean treatment 
effect between NCX 470 and latanoprost 0.005% in the study eye. A secondary 
efficacy analysis is the superiority comparison of the treatment effect between 
NCX 470 and latanoprost 0.005% in the study eye.   
 
 
 
 
Safety Measures 
• 
Intraocular pressure 
• 
Slit-lamp biomicroscopy 
• 
Conjunctival hyperemia 
• 
Dilated ophthalmoscopy 
• 
Pachymetry 
• 
Perimetry 
• 
Pupil size 
• 
Iris color 
• 
Best-corrected visual acuity (BCVA) 
• 
Urine pregnancy tests (for females of childbearing potential) 
• 
Rate of discontinuation from the study 
• 
Treatment-Emergent Adverse Events 
Statistical 
Methods 
Sample size determination and efficacy analyses:  
The primary objective of this study is to demonstrate that mean IOP reduction from 
time-matched baseline (baseline minus follow-up) for NCX 470 (0.065% or 0.1%) is 
non-inferior to latanoprost ophthalmic solution, 0.005%.   
The secondary objective of this study is to demonstrate that mean IOP reduction 
from time-matched baseline for NCX 470 (0.065% or 0.1%) is superior to 
latanoprost.   


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An additional secondary objective is to demonstrate that NCX 470 is safe and well 
tolerated.  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
   
Interim Adaptive Analysis 
A planned unmasked interim adaptive analysis will be performed by a limited number 
of independent personnel once at least 30 subjects randomized in each of the three 
armshave completed the Week 2 Visit
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
Information on the Adaptive Decision Committee (ADC) is provided in Section 11. 
Testing method and specifications regarding the decision rules for selecting the NCX 
470 treatment dose will be detailed in the Statistical Analysis Plan and the Adaptive 
Decision Committee Charter.  


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Final Analysis 
Primary Estimand 
The primary comparisons in this trial will be between NCX 470 (0.065% or 0.1%) QD 
and latanoprost 0.005% QD at the 8AM and 4PM time points at the Week 2,  
Week 6, and Month 3 Visits in the ITT population with intercurrent events handled as 
described in the following estimand.   
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Analyses 
The primary analysis of the primary outcome will employ a linear model with mean 
IOP at the given visit (Week 2, Week 6, and Month 3) and time point (8AM and 4PM) 
as the response, baseline IOP as a covariate, and treatment as a main effect, using 


NCX-470-02 version 2.0; 08-July-2020 
 
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the intent to treat population with multiple imputation techniques used to impute 
missing data (fully detailed estimand statements and handling of intercurrent events 
will be provided in the statistical analysis plan). 
The primary analysis for superiority will be completed similarly. 
Adjustments for Multiplicity 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Safety Analyses 
Safety analyses are based on the safety dataset. The safety population will include 
all subjects who received at least one dose of study medication. 
Subject disposition, demographics, and baseline characteristics will be summarized 
and presented in data listings. 
A treatment-emergent AE (TEAE) is defined as an AE that occurs on or after 
treatment is initiated. Ocular TEAEs by treatment group: NCX 470 (0.065% or 0.1%) 
and latanoprost 0.005%, will be summarized, by relationship to study drug, and by 
severity. Non-ocular TEAEs will be summarized by treatment group, by relationship 
to study drug, and by severity. Serious AEs (SAEs), AEs resulting in study drug 
discontinuation, and deaths will be presented in data listings. 
Safety data will be summarized for treated study eyes and fellow eyes separately, 
with the exception of ocular adverse events, which will be summarized at the subject 
level accounting for all treated eyes. 
 


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1. INTRODUCTION 
1.1 
Background and Rationale 
Glaucoma is a leading cause of blindness worldwide (Jonas, 2017).  Globally it has been 
estimated that 57.5 million people were affected by primary open-angle glaucoma (POAG) 
in 2015, with this number projected to rise to 65.5 million by 2020 (Kapetanakis, 2016).  
Intraocular pressure (IOP) is the primary risk factor for glaucoma, and lowering IOP to 
prevent optic nerve injury is currently the only proven effective treatment (Jonas, 2017).  
Topical PGAs, such as bimatoprost, are considered as the mainstay of treatment due to their 
efficacy and safety in lowering IOP (Daka, 2014).  Clinical trials reported greater reduction in 
IOP in subjects with OAG or OHT with bimatoprost 0.03% compared with either travoprost 
0.004% or latanoprost 0.005% in some instances, and equivalence among the three 
treatments in others (Parrish, 2003; Gandolfi, 2001).  All treatments presented an acceptable 
safety profile although lower incidences of conjunctival hyperemia have been reported with 
latanoprost 0.005% than with the other PGAs (Canadian Agency for Drugs and Technologies 
in Health, 2015; Daka, 2014). 
Nicox is developing NCX 470, a nitric oxide (NO)-donating bimatoprost prostaglandin analog, 
as a new therapy for lowering IOP in patients with OAG or OHT. When exposed to esterases 
in the eye, NCX 470 is cleaved into its active metabolites, the prostamide bimatoprost, which 
in turn is converted to bimatoprost acid, a prostaglandin F2α receptor agonist, and into 6-
(nitrooxy)-hexanoic acid, a NO-donating moiety. The active metabolites of NCX 470 include 
bimatoprost, the active ingredient in LUMIGAN®, (NDAs 021275 and 022184), and 6-
(nitrooxy)-hexanoic acid which leads to the release of NO. Another NO-donating PGA 
(VYZULTA®, latanoprostene bunod ophthalmic solution, 0.024%), also discovered and 
invented by Nicox, received US FDA (Food and Drug Administration) approval in November 
2017 for the reduction of IOP in patients with OAG or OHT (NDA 207795). 
Bimatoprost and NO provide robust IOP-lowering activity by concomitantly activating two 
independent mechanisms: uveoscleral outflow and trabecular/Schlemm’s canal conventional 
outflow facilities (Woodward, 2010; Cavet, 2014). Nitric oxide donors relax the TM and 
increase aqueous humor outflow (Gabelt, 2011; Heyne, 2013; Cavet, 2014).  As a result, NO 
modulates IOP through the conventional pathway.  In contrast, bimatoprost acts by 
increasing the outflow of aqueous humor primarily through the uveoscleral pathway (Krauss, 
2004). 
The additive effect of a NO donor and a prostaglandin F2α receptor agonist has been 
confirmed with latanoprostene bunod, a dual-acting NO-donating latanoprost developed for 
the reduction of IOP in patients with OAG or OHT (Medeiros, 2016; Weinreb, 2016).  This 
approach is supported by the nonclinical data package compiled for NCX 470, as well as the 
publicly available data for bimatoprost. 
NCX 470 exhibited potent and effective IOP-lowering activity in three ocular hypertensive 
animal models (Impagnatiello, 2015). Nonclinical pharmacology studies in well-established 
animal models of glaucoma and OHT have demonstrated that the IOP-lowering efficacy of 
NCX 470 is greater than that of equimolar doses of bimatoprost.  In particular, in transient 
ocular hypertensive rabbits, known to respond poorly to PGF2α analogs and prostamides, 
NCX 470 lowers IOP likely via NO release.  Additionally, an equimolar dose of NCX 470 at 
0.042% lowers IOP more effectively than bimatoprost at 0.03% in ocular normotensive dogs 
at 12 hours post dose, as well as in laser-induced ocular hypertensive non-human primates.  
The results of the first-in-man Phase 2 trial “Dolomites”, NCX-470-17001 demonstrated that 
all tested concentrations of NCX 470 (0.021%, 0.042%, and 0.065%) QD met the primary 


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efficacy endpoint of non-inferiority to latanoprost 0.005% QD for reduction from baseline in 
mean diurnal IOP at Day 28. In pre-specified secondary efficacy analyses, NCX 470 0.065% 
was superior to latanoprost for mean IOP reduction from baseline at all 3 time points (8AM, 
10AM and 4PM) on Day 28, with the difference reaching up to 1.4 mmHg. Mean IOP 
reduction from baseline at the 3 time points across Days 7, 14 and 28 ranged from 7.6 to 9.8 
mmHg for NCX 470 0.065% compared with 6.3 to 8.8 mmHg for latanoprost.  Additionally, 
all 3 concentrations of NCX 470 were well tolerated. The most frequent adverse event was 
conjunctival hyperemia. There were no treatment-related serious adverse events, and no 
evidence of treatment-related systemic side effects. The linearly increasing, dose-dependent 
IOP-lowering efficacy of NCX 470 without reaching a plateau, and the plateauing of ocular 
adverse events at the mid-dose of NCX 470 (0.042%) in the Phase 2 Dolomites trial (NCX-
470-17001) indicated that a higher dose (0.1%) has the potential for greater IOP lowering 
without apparent significant additional risks. Therefore, an adaptive design will be utilized in 
the current trial whereby one of the NCX 470 doses (0.065% or 0.1%) will be discontinued 
during the adaptive evaluation, which will occur after at least 30 subjects randomized in each 
arm complete their Week 2 Visit. 
1.2 
Study Background 
Nonclinical and Clinical Studies of NCX 470  
A summary of all nonclinical and clinical studies with NCX 470 can be found in the 
Investigator’s Brochure. 
Description of the Study Medication 
 
Description of Active Comparator 
 
Justification of the Study Design  
The proposed Phase 3 is a randomized, multi-regional, double-masked, parallel groups, 
active comparator-controlled clinical trial with adaptive dose selection.  
During the initial adaptive design dose-ranging phase, at least 30 subjects will be randomized 
in each arm in a 1:1:1 ratio to receive NCX 470 ophthalmic solution (0.065% or 0.1%), or 
latanoprost ophthalmic solution, 0.005% QD in the evening, one drop in each eye. 
• 
NCX 470 ophthalmic solution, 0.065% (minimum 30 subjects randomized) 
• 
NCX 470 ophthalmic solution, 0.1% (minimum 30 subjects randomized) 
• 
Latanoprost ophthalmic solution, 0.005% (minimum 30 subjects randomized) 
 
 
 
 
 
 
 


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The adaptive dose selection will be made at the end of the Adaptive Dose Selection Period 
during which at least 30 randomized subjects in each arm complete their Week 2 Visit 
 
 
 
 
• 
 
 
 
 
  
 
 
 
 
 
 
 
 
Justification of the Route of Delivery 
The topical ophthalmic route of delivery selected for the NCX 470 is the same as for the 
topical ophthalmic IOP-lowering product VYZULTA. NCX 470 and VYZULTA have the same 
postulated mechanism of action, both comprised of a PGA and a NO-donating moiety. 
 
 
 
 
 
 
 
Justification of the Dose Selection for NCX 470 
The IOP-lowering effect of NCX 470 was initially established in normotensive beagle dogs 
and ocular hypertensive non-human primates. In these nonclinical models, topical 
ophthalmic formulations of NCX 470 0.042%, formulated to be equimolar to topical 
ophthalmic formulation of 0.03% bimatoprost, demonstrated 2.0 to 3.5 mmHg superiority in 
IOP-lowering effect compared to 0.03% topical ophthalmic bimatoprost.  
Therefore, clinical dose ranging in the Phase 2 trial was centered on the mid dose of 0.042% 
NCX 470 (equimolar with 0.03% bimatoprost); a low dose of 0.021% NCX 470 (equimolar to 
0.015% bimatoprost); and a high dose of 0.065% NCX 470 (equimolar to 0.05% 
bimatoprost).  
The once-daily (in the evening) dosing regimen for NCX 470 is consistent with that of other 
PGAs. 
The results of the Phase 2 trial “Dolomites”, NCX-470-17001 demonstrated that all tested 
concentrations of NCX 470 (0.021%, 0.042%, and 0.065%) QD met the primary efficacy 
endpoint of non-inferiority to latanoprost 0.005% QD for reduction from baseline in mean 
diurnal IOP at Day 28. In pre-specified secondary efficacy analyses, NCX 470 0.065% was 
superior to latanoprost for mean IOP reduction from baseline at all 3 time points (8AM, 10AM 


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and 4PM) on Day 28, with the difference reaching up to 1.4 mmHg. Mean IOP reduction from 
baseline at the 3 time points across Days 7, 14 and 28 ranged from 7.6 to 9.8 mmHg for 
NCX 470 0.065% compared with 6.3 to 8.8 mmHg for latanoprost. Additionally, all 
3 concentrations of NCX 470 were well tolerated. The most frequent adverse event was 
conjunctival hyperemia. There were no treatment-related serious adverse events, and no 
evidence of treatment-related systemic side effects. NCX 470 showed linearly increasing 
IOP-lowering efficacy with each incremental concentration of NCX 470 without reaching a 
plateau, with a conjunctival hyperemia dose-response which plateaued at the middle dose 
(0.042%). The separation of the dose-response curves in IOP lowering vs. conjunctival 
hyperemia showed a favorable therapeutic index thereby allowing for a higher concentration 
of NCX 470 (i.e., 0.1%) to be evaluated in this trial alongside the highest dose tested (0.065% 
NCX 470) in the Phase 2 Dolomites trial. An adaptive design will be utilized wherein one of 
the NCX 470 doses will be discontinued during the adaptive evaluation, which will occur after 
at least 30 randomized subjects in each arm complete their Week 2 Visit. 
Justification of the Active Comparator Selection 
Topical PGAs, such as latanoprost, bimatoprost and travoprost, are considered the mainstay 
of treatment for patients with OAG or OHT due to their efficacy and safety in lowering IOP 
(Li, 2016; Daka, 2014). Latanoprost accounted for 71% of all PGA prescriptions in the US in 
2017, and more than one third of all prescribed IOP-lowering medications (IMS Data). As 
latanoprost was the first approved and remains the most widely prescribed PGA, latanoprost 
has a well-established safety and efficacy profile. Latanoprost has been used as comparator 
in the Phase 2 dose-ranging study NCX-470-17001 and NCX 470 0.065% demonstrated its 
superiority to this standard-of-care treatment for mean IOP reduction from baseline at all 
3 time points (8AM, 10AM and 4PM) at the Week 4 Visit, with the difference reaching up to 
1.4 mmHg. Therefore, latanoprost 0.005% is a reasonable choice for an active comparator 
for the NCX 470 Phase 3 program.  
Selection of the Study Population 
A total of approximately 670 male and female adults with OAG or OHT in both eyes will be 
randomized in this clinical study at approximately 50 investigative sites in the US and 
approximately 1 to 3 investigative sites in China. Up to 15 additional sites may be added 
based on enrollment rates.  
 
 
 
1.3 
Potential Risks and Benefits to Human Subjects 
The potential risks to subjects that may occur in this study are likely to be similar to those 
reported during the Phase 2 NCX-470-17001 trial, as well as the clinical development and 
marketing experience of bimatoprost, latanoprost, and latanoprostene bunod ophthalmic 
solutions. 
 
 
 
 
 
 
 
 
For further information, please refer to the Investigator Brochure for NCX 470.  


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The potential benefit to subjects is lowering of IOP. Elevated IOP represents a major risk 
factor for glaucomatous visual field loss. The higher the level of IOP, the greater the likelihood 
of optic nerve damage and visual field loss. 
The results of the Phase 2 “Dolomites” trial, NCX-470-17001 demonstrated that all tested 
concentrations of NCX 470 (0.021%, 0.042%, and 0.065%) QD met the primary efficacy 
endpoint of non-inferiority to latanoprost 0.005% QD for reduction from baseline in mean 
diurnal IOP at the Week 4 Visit. In pre-specified secondary efficacy analyses, NCX 470 
0.065% was superior to latanoprost for mean IOP reduction from baseline at all 3 time points 
(8AM, 10AM and 4PM) at the Week 4 Visit, with the difference reaching up to 1.4 mmHg. 
Mean IOP reduction from baseline at the 3 time points across the Week 1, 2 and 4 Visits 
ranged from 7.6 to 9.8 mmHg for NCX 470 0.065% compared with 6.3 to 8.8 mmHg for 
latanoprost. Additionally, all 3 concentrations of NCX 470 were well tolerated. The most 
frequent adverse event was conjunctival hyperemia. There were no treatment-related 
serious adverse events, and no evidence of treatment-related systemic side effects. 
NCX 470 showed increased IOP-lowering efficacy with each incremental concentration of 
NCX 470, with a conjunctival hyperemia dose-response which plateaued at the mid-dose 
(0.042%). The separation of the dose-response curves in IOP lowering vs. conjunctival 
hyperemia showed a favorable therapeutic index thereby allowing for a higher concentration 
of NCX 470 (i.e., 0.1%) to be evaluated in this trial alongside the highest dose tested (0.065% 
NCX 470) in the Phase 2 trial. 
 


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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
Primary Objective 
The primary objective is to demonstrate that NCX 470 (0.065% or 0.1%) QD is non-inferior 
to latanoprost 0.005% QD based on mean IOP reduction from time-matched baseline at the 
8AM and 4PM time points at the Week 2, Week 6 and Month 3 Visits. 
 
 
 
 
 
2.2 
Study Endpoints 
The following endpoints will be collected in the course of the study: 
• 
IOP  
• 
Slit-lamp biomicroscopy 
• 
Conjunctival hyperemia 
• 
Dilated ophthalmoscopy 
• 
Pachymetry 
• 
Perimetry 
• 
Pupil size 
• 
Iris color 
• 
Best Corrected Visual Acuity (BCVA) 
• 
Urine pregnancy tests (for females of childbearing potential) 
• 
Rate of discontinuation from the study 
• 
Treatment-Emergent Adverse Events 
2.3 
Efficacy Evaluations 
Primary Endpoint: The primary efficacy endpoint for this trial is mean IOP reduction 
from time-matched baseline (based on Eligibility 1 and Eligibility 2 Visits) at the 8AM 
and 4PM time-points at the Week 2, 6 and Month 3/Exit Visits in the study eye 
 
 
 
 
2.4 
Safety Evaluations 
Evaluations of safety include but are not limited to the collection of: adverse events, IOP, slit 
lamp biomicroscopy parameters, conjunctival hyperemia, dilated ophthalmoscopy 
parameters, pachymetry, perimetry, pupil size, iris color, BCVA, pregnancy tests (for women 
of child bearing potential (WOCBP)) and rate of discontinuation from the trial. 
Review of Safety Data by Medical Monitor 
A review of masked ocular and systemic safety data from each subject will be performed on 
an ongoing basis by the Medical Monitor. 
 


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3. STUDY DESIGN 
3.1 
Overall Study Design 
This is a randomized, multi-regional, double-masked, parallel-group, active comparator-
controlled, Phase 3 clinical trial with adaptive dose selection.  This trial will be conducted in 
approximately 50 sites in the United States and 
 China.
 
 
Subjects will be assessed for initial eligibility at the Screening Visit (Figure 1). Subjects 
currently being treated with an IOP-lowering medication will be required to discontinue their 
IOP-lowering medication during a washout period which will occur between the Screening 
Visit and the Eligibility 1 Visit.
 
 
 
Successful washout and IOP-based eligibility for all subjects will be determined at the 
Eligibility 1 Visit (Day 
 and the Eligibility 2 Visit (Day 
) with diurnal IOP 
measurements at 8AM, 10AM, and 4PM at both visits. The baseline IOP for study eligibility 
will be based on the study eye IOP measurements from the Eligibility 1 and Eligibility 2 Visits. 
Subjects meeting eligibility requirements will be randomized at the end of the Eligibility 2 
Visit.  
 
During the initial adaptive design dose-ranging phase, at least 30 subjects will be 
randomized in each arm in a 1:1:1 ratio to receive NCX 470 ophthalmic solution (0.065% 
or 0.1%), or latanoprost ophthalmic solution, 0.005% QD in the evening, one drop in each 
eye. 
• 
NCX 470 ophthalmic solution, 0.065% (minimum 30 subjects randomized) 
• 
NCX 470 ophthalmic solution, 0.1% (minimum 30 subjects randomized) 
• 
Latanoprost ophthalmic solution, 0.005% (minimum 30 subjects randomized) 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
• 
 


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• 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
All doses will be self-administered or administered by a caregiver topically as eye drops in 
the evening. 
Approximately 640 subjects will be studied for 3 months 
 
 
 
A subject will be considered as having completed the study after completion of the 
Month 3/ Exit Visit (Day 90 [± 3 days]). The overall study duration is estimated to be 
approximately 12 to 15 months from the first subject enrolled until completion of the last 
subject. The maximum duration of subject participation (from the Screening Visit to the 
Month 3/Exit Visit) is approximately 139 days (or approximately 167 days for subjects for 
whom the washout period may be extended during the Adaptive Dose Selection Period).  
 
 
 
*
3.2 
Washout Period for Majority of the Study Subjects 
Subjects currently using IOP-lowering medication(s) must undergo a minimum washout 
period as specified in Table 1 below according to the pharmacological class of their IOP-
lowering therapy.
 
 
 


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The minimum washout period will begin at the Screening Visit and will be completed at the 
Eligibility 1 Visit (day 
 (Figure 1).  The time between the Screening Visit and the 
Eligibility 1 Visit should not 
 for any subject.  
After the Eligibility 1 Visit there will be an additional 
 without any IOP-lowering 
treatment before eligibility confirmation and randomization at the Eligibility 2 Visit. The time 
between the Screening Visit and the Eligibility 2 Visit should 
. 
 
 
 
For treatment-naïve subjects the Eligibility 1 Visit will be scheduled a minimum of 5 days 
after the Screening Visit. 
 
 
 
 
 
 
Table 1: Minimum Washout Period(s) for IOP-Lowering Medications  
IOP-Lowering Medication 
Minimum Washout Period  
  
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
3.3 
Washout Period and Handling of Eligibility 1 and Eligibility 2 Study Visits for 
the Study Subjects during Adaptive Dose Selection Period  
 
 


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Table 2:  
 
Scenario 
Handling 
 
od 
• 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 


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Scenario 
Handling 
 
 
• 
 
 
 
 
 
 
4. 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
5. 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4. SUBJECT SELECTION  
4.1 
Number of Subjects and Sites 
This study will be conducted at approximately 50 clinical sites in the US and 
 
 in China. 
 
670 subjects will be 
randomized into the study. 
4.2 
Subject Population Characteristics 
The target population in this study will be adult men and women with a diagnosis of OAG or 
OHT in both eyes. 
Subjects must meet the following IOP requirements at the Eligibility 1 Visit (Day 
) and 
the Eligibility 2 Visit (Day ): 
• 
 
 
 
 
 
  
4.3 
Inclusion Criteria 
Prior to inclusion in the study, each subject must fulfill all of the following criteria: 
1) Subjects 
 years old. Subject must be of legal age (at least 18 years of age) 
on the date the informed consent form (ICF) is signed and must be able to provide a 
written informed consent to participate in the study, in accordance with the International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines and local 
regulations, before initiating any study-related procedures. 
2) Subjects will have a diagnosis of OAG or OHT in both eyes 
 
 
3) If treated for OAG or OHT, treatment nature and dose regimen must have been stable 
 
4) Subjects will meet the following IOP requirements at the Eligibility 1 (Days 
 and 
Eligibility 2 (Day ) Visits: 
• 
 
 
 
 
 
5) 
 
 
 
6) Subjects with best-corrected visual acuity (BCVA), using Early Treatment of Diabetic 
Retinopathy Study (ETDRS) chart, of 
 logMAR units (Snellen equivalent 
) 
or better in each eye. 


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7) If female, subjects must either be incapable of pregnancy because of bilateral 
oophorectomy, hysterectomy, bilateral tubal ligation, or be post-menopausal (have been 
amenorrheic for at least 2 years) or must use an effective (e.g., double barrier) method 
of birth control for the duration of the study. Female subjects of childbearing potential 
must have a negative pregnancy test and not be nursing. 
8) Subjects who are able and willing to comply with all study procedures. 
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
Ocular 
1) Subjects with advanced glaucoma or subjects with a cup/disc ratio greater than 
 or 
 
Subjects who are unable to reliably perform perimetry in either eye  (see Appendix 2 for 
reliability criteria). 
2) Subjects unwilling or unable to discontinue their current IOP-lowering medication(s). 
(An IOP-lowering medication with a shorter washout period is permitted between the 
Screening Visit and Eligibility 1 Visit – see Table 1. Refer also to Table 2 for use of an 
IOP-lowering medication with a short washout period in non-randomized subjects 
during the Adaptive Dose Selection Period. 
3) Subjects with narrow angles 
 Shaffer 
anterior chamber angle grading system) and subjects with angle closure, clinically 
significant peripheral anterior synechiae, congenital glaucoma, or a history of angle 
closure in either eye. 
4) Subjects with an iris or pupil anomaly (e.g., synechiae, coloboma) preventing reliable 
assessment of pupil diameter in either eye. 
5) Subjects whose central corneal thickness is less than 
 or greater than 
 
in either eye. 
6) Subjects with any condition that prevents reliable applanation tonometry in either eye 
(e.g., significant corneal surface abnormalities, scars, keratoconus).  
7) Subjects with 
 conjunctival hyperemia in either eye at the 8AM assessment 
at the Eligibility 1 or Eligibility 2 Visits graded on high resolution, color photography 
scale. 
8) Subjects with previous or currently active clinically significant corneal disease in either 
eye that could affect study outcome per Investigator’s judgment.  
9) Subjects with a history of severe dry eye in either eye. 
10) Subjects with any active or recurrent intraocular infection, inflammation, iritis or uveitis 
in either eye.  
11) Subjects with a diagnosis of a clinically significant retinal disease 
 
 
12) Subjects unwilling or unable to discontinue
 
 
 


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Ocular Surgery 
13) Subjects with history of previous glaucoma or angle surgery 
  
 
14) 
 
15) 
 
  
16) Subjects with history of previous complicated cataract surgery 
 
 
 
 
 
 
17) Subjects who had incisional ocular surgery or severe trauma in either eye within the 
previous 6 months 
 
 
Medication 
18) Subjects with a known hypersensitivity or contraindications to PGA(s) or any of the 
ingredients in the study medications. 
19) Subjects with known contraindications to NO treatments 
 
 
20) Subjects whose concomitant use of medications may interact with the safety or efficacy 
of a NO-donating compound 
 
21) Subjects who currently require treatment or are expected to require treatment with 
ocular or systemic corticosteroids 
 
 
22) Subjects with an anticipated need to initiate or modify medication
 
 
 
 
23) Subjects who currently require treatment or are expected to require treatment with any 
ocular medications,
 
  
24) 
 
 
 
Other 
25) Subjects with a history or presence of uncontrolled systemic disease
 
 
 


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26) 
 
 
 
27) Subjects who were randomized in the Phase 2 NCX-470-17001 clinical trial. 


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5. CONCOMITANT MEDICATION(S) 
5.1 
Previous and Concomitant Medication(s) 
All non-ophthalmic medications used in the 3 months prior to the Screening Visit, and all 
ophthalmic medications, including investigational ophthalmic products, used in the 
12 months prior to the Screening Visit must be recorded. Additionally, all medications used 
between the Screening Visit and the Month 3/Exit Visit must be recorded. 
Eligible subjects will discontinue all previous IOP-lowering medication(s), if applicable, on the 
day of the Screening Visit. However, the initiation of treatment with an IOP-lowering 
medication with a shorter washout period than the subject’s IOP-lowering medication at 
screening is permitted between the Screening Visit and Eligibility 1 Visit (see Table 1). 
Additionally, an IOP-lowering medication with a short washout period (e.g., a topical carbonic 
anhydrase inhibitor such as AZOPT) is permitted in non-randomized subjects during the 
Adaptive Dose Selection Period. 
The use of over-the-counter artificial tears or antihistamine eye drops is allowed provided 
they are administered a minimum of 5 minutes before or after the instillation of the study 
medication. 
Diagnostic ophthalmic agents administered throughout the study will not be captured in the 
concomitant medication log.  
5.2 
Prohibited Medication(s)  
All the prohibited drugs mentioned below are also listed in Section 4.4 (“Exclusion Criteria''). 
From the Screening Visit through the Month 3/Exit Visit subjects must not receive: 
• 
 
 
 
 
 
 
 
 
 
 
 
  
• 
 
 
 
  
Medication which is considered necessary for the subject's safety may be given at the 
discretion of the Investigator and/or their health care provider during the study. If possible, 
the Medical Monitor should be consulted prior to the administration of the disallowed 
medication (if not possible, the Medical Monitor should be notified as soon as possible 
thereafter) to determine whether the subject may continue in the study.   
 


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6. STUDY SUPPLIES 
6.1 
Description of Study Medication 
 
 
 
 
 
6.2 
Description of Active Comparator 
The active comparator, latanoprost ophthalmic solution, 0.005%, is a sterile, preserved, 
isotonic, buffered ophthalmic aqueous solution containing 0.005% latanoprost.
 
 
 
XALATAN® (latanoprost ophthalmic solution) 0.005% will be used as the active comparator 
in China and an FDA-approved generic of latanoprost ophthalmic solution, 0.005% will be 
used as the active comparator in the US. 
6.3 
Packaging of the Study Medication 
 
 
 
 
  
All study medication will be packaged, labeled, and supplied to the site by the study 
medication supplier under the direction of Nicox. Each kit 
 
assigned for a given subject contains sufficient study medication for the duration of the study 
treatment period.    
6.4 
Labeling of the Study Medication  
All labeling will be in English and the local language, as applicable, and will comply with US 
federal regulations and other local regulations, as applicable, for investigational drug product. 
The 
 boxes will be labeled minimally with the following information: protocol 
number, investigational product name(s), quantity, storage conditions, and Caution 
statement: New Drug - Limited by Federal Law to Investigational Use. The 
 label will 
minimally consist of two parts and list the unique kit number which will correspond to the 
treatment assignment; the second part of the 2-part label will contain masking information 
which is only to be revealed in the event of an emergency unmasking by the investigator 
upon approval by the Sponsor or designee. 
The 
 and individual bottles will be labeled minimally with the protocol number and 
unique kit number which will correspond to the treatment assignment. 
The 
 will have a label consisting of 2 parts: 
• 
A permanent portion affixed to the kit, and 
• 
A tear-off portion attached to the permanent portion by a perforated joint. 


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The tear-off portion of the masked label will be removed from the kit (one tear-off label per 
kit) and placed on the subject’s source documentation where it will remain available to the 
Investigator throughout the subject's participation in the study (date of dispensing must be 
reported in the subject’s source documentation). 
The 
, the 
, and the bottles will be labeled as described below:  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
Assigned Treatment 
 
XXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXX 
The 
 will also have a storage temperature sticker to clearly indicate whether the kit 
and its contents should be stored at room temperature or refrigerated. 
 
 
 
 
 
 
 
.  
 
  
  
 
 
 
 


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Bottle Label 
 
  
 
 
 
 
6.5 
Storage of the Study Medication  
It is the Principal Investigator’s responsibility to ensure that all study medication is stored in 
a secure area and administered only to randomized subjects and in accordance with 
conditions specified in this protocol.  Only the unmasked site designee authorized by the 
Principal Investigator may have access to the study medication and will be responsible for 
delivering/collecting the study medication to/from the subjects. 
 
 
 
 
 
6.6 
Accountability of Study Medication 
The study medication will be shipped by the study medication supplier to each study site.  
The receipt of study medication by the unmasked site designee should be documented. The 
dispensed and returned study medication will be recorded by the unmasked site designee 
on an inventory log. 
It is the responsibility of the unmasked site designee to maintain detailed study medication 
accountability records.  The importance of returning the kits with all dispensed bottles must 
be emphasized to the subjects.  Study medication deliberately and/or accidentally destroyed 
must be accounted for and the reason must be documented.  Any discrepancy between 
dispensed and returned study medication must be explained and documented by the 
unmasked site designee. 
6.7 
Assigning Subjects to Treatment and Study Masking 
Each site will be assigned a 
 by the Sponsor or its representative. At the 
Screening Visit, the site will assign 
 to 
each subject and record it in the screening log.  The site will then register the subject in the 
EDC system in which they will be issued a 
 
 
At the Eligibility 2 Visit (Day 1),
 
 


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The subjects, investigators, site staff measuring IOP or evaluating safety parameters, the 
Sponsor, the Medical Monitor, and the CRO personnel interacting with the clinical sites (or 
handling study data) will be masked to the treatment assignment. The unmasked site 
designee will only perform handling of study medication, and a limited set of 
procedures
 
 
 
 
   
IRT assignment is based on a randomization schedule created by an unmasked statistician. 
6.8 
Study Medication Dispensing and Collection  
For each subject fulfilling eligibility criteria, the clinical site staff will access the EDC and IRT 
to randomize study subject(s) at the Eligibility 2 Visit (Day 1).  A randomization number will 
be allocated to each subject and study medication kit number will be issued. 
 
 
 
Once all Eligibility 2 Visit study procedures have been completed 
 
 
 
 
 
 
 
 
 
In the event a subject needs a replacement kit, utilize the IRT. If a subject’s study medication 
is lost or destroyed, the subject will be assigned a 
 
from within that 
 will be dispensed.  
Subjects will be instructed to return their study medication 
 only to the 
site’s unmasked site designee at the Week 6 and Month 3/Exit Visits. An inventory will be 
conducted by the unmasked site designee during the conduct of the trial.  
6.9 
Instructions for Use and Administration 
The study medication must be administered one drop in each eye by the subject or caregiver, 
at 
 from the evening of the Eligibility 2 Visit (Day ) to the evening prior 
to the subject’s last study visit. 
No study medication will be administered by the investigational site staff.  
Each subject will be given a copy of the study medication dosing and storage instructions. 


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6.10 
Emergency Subject Unmasking 
If unmasking of a subject becomes critical to the subject’s safety, the Principal Investigator 
must authorize such decision. If possible, such decision should be first consulted with both 
the study Sponsor and the Medical Monitor. The study treatment assignment of a subject 
should be unmasked via the IRT. In a situation when the IRT system is not accessible, the 
unmasking can be achieved via the scratch-off portion of the study kit label located in the 
source documentation. The Sponsor and the Medical Monitor must be notified within 
24 hours following an emergency unmasking of any subject.  
6.11 
Study Medication Compliance 
It is important to encourage the subject to be compliant with the study treatment. Compliance 
will be captured in a subject diary, and collected at the Week 2, Week 6, and Month 3/Exit 
Visits. The subject will be instructed on diary completion.  
6.12 
Return of Study Medication by the Clinical Sites 
Return of used and unused study medication by the clinical site to the study medication 
supplier should be performed following onsite verification by the CRA. 
6.13 
Other Study Supply 
Sites will also be provided with: 
• 
 
 
 
 
 
 
 
 
 
 
Additional supplies may be provided once discussed and approved by the Sponsor.  
 


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7. STUDY PROCEDURES BY VISIT 
The following sections provide a list of procedures and assessments for each study visit as 
outlined in the Times and Events Schedule (Appendix 1).   
Ocular examination procedures will be performed 
 
in accordance with the site’s standard clinical practice. Refer to Appendix 2 for information 
on the methods of clinical evaluation. 
7.1 
Screening Visit  
Prior to any study assessments, potential subjects will be identified and the Investigator (or 
designee) will conduct the informed consent process. The purpose of the study, the study 
methods (visits and assessments), risks/benefits, and subject responsibilities will be 
discussed.  The subject’s willingness and ability to participate in the study will be assessed.  
If the subject chooses to proceed with study participation, written informed consent and 
subject authorization will be obtained as appropriate for local privacy regulations. The original 
signed document will be retained in the subject records and a copy will be provided to the 
subject. 
Perform the following procedures and/or collect the following information: 
• 
Assign the screening number and record in the screening log 
• 
Record any AEs from the time the subject signs the ICF 
• 
Record demographic data 
• 
Record past and current relevant medical and ophthalmic history (history of OAG or 
OHT must be documented), including previous ocular surgery(ies)/procedure(s) 
• 
Record concomitant medication(s), including any ongoing IOP-lowering treatment(s) 
at Screening and in the past 
 months for non-ophthalmic and 
 months for 
ophthalmic medications  
• 
   
 
  
 
 
 
 
 
 
 
 
• 
 
 
 
  
 
 
 
 
 
 
 
 
 


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• 
  
Washout Period  
At the Screening Visit, eligible subjects will be instructed to discontinue their current IOP-
lowering medication(s), if applicable. The duration of the washout period will be based on 
their previous IOP-lowering medication(s). Refer to Washout Period (Section 3.2) to 
determine the duration of the washout period for each subject. 
Subjects who are not required to undergo a washout period may proceed to the Eligibility 1 
Visit
 
 
 
  
 
 
 
 
 
7.2 
Eligibility 1 Visit (Day 
 
• 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
  
 
  
• 
Review inclusion/exclusion criteria and determine eligibility 
If subject meets all criteria assessed, schedule Eligibility 2 Visit, and instruct subject to not 
resume IOP-lowering medication. Remind contact lens wearers 
 
 
 
 
 
 
 
 
 
 


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7.3 
Eligibility 2 Visit (Day ) 
Eligibility 2 Visit will occur 
 days after the Eligibility 1 Visit. Additionally, Eligibility 2 Visit 
will occur no more than 
days from the Screening Visit (except during the Adaptive Dose 
Selection Period as noted in Table 2).  
• 
Record any AEs which occurred since the last visit and during this visit 
• 
Record any changes in concomitant medication(s), medical/ophthalmic history  
• 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
   
 
  
 
 
 
• 
Dispense subject diary and subject dosing instructions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.4 
Week 2 Visit (Day 14 
 
• 
Record any AEs which occurred since the last visit and during this visit 
• 
Record any changes in concomitant medication(s), medical/ophthalmic history 
• 
 
 


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• 
 
 
  
 
 
 
 
 
 
 
 
• 
Review the subject diary for compliance and collect it; dispense new subject diary 
and dosing instructions 
7.5 
Week 6 Visit (Day 42 
 
• 
Record any AEs which occurred since the last visit and during this visit 
• 
Record any changes in concomitant medication(s), medical/ophthalmic history 
• 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
• 
Review the subject diary for compliance and collect it; dispense new subject diary 
and dosing instructions 
 
Note: If a subject, who was randomized to the discontinued dose of NCX 470, is discontinued 
at the Week 6 Visit, the Month 3/Exit Visit assessments should be performed and 
documented. 
7.6 
Month 3 Visit (Day 90 
Exit Visit 
• 
Record any AEs which occurred since the last visit and during this visit 
• 
Record any changes in concomitant medication(s), medical/ophthalmic history 
• 
 
 
 
 


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• 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
• 
Review subject diary for compliance and collect it 
• 
Utilize IRT/EDC to exit the subject 
7.7 
Unscheduled Visits 
Additional examinations or analyses may be performed as necessary to ensure the safety of 
subjects during the study period. An electronic Case Report Form (eCRF) must be completed 
for each unscheduled visit with documentation of the following mandatory assessments: 
- 
Adverse event(s) (if applicable)  
- 
Concomitant medications, changes in medical/ophthalmic conditions 
- 
 
 
 
 
 
The Investigator may perform any other examination that is regarded as appropriate.  Please 
refer to the eCRF Completion Guidelines for detailed instructions. 
Note that completion of an Unscheduled Visit eCRF is not required for subjects returning to 
complete perimetry on a separate day from the initial Screening Visit. 


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8. SCREEN FAILURES, COMPLETION AND DISCONTINUATION 
8.1 
Subject Screen or Eligibility Failures 
Subjects who are screen or eligibility failures should not be randomized into the study. The 
reason for screen/eligibility failure must be documented in the source document and in the 
eCRF. 
Subjects may be rescreened for participation in the trial following Sponsor’s approval. 
8.2 
Subject Completion 
A subject is considered to have completed the study at the end of the Month 3/Exit Visit. 
8.3 
Subject Early Discontinuation 
A subject may be discontinued from the study prior to the final study visit at the discretion of 
the Investigator, Sponsor, and/or IRB. Subjects may also discontinue their participation in 
the study at any time per their own decision. 
A subject may be discontinued from the study for the following reasons, including but 
not limited to: 
• 
Serious adverse event: If it is determined by the Investigator that only removal 
from the study could reduce subject’s risk or that the occurred SAE prevents the 
subject from further participation in the study treatment or follow-up, the subject 
may be withdrawn.   
• 
Violation of eligibility criteria: In case a subject has been randomized into the study 
despite not meeting study inclusion/exclusion criteria, or non-compliance with 
inclusion or exclusion criteria has occurred during the course of the study, the 
subject may be discontinued.   
• 
Lack of compliance with the study procedures or loss to follow-up.  
• 
.  
A subject must be discontinued from the study for the following reasons, including 
but not limited to: 
• 
 
• 
Withdrawal of consent 
• 
Subject becoming pregnant in the course of the study 
Procedures for Discontinuation 
If a subject is discontinued or withdraws consent during the washout period, no procedures 
other than those which may be related to the follow-up of AEs will be required.  The 
Investigator will document the reason for the subject withdrawal.  
If a subject is discontinued for reasons other than withdrawal of consent during the treatment 
period, the Month 3/Exit Visit assessments should be performed and documented. 
If a subject withdraws their consent during the study treatment period, all efforts should be 
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If a subject is discontinued due to an AE, the status of the AE at the time of discontinuation 
will be recorded in the eCRF.   
 
 
 
Study medication must be returned by the subject to the site unmasked designee, as 
applicable. 
8.4 
Subject Lost to Follow-up 
Subjects who fail to present for a study visit should be contacted in an attempt to have the 
subject comply with the protocol and to return the diary and study medication, if applicable. 
If a subject cannot be contacted with a minimum of three documented telephone calls 
followed by a certified letter and there is no known reason for withdrawal (e.g., withdrawn 
consent), the reason for withdrawal from the study will be recorded as “lost to follow-up”. The 
date of withdrawal will be considered as seven days after the certified letter was mailed. 
8.5 
Study Termination 
Investigators and subjects should understand that the study may be discontinued by the 
Sponsor (Nicox) at any time, without their consent. 
8.6 
Subjects Discontinued Per Protocol Following Adaptive Evaluation 
Subjects, who were randomized to the discontinued dose of NCX 470, must discontinue at 
the next scheduled study visit following the completion of the Adaptive Dose Selection 
Period. 
 
 
 
  
 
 


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9. PROTOCOL COMPLIANCE 
Subjects who experience major protocol deviations will have all their data excluded from the 
Per Protocol (PP) analysis.  The list of major protocol deviations, as well as minor protocol 
deviations, will be finalized prior to database lock. 
In order to correctly identify and document protocol deviations, protocol deviations will be 
categorized as follows: 
• 
Minor Deviation: Deviation considered to not impact the primary efficacy outcome 
of the study (i.e., does not affect the study results). 
• 
Major Deviation: Deviation considered to impact the primary efficacy outcome of 
the study (i.e., affects the study results). 
All deviations will be recorded by the site and classified by the Sponsor.  
 


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10. ADVERSE EVENTS 
10.1 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have 
a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal (investigational) 
product.  Lack of efficacy will be reported as a treatment failure, not as an AE. 
10.2 
Severity of Adverse Event 
The severity of an AE should be categorized as mild, moderate or severe per Investigator’s 
judgment with the following scale in consideration: 
• 
Mild: Awareness of a sign or symptom that does not interfere with the subject’s usual 
activities or is transient, resolved without treatment and with no sequelae. 
• 
Moderate: interferes with the subject’s usual activities, and or requires symptomatic 
treatment. 
• 
Severe: symptom(s) causing severe discomfort and significant impact of the subject’s 
usual activities and requires treatment. 
10.3 
Causal Relationship with Study Medication 
A determination of the relationship between an AE and the study medication must be made 
by the Investigator for each AE. The following terms to evaluate the causality of the AE with 
the study drug should be used: 
• 
Unrelated: a simultaneous disease, a simultaneous treatment or any other known 
cause is clearly responsible for the safety event and the AE is not related to the study 
medication. 
• 
Unlikely: on the basis of the available knowledge regarding the subject’s history, 
the disease process, the timing of the safety event in relation to the administration 
of the study medication and the mode of action of study medication, a relation 
between the study medication and the safety event is unlikely, but cannot be totally 
excluded.  
• 
Possible: this relation exists when the safety event follows the reasonable 
chronological sequence from the moment of the study medication administration, but 
when the safety event could also have been caused by the clinical condition of the 
subject or by other treatment administered to the subject.  
• 
Probable: this relation exists when the safety event follows a reasonable 
chronological sequence from the moment of the study medication administration, 
corresponds to a known effect of the study medication, is confirmed by the 
observation of an improvement upon discontinuation of the study medication 
administration, and therefore the study medication is the most probable of all the 
causes.  
• 
Definite: this relation exists when the safety event follows a reasonable 
chronological sequence from the moment of the study medication administration, 
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by the observation of an improvement upon discontinuation of the study medication, 
and no other reasonable cause exists.  
Early exit for lack of efficacy/worsening of the disease will not be considered as an adverse 
event but as a treatment failure.  
10.4 
Serious Adverse Events  
SAE is any untoward medical occurrence that at any dose: 
• 
Results in death, or 
• 
Results in-subject hospitalization or prolongation of existing hospitalization, or 
• 
Results in persistent or significant disability/incapacity, or 
• 
Results in a congenital anomaly/birth defect (Section 12.2 - Procedure in Case of 
Pregnancy), or 
• 
Results in life-threatening illness or injury (Note: The term “life-threatening” in the 
definition of “serious” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it was more severe, or had continued untreated). 
• 
Results in a significant and persistent loss or impairment of vision.  
Additionally, medical events that may not meet these criteria, may be considered an SAE if, 
based on the medical judgment of the Investigator, such medical events may require an 
intervention to prevent any of the outcomes listed above.  
To ensure no confusion or misunderstanding of the difference between the terms "serious" 
and "severe," which are not synonymous, the following note of clarification is provided: the 
term "severe" is often used to describe the intensity of a specific event.  This is not the same 
as "serious," which is based on subject/event outcome or action criteria usually associated 
with events that pose a threat to a subject's life or functioning. 
Elective or planned procedures requiring hospitalization will not be considered SAE’s; 
however, other events may occur during this hospitalization that may be considered serious 
or non-serious adverse events and will need to be captured according to the protocol. 
Subjects must not undergo any elective, or plan any non-urgent procedures for the study 
duration and 30 days following the last treatment administration. 
10.5 
Adverse Event Reporting 
In this study, subjects should be encouraged to report AEs spontaneously or in response to 
general, non-directed questioning (e.g., “How has your health been since the last visit?”).  If 
it is determined that an AE has occurred, the Investigator should obtain all the information 
required to complete the AE Form(s).  
Additionally, subjects will be instructed to contact the Investigator, and/or study coordinator 
if any significant AEs occur between study visits.  
All AEs that occur from the signing of the ICF on the day of the Screening Visit through the 
Month 3/Exit Visit must be recorded on the appropriate AE form.  All AEs must be reported 
whether or not considered causally related to study medication.  For every AE, the Principal 
Investigator will provide an assessment of the severity and causal relationship to study 
medication, document all actions taken with regard to study medication, and any other 
treatment measures for the AE.   


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10.6 
Serious Adverse Event Reporting 
Any SAE occurring from the signing of the ICF on the day of the Screening Visit, and up to 
30 days following the most recent study drug administration (for a subject who exited the 
study early or after normal study completion) must immediately be reported to the company 
representing Nicox, and recorded on the appropriate forms.  All subjects with an SAE must 
be followed up and the outcomes reported. Subjects must be followed until complete healing 
or stabilization or blood tests are back to normal or up to 30 days after the end of the study 
treatment, whichever occurs first.  The Investigator must supply the company representing 
Nicox with any additional requested information (e.g., autopsy reports and final medical 
reports). 
In the event of an SAE, the Investigator must: 
1) Notify Sponsor’s Primary Contact for Study Related Matters and SAEs immediately 
(see contact information on Page 3 and Section 12.1), at the latest within 24 hours 
of becoming aware of the initial SAE.  Complete an SAE Form (see instructions for 
completion of SAE Form in Appendix 3) and send it to the Primary Contact for Study 
Related Matters and SAEs. Retain all submission confirmations with the items 
submitted.  
2) Obtain and maintain in subject’s files pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the subject.  
3) Complete and submit further follow-up reports for data collected until the SAE has 
resolved or a decision for no further follow up has been taken.  
4) Promptly inform the local IRB and/or other applicable regulatory body as required by 
local regulations. 


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11. STATISTICAL CONSIDERATIONS AND METHODS OF ANALYSIS 
A final analysis plan containing detailed statistical methods, including accounting for 
multiplicity, will be generated and finalized prior to database lock following the completion of 
the 3-month safety and efficacy evaluation period. There will be a single final statistical 
analysis plan for this multi-regional trial. 
Additionally, an interim analysis plan containing detailed statistical methods, including 
accounting for multiplicity, will be generated and finalized prior to the interim analysis 
supporting the adaptive evaluation of at least 30 subjects in each treatment arm through 
Week 2.  
11.1 
Determination of Sample Size and Power Calculations 
The primary objective of this study is to demonstrate that mean IOP reduction from time-
matched baseline (baseline minus follow-up) for NCX 470 (0.065% or 0.1%) is non-inferior 
to latanoprost ophthalmic solution, 0.005%.   
  
  
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
11.2 
Analysis Population 
For the 3-month treatment evaluation period, three different populations will be used in the 
analysis: an intent-to-treat (ITT) population, a Per Protocol (PP) population, and a safety 
population. 
The ITT population will include all randomized subjects. Demographics, baseline 
characteristics, and efficacy variables will be analyzed using the ITT population. These 
analyses will be performed on an as-randomized basis. 
The PP population will include all randomized subjects who received study medication, who 
had at least one follow-up visit and who had no major protocol deviations (see Section 9) 


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during the 3-month treatment period. The final PP population will be determined and 
approved by Nicox prior to database lock.  Demographics, baseline characteristics, and 
efficacy variables will be analyzed using the PP population. These analyses will be performed 
on an as-treated basis.   
The safety population will include all randomized subjects who received at least one dose of 
the study medication during the 3-month treatment period and will be used for the safety 
analyses. All safety variables will be analyzed on an as-treated basis using the safety 
population. 
11.3 
Data Display 
Data will be analyzed separately using the following treatment groups wherever appropriate: 
• 
NCX 470 ophthalmic solution, 0.065% 
• 
NCX 470 ophthalmic solution, 0.1% 
• 
Latanoprost ophthalmic solution, 0.005% 
11.4 
Collection and Derivation of Primary Efficacy Assessments 
At the Screening Visit, IOP will be measured at 8AM 
min., 10AM 
 min., or 4PM ± 
min. From the Eligibility 1 Visit to the Month 3 Visit, IOP will be measured at 8AM 
 min., 
10AM 
 min. and 4PM 
 min. IOP measurements will be conducted in both eyes. 
Handling of missing values: 
The primary efficacy analyses will be based on the ITT population with multiple imputation 
(MI) methods. To check for robustness of outcomes, missing data will be handled using 
 
 detailed in the formal statistical analysis 
plan. 
11.5 
Hypothesis and Methods of Analysis 
11.5.1 Primary Efficacy Analysis  
The primary efficacy assessment is the non-inferiority analysis of the difference in the 
treatment effect between NCX 470 and latanoprost 0.005% for mean IOP reduction from 
time-matched baseline at the 8AM and 4PM time-points at the Week 2, Week 6 and Month 3 
Visits in the study eye. 
Efficacy will be assessed by the primary variable: 
Mean reduction from baseline (average of Eligibility 1 and Eligibility 2 Visits) in time-matched 
IOP at the 8AM and 4PM time points at the Week 2, Week 6 and Month 3 Visits. 
The primary analysis of the primary outcome will employ a linear model with mean IOP at 
the given visit (Week 2, Week 6, and Month 3) and time point (8AM and 4PM) as the 
response, baseline IOP as a covariate, and treatment as a main effect, using the ITT 
population with multiple imputation techniques used to impute missing data.  
The primary analysis for superiority will be completed similarly. 
Adjustments for Multiplicity 
 
 
 


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Detailed statistical methodology will be provided in the Statistical Analysis Plan. 
Primary Estimand 
The primary comparisons in this trial will be between NCX 470 (0.065% or 0.1%) QD and 
latanoprost 0.005% QD at the 8AM and 4PM time points at the Week 2, Week 6, and Month 3 
Visits in the 
 population with intercurrent events handled as described in the following 
estimand.   
• 
 
 
 
 
 
 
: 
- 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 


CONFIDENTIAL 
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Page 59 of 78 
 
 
Interim Adaptive Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adaptive Decision Committee 
 
 
 
 
 
 
 
 
Safety data will be summarized for treated study eyes and fellow eyes separately, with the 
exception of ocular adverse events, which will be summarized at the subject level accounting 
for all treated eyes. 
 
 
11.5.2 Secondary Efficacy Analyses 
 
 
  Detailed statistical methodology for the secondary efficacy analyses 
will be provided in the Statistical Analysis Plan. 


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Page 60 of 78 
11.5.3 Safety Analysis 
Safety analyses are based on the safety dataset.  The safety population will include all 
subjects who receive at least one dose of study medication. 
Subject disposition, demographics, and baseline characteristics will be summarized and 
presented in data listings. 
A treatment-emergent AE (TEAE) is defined as an AE that occurred on or after the treatment 
was initiated.  Ocular TEAEs by treatment group: NCX 470 0.065, NCX 470 0.1% and 
latanoprost 0.005%, will be summarized, by relationship to study drug, and by severity.  Non-
ocular TEAEs will be summarized by treatment group as follows: non-ocular TEAEs, by 
relationship to study, and by severity.  Serious AEs (SAEs), AEs resulting in study drug 
discontinuation, and deaths will be presented in data listings. 
Other ocular safety data will be summarized for treated study eyes and fellow eyes 
separately, with the exception of ocular adverse events, which will be summarized at the 
subject level accounting for all treated eyes. 


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Page 61 of 78 
12. EMERGENCY PROCEDURES 
12.1 
Emergency Contact Procedure 
In case of any Safety Event including an SAE, the first person to contact is: 
 
 
 
 
The secondary contact is the study Medical Monitor: 
 
 
 
 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to cope with medical emergencies during the study.  Each subject will receive the 
Investigator’s emergency contact information (to call if needed).   
12.2 
Procedure in Case of Pregnancy 
If a pregnancy occurs during the study, pregnancy itself is not regarded as an AE unless 
there is a suspicion that the study medication may have interfered with the effectiveness of 
a contraceptive medication. 
If a female subject becomes pregnant during the study, the subject will be withdrawn from 
the study immediately.  However, any pregnancies must be followed up, and their outcomes 
must be reported to Nicox or to the company representing Nicox (i.e., mother and fetus(es) 
must be followed up at least until the birth of the infant and one month after the birth of the 
infant). Follow-up will include course, duration, outcome of the pregnancy and the health of 
the infant, as applicable. 
If the outcome of pregnancy is:  
• 
Elective abortion without complications: it must be documented and reported to Nicox 
or to the company representing Nicox, but it should not be handled as an AE.   
• 
Any spontaneous miscarriage or abortion for medical reasons or congenital anomaly 
or birth defect: it must be documented and handled as a SAE and full details will be 
requested.   
Any complications during pregnancy must be recorded as AEs and may constitute SAEs if 
they fulfill any of the specified criteria for a SAE.  
 


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Page 62 of 78 
13. STUDY MANAGEMENT 
13.1 
Monitoring 
Site monitoring is conducted to assess that subject protection, study procedures, study drug 
administration, and data collection processes meet protocol, ICH, GCP, and regulatory 
guidelines/requirements.   
Before the study starts, the company representing Nicox will visit/call the investigational sites 
to: 
• 
Determine the adequacy of the facilities, 
• 
Discuss with the Investigator(s), and other personnel involved in the study, about their 
responsibilities with regard to protocol adherence, and also about Sponsor’s 
responsibilities. 
During the study, a masked Clinical Research Associate (CRA) will monitor the study on a 
periodic basis by having regular contacts with the investigational sites, including on-site 
and/or remote visits, to: 
• 
Provide information and support to the Investigator(s), 
• 
Confirm that facilities and investigational site staff remain acceptable, 
• 
Ensure that the investigational site study team is adhering to the protocol, including 
verifying the accuracy of data recorded in the eCRF. 
Additionally, an unmasked CRA will monitor the site on a regular basis to ensure that all 
study medication is stored in a secure area and in accordance with the storage conditions 
indicated on the label of the outer kits. The unmasked CRA will also provide oversight of 
temperature excursions. Finally, the unmasked CRA will monitor the site to ensure that study 
medication is only dispensed to randomized subjects, and that all dispensed and returned 
study medication is recorded by the unmasked site designee on an inventory log. 
Any detected non-compliance with the approved study protocol, GCP, or any applicable 
regulatory requirements will be fully documented by the monitor. During the monitoring visits, 
the Investigator and clinical study staff should be available for questions, verification of data 
from the source documentation, and possible correction to the eCRF. 
Following each monitoring visit, the Investigator will be sent a follow up letter detailing any 
actions required by either the investigational site staff or the monitor.  Any actions must, 
wherever possible, be addressed immediately, or by the next scheduled monitoring visit. 
The monitor and the CRO’s clinical operations team will be reachable between visits if the 
Investigator, or other study staff at the site, needs information and advice. 
13.2 
Source Documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6(R2) GCP Section 4.9, and regulatory and institutional requirements 
for the protection of subject confidentiality. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 


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Page 63 of 78 
Source documents may include, but are not limited to, a subject’s medical records, hospital 
charts if any, clinic charts if any, the Investigator’s subject study files, pharmacy dispensing 
records, recorded data from automated instruments, as well as the results of diagnostic tests. 
13.3 
Source Data Verification 
To ensure that data in the eCRF is accurate and complete and in accordance with subject 
source documents and other source data, source data verification (SDV) will be performed 
by the monitor on eCRF’s and SAE and pregnancy related documents as detailed in the 
Monitoring Plan (MP).  The SDV consists of a comparison of the source documentation and 
other relevant records to the eCRFs.  This will require direct access to all original records for 
each subject. 
It will be verified that documentation of the informed consent is on file for all subjects 
screened whether or not they were randomized into the study. 
13.4 
Completion of Electronic Case Report Forms  
eCRFs must be completed for each subject enrolled in the trial, including screening 
failures.  eCRFs should be completed as soon as possible after the subject visit.  All 
eCRFs must be checked for consistency, accuracy, and completeness by the responsible 
Investigator and personally electronically signed and dated by them.   
13.5 
Data Management 
The study Data Management Plan (DMP) will describe the methods used to collect, check 
and process clinical data, as well as the process for database locks.  The DMP will be 
developed by the company representing Nicox and approved by Nicox.  It will also list the 
roles and responsibilities of the various functions and personnel involved in the data 
management process. 
 
 
13.6 
Audits and Inspections 
Authorized representatives of Nicox or the company representing Nicox, a regulatory 
authority, or an IRB/IEC may visit the site to perform audits or inspections, including source 
data verification.  The purpose of such 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 approved protocol, GCP, ICH guidelines, and any applicable regulatory 
requirements.  The Investigator must contact Nicox or the company representing Nicox 
immediately if contacted by a regulatory agency about an inspection at their site. 
The presence of the CRA at the site is mandatory in case of an inspection or audit (at least 
for the SDV audit and the debriefing with the Principal Investigator).  Nevertheless, when 
justified, the CRA may be represented by another CRO representative involved in the study 
(e.g., lead CRA).  
13.7 
Access to Source Data 
Nicox, authorized representatives of the company representing Nicox, or regulatory authority 
representatives will be allowed to have full and direct access to the various records relating 


CONFIDENTIAL 
NCX-470-02 version 2.0; 08-July-2020 
 
Page 64 of 78 
to the trial (e.g., Subject’s data records, diagnostic tests) to verify adherence to the protocol 
and the completeness, consistency, and accuracy of the data being reported. 
13.8 
Training of Staff 
The Principal Investigator will maintain records of all individuals at their site involved in the 
study (medical, nursing, and other staff).  The Principal Investigator will ensure that 
appropriate training relevant to the study is given to all of the study staff, and that any new 
information of relevance to the performance of this study is forwarded to the staff involved.  
The Principal Investigator must inform the monitor, in a timely manner, of any change in the 
study site staff. 
13.9 
Changes to the Protocol 
Neither the Investigator nor the site staff may implement any changes to the protocol without 
approval by Nicox and prior review and documented approval/favorable opinion from the IRB 
of a protocol amendment, except where necessary to eliminate immediate hazards to study 
subjects, or when the changes involve only logistical or administrative aspects of the study 
(e.g., change in monitors, change of telephone numbers).  If a protocol amendment requires 
a change to a particular site's Informed Consent Form, then Nicox or the company 
representing Nicox and the site's IRB must be notified.  Approvals of the revised Informed 
Consent Form by Nicox or the company representing Nicox, and the IRB are required before 
the revised form is used. 
Nicox or the company representing Nicox will distribute amendments and new versions of 
the protocol to each Principal Investigator(s) and site study staff for review and any applicable 
training.   
 


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14.  ADMINISTRATIVE, LEGAL, AND ETHICAL ASPECTS 
14.1 
Conduct of the Trial 
The trial will be conducted according to the protocol, the ICH Consolidated Guideline for 
Good Clinical Practice (ICH GCP E6 (R2) - March 2018), and the applicable regulatory 
requirements.  
14.2 
Ethical Principles 
The study has to be conducted in accordance with the principles of the Declaration of Helsinki 
(1964), as amended or clarified by the General Assembly of the World Medical Association 
(World Medical Association Declaration of Helsinki, last amended October 2013). 
14.3 
Health Authorities and Institutional Review Board (IRB)  
This study is to be conducted in accordance with IRB regulations (U.S. 21 CFR Part 56). 
The study protocol and subject informed consent form must be submitted to the appropriate 
properly constituted IRB.  The approval from the IRB must refer to the exact protocol title and 
number, and identify all documents reviewed and their corresponding versions.  A list of the 
IRB review board members as well as a statement of compliance with GCP and applicable 
laws and regulations should be also provided.  Copies of all IRB correspondence with the 
Investigator should be given to the company representing Nicox. 
The company representing Nicox is to be notified immediately if the responsible IRB has 
been disqualified or if proceedings leading to disqualification have begun. 
The Principal Investigator is also responsible for providing the IRB with safety reports of any 
unexpected SAEs from any clinical study conducted with the study medication, as dictated 
by the IRB requirements.  These safety reports will be provided to the Principal Investigator 
by the company representing Nicox. 
The Principal Investigator is responsible for informing the IRB of any amendment to the 
protocol.  In addition, the IRB must approve all materials used to recruit subjects for the 
study.  Either the Principal Investigator, or the company representing Nicox, must submit 
progress reports to the IRB according to the IRB requirements and local regulations and 
guidelines.  The Principal Investigator must also provide the IRB with any reports of Serious 
Adverse Events from the study site, as dictated by the IRB requirements. 
14.4 
Subject Information and Consent 
It is the responsibility of the Investigator to obtain written and signed informed consent prior 
to enrollment into the study (i.e., at the Screening Visit) and before any procedure related to 
the trial is performed.   
The methods of obtaining and documenting informed consent and the contents of the ICF 
will comply with ICH GCP guidelines, the requirements of 21 CFR Part 50 “Protection of 
Human Subjects”, the Health Insurance Portability and Accountability Act (HIPAA) 
regulations for subjects in the U.S. and appropriate local guidelines, requirements, and 
regulations for the subjects in China, and all other applicable regulatory requirements. 
The Investigator or their designee must fully explain and adequately inform the subject of the 
purpose of the study prior to entering a subject into the clinical trial or performing any trial-
specific procedures.  


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Page 66 of 78 
Once the subject fully agrees to participate in this study, written ICF must be documented by 
the subject’s personally dated signature and the personally dated signature of the informing 
Investigator/designated person conducting the informed consent discussion.  The subject will 
receive one copy and the original ICF will be filed in the subject study file on site. 
The dates when the written informed consent was obtained for the subject and when the 
subject withdraws or exits the study, must be documented in the subject source documents 
so that it is known if the subject is currently participating in a clinical study. 
In signing the ICF, a subject accepts direct access to their data by Nicox, the company 
representing Nicox, monitor, auditor, and Health Authority representatives. 
14.5 
Confidentiality Regarding Trial Subjects Data 
In order to maintain subjects’ privacy, all study materials will identify subjects in a fully 
anonymized manner. The Investigator will grant the company or its designated 
representatives, or regulatory authorities the right to access subject’s original medical 
records for verification of the data gathered in the study. Subject’s confidentiality will be 
maintained and will not be made publicly available unless mandated by applicable laws and 
regulations. 
14.6 
Archiving at the End of the Study 
After the close-out visit at each site, the study is considered completed.  A copy of the final 
completed CRFs will be stored in the Investigator's archives for up 2 years following the final 
approval of the last marketing authorization, together with all the other site study-specific 
documents (including Investigator’s site file).  Neither of these is ever transferred to the 
Sponsor. 
All study-related materials must be stored in a secure manner and must remain available 
upon request from Nicox or any Health Authority. 
14.7 
Coordinating Investigator 
The Coordinating Investigator for this trial is 
 
 
 


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Page 67 of 78 
15. PUBLICATION POLICY 
The institutions, investigators, and all study personnel shall regard all study data as confidential 
until analyses and review of the analyses are performed by Nicox.   
The institutions and investigators participating in this trial shall have no right to publish or present 
the results of this study without the prior written consent of Nicox. 
 


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Page 68 of 78 
16. REFERENCES 
Canadian Agency for Drugs and Technologies in Health. Prostaglandin analogues for 
ophthalmic use: a review of the comparative clinical effectiveness and cost-effectiveness. 
2015 July 30. 
Cavet ME, Vittitow JL, Impagnatiello F, Ongini E, Bastia E. Nitric oxide (NO): An emerging 
target for the treatment of glaucoma. Invest Ophthalmol Vis Sci. 2014;55:5005-15. 
Daka Q, Trkulja V. Efficacy and tolerability of mono-compound topical treatments for 
reduction of intraocular pressure in patients with primary open angle glaucoma or ocular 
hypertension: an overview of reviews. Croat Med J. 2014;55:468-80. 
Gabelt BT, Kaufman PL, Rasmussen CA. Effect of nitric oxide compounds on monkey ciliary 
muscle in vitro. Exp Eye Res. 2011;93:321-7. 
Gandolfi S, Simmons ST, Strum R, Chen K, VanDenburgh AM, Bimatoprost Study Group 3. 
Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and 
ocular hypertension. Adv Ther. 2001 May-Jun;18(3):110-21. 
Heyne GW, Kiland JA, Kaufman PL, Gabelt BT. Effect of nitric oxide on anterior segment 
physiology in monkeys. Invest Ophthalmol Vis Sci. 2013;54:5103-10. 
Impagnatiello F, Toris CB, Batugo M, Prasanna G, Borghi V, Bastia E, et al. Intraocular 
pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in preclinical 
models. Invest Ophthalmol Vis Sci. 2015;56:6558-64. 
Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) 
Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results 
of the First International Workshop. Am J Ophthalmol 2005;140:509-16. 
Jonas JB, Aung T, Bourne, RR, Bron AM, Ritch R, Panda-Jonas S.  Glaucoma. Lancet 2017 
Nov 11;309(10108):2183-93. 
Kapetanakis VV, Chan MP, Foster PJ, Cook DG, Owen CG, Rudnicka AR. Global variations 
and time trends in the prevalence of primary open angle glaucoma (POAG): a systematic 
review and meta-analysis. Br J Ophthalmol 2016;100:86-93. 
Krauss AHP, Woodward DF. Update on the mechanism of action of bimatoprost: a review 
and discussion of new evidence. Surv Ophthalmol. 2004;49 (suppl 1):S5-11. 
Li T, Lindsley K, Rouse B, Hong H, Shi Q, Friedman DS, et al. Comparative effectiveness of 
first-line medications for primary open-angle glaucoma: a systematic review and network 
meta-analysis. Ophthalmology. 2016 Jan;123(1):129-40. 
Medeiros FA, Martin KR, Peace J, Scassellati SB, Vittitow JL, Weinreb RN. Comparison of 
latanoprostene bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular 
hypertension: the LUNAR Study. Am J Ophthalmol. 2016;30223-9. 


CONFIDENTIAL 
NCX-470-02 version 2.0; 08-July-2020 
 
Page 69 of 78 
Parrish RK, Palmberg P, Sheu WP, for the XLT Study Group. A comparison of latanoprost, 
bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, 
randomized, masked-evaluator multicenter study. Am J Ophthalmol. 2003 May;135(5):688-
703. 
Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a 
review. JAMA. 2014 May 14;311:1901-11. 
Weinreb RN, Sforzolini BS, Vittitow J, Liebmann J. Latanoprostene bunod 0.024% versus 
timolol maleate 0.5% in subjects with open-angle glaucoma or ocular hypertension: the 
APOLLO study. Ophthalmology. 2016 May;123(5):965-73. 
Woodward DF, Krauss AHP, Nilsson SFE. Bimatoprost effects on aqueous humor dynamics 
in monkeys. J Ophthalmol. 2010;23:926192. 
 


APPENDIX 1 
CONFIDENTIAL 
NCX-470-02 version 2.0; 08-July-2020 
 
Page 70 of 78 
APPENDIX 1: TIME AND EVENTS TABLE 
 
Table 3: Times and Events 
Schedule 
Screening 
Visit 
Eligibility 1 
Visit 
Day  
 
Eligibility 2 
Visit 
Day  
Week 2 
Visit 
Day 14 
 days) 
Week 6 
Visit 
Day 42  
 days) 
Month 3/ 
Exit Visit 
Day 90 
 days) 
Time 
8 
AM 
10 
AM 
4 
PM 
8 
AM 
10 
AM 
4 
PM 
8 
AM 
10 
AM 
4 
PM 
8 
AM 
10 
AM 
4 
PM 
8 
AM 
10 
AM 
4 
PM 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening number (IRT/EDC) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Ophthalmic history/Changes 
in MH/OH 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Concomitant medicationsa 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Xl 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
Xk 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
y 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventsg 
X 
X 
X 
X 
X 
X 
Randomization (IRT/EDC)h 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Dispense study medicationi 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Collect study medication 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Dispense/collect subject diaryj 
 
 
 
 
 
 
X 
X 
X 
X 
Study exit (IRT/EDC) 
 
 
 
 
 
X 


APPENDIX 1 
CONFIDENTIAL 
NCX-470-02 version 2.0; 08-July-2020 
 
Page 71 of 78 
(a)
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 


APPENDIX 2 
 
CONFIDENTIAL 
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Page 72 of 78 
APPENDIX 2: METHODS OF CLINICAL EVALUATION 
 
For all assessments, sites should use the same instrument(s) and the same examiner whenever 
possible throughout the study. All ophthalmic assessments will be performed bilaterally.  The 
right eye will be assessed first, then the left eye.  
1. URINE PREGNANCY TEST 
Urine pregnancy test is to be conducted on site by study staff per the instructions on the 
pregnancy kit at Screening, Eligibility 1, Week 6 and Month 3/Exit Visits.  
 
2. MANIFEST REFRACTION AND BEST CORRECTED VISUAL ACUITY (BCVA) 
The manifest refraction and visual acuity (VA) measurements should be obtained by a 
physician, optometrist, or trained technician, and every effort should be made to have the same 
assessor complete the assessment for a given subject using the same equipment and method 
every time. 
2.1 
Manifest Refraction  
Manifest refraction will be performed using the site’s standard procedures.  Refraction will be 
assessed at the Screening Visit and must be repeated
 
. 
The correction obtained and recorded at Screening will be used (i.e., placed in trial frames, 
use of phoropter/optometer or equivalent) for each measurement of best corrected visual 
acuity (BCVA) at follow-up visits.  
2.2 
Best Corrected Visual Acuity (BCVA) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  


APPENDIX 2 
 
CONFIDENTIAL 
NCX-470-02 version 2.0; 08-July-2020 
 
Page 73 of 78 
 
 
 
 
 
 
 
 
 
 
 
 
  
. 
 
 
 
 
    
   
 
 
 
 
  
  
 
 
  
 
 
 
    
 
 
    
 
 
3. 
   
 
  
 
 
 
 
  
4. PUPIL SIZE 
Measurement of pupil diameter will be performed at the Screening, Eligibility 1, Eligibility 2, 
Week 2, Week 6 and Month 3/Exit Visits using a pupillary gauge. 
Measurement of pupil size should occur after assessment of BCVA and using the same 
illumination for each subject visit at each visit throughout the course of this study.  
Measurement of pupil diameter should occur to the nearest 0.5 mm using a pupillary gauge 
while the subject fixates on a distant, non-accommodative target. To avoid stimulating the 
accommodative response and consequential constriction, the pupillary gauge should be held 
away from the visual axis of the subject. 


APPENDIX 2 
 
CONFIDENTIAL 
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Page 74 of 78 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


APPENDIX 2 
 
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Page 75 of 78 
8. INTRAOCULAR PRESSURE (IOP) 
Intraocular pressure will be measured at 8AM 
), 10AM 
), and 4PM  
) at all visits except the Screening Visit, at which it will be measured at 8AM 
), 10AM 
) or 4PM 
). 
Intraocular pressure will be taken 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
Pachymetry will be performed by trained personnel
 
 
 
 
.   
 
  
 
 
  
 
 
  
 
 
 
 


APPENDIX 2 
 
CONFIDENTIAL 
NCX-470-02 version 2.0; 08-July-2020 
 
Page 76 of 78 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
12. INTERACTIVE RESPONSE TECHNOLOGY (IRT) 
Interactive response technology (IRT) activities will be performed as described in the IRT Site 
User Manual.  
 


APPENDIX 3 
CONFIDENTIAL 
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Page 77 of 78 
APPENDIX 3: GENERAL INSTRUCTIONS FOR COMPLETION OF SAE FORMS 
 
1. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


APPENDIX 3 
CONFIDENTIAL 
NCX-470-02 version 2.0; 08-July-2020 
 
Page 78 of 78 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan for: 
Phase 3 Trial of NCX 470 vs Latanoprost in Subjects with Open-Angle Glauocma or Ocular 
Hypertension (Mont Blanc) 
 
NCT#04445519 
 
06-May-2022 


 
 
Confidential & Proprietary 
 
STATISTICAL ANALYSIS PLAN  
A Phase 3, Randomized, Adaptive Dose-Selection, Multi-Regional, 
Double-Masked, Parallel-Group, 3–Month Trial Evaluating the Safety 
and Efficacy of NCX 470 vs. Latanoprost 0.005% in Subjects with 
Open-Angle Glaucoma or Ocular Hypertension (Mont Blanc) 
 
 
Sponsor: 
 
Nicox Ophthalmics, Inc. 
 
 
Protocol Number: 
NCX-470-02 
 
 
Author:  
 
 
 
 
 
 
 
 
  
 
 
 
Date:    
 
06MAY2022 
Version:  
 
2.0 
 


Protocol NCX-470-02 SAP, Version 2.0 
06MAY2022 
Confidential & Proprietary 
Page 2 of 47 
A Phase 3, Randomized, Adaptive Dose-Selection, Multi-Regional, Double-Masked, Parallel-Group, 
3–Month Trial Evaluating the Safety and Efficacy of NCX 470 vs. Latanoprost 0.005% in Subjects 
with Open-Angle Glaucoma or Ocular Hypertension (Mont Blanc) 
Protocol Number: 
NCX-470-02 
 
SAP Version:   
2.0  
Date: 
 
 
06MAY2022 
Statistical Analysis Plan Approval 
 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Reviewed by:  
 
 
 
 
 
___________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol NCX-470-02 SAP, Version 2.0 
06MAY2022 
Confidential & Proprietary 
Page 3 of 47 
Table of Contents 
Table of Contents ................................................................................................................................. 3 
1. 
Introduction............................................................................................................................... 6 
 Update After the Adaptive Dose Selection ............................................................................... 6 
2. 
Study Objectives ...................................................................................................................... 6 
 Study Endpoints ....................................................................................................................... 7 
2.1.1 
Efficacy Endpoints ............................................................................................................ 7 
2.1.2 
Safety Endpoints .............................................................................................................. 7 
 Primary and Secondary Hypotheses ....................................................................................... 7 
 Primary Estimand ..................................................................................................................... 8 
3. 
Study Design and Procedures ............................................................................................... 10 
 General Study Design ............................................................................................................ 10 
 Study Visit Windows ............................................................................................................... 11 
 Schedule of Visits and Assessments ..................................................................................... 12 
 Timing of the Interim Adaptive Dose Selection ...................................................................... 12 
 Strategy for the Adaptive Dose Selection .............................................................................. 13 
4. 
Study Treatments ................................................................................................................... 14 
 Method of Assigning Subjects to Treatment Groups ............................................................. 14 
 Masking and Unmasking ........................................................................................................ 14 
5. 
Sample Size and Power Considerations ................................................................................ 14 
 Justification of Non-inferiority Margin ..................................................................................... 15 
6. 
Data Preparation .................................................................................................................... 15 
 Data Preparation for the Interim Adaptive Dose Selection .................................................... 15 
 Input Data for Final Analysis .................................................................................................. 16 
 Output Data for Final Analysis ............................................................................................... 16 
7. 
Analysis Populations .............................................................................................................. 17 
7.1.1 
Intent-To-Treat (ITT) Population .................................................................................... 17 
7.1.2 
Modified Intent-To-Treat (mITT) Population ................................................................... 17 
7.1.3 
Per Protocol (PP) Population ......................................................................................... 17 
7.2.3.1 
Protocol Deviations ................................................................................................ 17 
7.1.4 
Safety Population ........................................................................................................... 18 
8. 
General Statistical Considerations ......................................................................................... 18 
 Unit of Analysis....................................................................................................................... 18 
 IOP Unit of Analysis and Baseline IOP Definition .................................................................. 18 
 Baseline Definition for Variables Other Than IOP.................................................................. 19 
 Missing or Inconclusive Data Handling .................................................................................. 19 
8.4.1 
Missing Efficacy Data Handling ...................................................................................... 19 


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8.4.2 
Missing or Inconclusive Dates ........................................................................................ 20 
 Data Analysis Conventions .................................................................................................... 20 
9. 
Disposition of Subjects ........................................................................................................... 21 
10. 
Demographics and Baseline Characteristics ......................................................................... 22 
11. 
Medical History and Concomitant Medications ...................................................................... 23 
 Medical History ....................................................................................................................... 23 
 Prior and Concomitant Medications ....................................................................................... 23 
12. 
Treatment Exposure  of Study Drug and Compliance ........................................................... 24 
13. 
Efficacy Analyses ................................................................................................................... 24 
 Primary Analysis .................................................................................................................... 27 
 Sensitivity Analyses ............................................................................................................... 29 
 Secondary Analyses .............................................................................................................. 29 
 Exploratory Analyses ............................................................................................................. 29 
 Subgroup Analyses ................................................................................................................ 31 
14. 
Safety Analyses ..................................................................................................................... 31 
 Adverse Events ...................................................................................................................... 31 
 Best-Corrected Visual Acuity ................................................................................................. 32 
 Slit-Lamp Biomicroscopy Examination ................................................................................... 32 
 Anterior Chamber ................................................................................................................... 33 
 Conjunctival Hyperemia ......................................................................................................... 33 
 Dilated Ophthalmoscopy Examination ................................................................................... 33 
 Pachymetry ............................................................................................................................ 34 
 Intraocular Pressure ............................................................................................................... 34 
 Pupil Size ............................................................................................................................... 34 
 
Visual Field ..................................................................................................................... 34 
 
Iris Color ......................................................................................................................... 35 
 
Urine Pregnancy Test .................................................................................................... 35 
15. 
Interim Analyses ..................................................................................................................... 35 
 Determination of the Alpha Spending Function ..................................................................... 36 
16. 
Changes from Protocol-Stated Analyses ............................................................................... 36 
17. 
Changes from Statistical Analysis Plan ................................................................................. 37 
18. 
References ............................................................................................................................. 37 
19. 
List of Tables and Listings...................................................................................................... 37 
 List of Tables .......................................................................................................................... 37 
 List of Listings......................................................................................................................... 43 
20. 
Appendix 1 Schedule of Visits and Assessments .................................................................. 45 
List of Abbreviations 




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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol NCX-470-02, Version 2.0 dated 08JUL2020. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. If additional analyses are required to supplement the planned 
analyses described in this SAP, they may be completed and will be identified in the Clinical Study Report. 
 
Update After the Adaptive Dose Selection 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2. Study Objectives 
The primary objective is to demonstrate that NCX 470 0.1% once daily (QD) is non-inferior to latanoprost 
0.005% QD based on mean IOP reduction from time-matched baseline at the 8 AM and 4 PM time points 
at the Week 2, Week 6, and Month 3 Visits.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
  
Another secondary objective is to demonstrate that NCX 470 0.1% QD is safe and well tolerated when 
administered to subjects for 3 months.  


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Study Endpoints 
2.1.1 
Efficacy Endpoints 
The primary efficacy endpoint for this trial is mean IOP reduction from time-matched baseline (based on 
Eligibility 1 and Eligibility 2 Visits) at the 8 AM and 4 PM time-points at the Week 2, Week 6, and Month 3 
Visits in the study eye. 
The primary efficacy analysis is the non-inferiority comparison of the mean treatment effect between NCX 
470 0.1% and latanoprost 0.005% in the study eye. A secondary efficacy analysis is the superiority 
comparison of the treatment effect between NCX 470 0.1% and latanoprost 0.005% in the study eye.  
The secondary efficacy endpoints for this trial include:  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
2.1.2 
Safety Endpoints 
Safety assessments will include but not limited to: 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Best-corrected visual acuity (BCVA) 
• 
Slit-lamp biomicroscopy  
• 
Conjunctival hyperemia 
• 
Dilated ophthalmoscopy  
• 
Pachymetry 
• 
Intraocular pressure (IOP) 
• 
Pupil size 
• 
Perimetry 
• 
Iris color 
• 
Urine pregnancy tests for females of child-bearing potential 
• 
Rate of discontinuation from study 
 
Primary and Secondary Hypotheses 
The primary and secondary endpoints will be tested in a hierarchical fixed sequence in the order below. 
The hypothesis language has been updated from the sample size and power calculations from the protocol 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  


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When testing if NCX 470 0.1% ophthalmic solution is non-inferior to latanoprost 0.005% ophthalmic solution 
the primary hypotheses are: 
H0: The upper bound of the 95.1% CI around the difference between study eyes treated with NCX 
470 0.1% and latanoprost 0.005% (NCX 470 – latanoprost), in the time-matched IOP reduction 
from baseline (follow-up minus baseline) is > 1.5 mmHg for at least one of the 6 time points 
(Week 2, 8 AM and 4 PM; Week 6, 8 AM and 4 PM; Month 3, 8 AM and 4 PM) or > 1.0 at least 
3 of the 6 time points. 
HA: The upper bound of the 95.1% CI around the difference between study eyes treated with NCX 
470 0.1% and latanoprost 0.005% (NCX 470 – latanoprost), in the time-matched IOP reduction 
from baseline (follow-up minus baseline) is ≤ 1.5 mmHg for all 6 time points (Week 2, 8 AM 
and 4 PM; Week 6, 8 AM and 4 PM; Month 3, 8 AM and 4 PM) and ≤ 1.0 at 4 or more of the 6 
time points. 
NCX 470 0.1% will be non-inferior to latanoprost if the null hypothesis (H0) is rejected (i.e., the upper limit 
of the two-sided 95.1% confidence interval [CI] around the differences between the least squares [LS] mean 
of NCX 470 0.1% and the LS mean of the latanoprost group [NCX 470 – latanoprost] is ≤ 1.5 mmHg). If 
NCX 470 is non-inferior to latanoprost, then the superiority of the NCX 470 to latanoprost will be tested.  
NCX 470 will be superior to latanoprost if the p-value for the testing treatment difference is ≤ 0.049 and the 
time-matched IOP LS mean difference in change from baseline at Week 2, Week 6, and Month 3 visits 
(NCX 470 – latanoprost) is < 0 at all 6 time points.  
The 95.1% CI for the final primary efficacy analysis and the alpha of 0.049 for the superiority efficacy 
analysis, take into account the Week 2 interim analysis for the adaptive dose selection. As the definition for 
overall statistical non-inferiority requires demonstration of statistical non-inferiority at all 6 time points, no 
adjustment for multiplicity will be made at each time point.  
Hierarchical fixed sequence testing will be made wherein superiority of NCX 470 0.1% QD to latanoprost 
0.005% QD will be tested only if overall clinical non-inferiority is demonstrated. Statistical superiority will be 
concluded if statistical superiority is demonstrated at all 6 time points. As the definition for overall statistical 
superiority requires demonstration of statistical superiority at all 6 time points, no adjustment for multiplicity 
will be made at each time point. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Primary Estimand 
The primary comparisons in this trial will be between NCX 470 0.1% QD and latanoprost 0.005% QD at 
the 8 AM and 4 PM time points at the Week 2, Week 6, and Month 3 Visits in the Intent-to-Treat (ITT) 
population with intercurrent events handled as described in the following estimand: 
• 
Population: subjects with Open-Angle Glaucoma or Ocular Hypertension defined through 
enrolment criteria 










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Strategy for the Adaptive Dose Selection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
. 


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4. Study Treatments 
 
Method of Assigning Subjects to Treatment Groups 
At the Eligibility 2 Visit, utilizing the Interactive Response Technology (IRT) system, approximately 670 
eligible subjects will be randomly assigned to one of two concentrations of NCX 470 or the active 
comparator latanoprost 0.005% solution in a masked fashion in a 1:1:1 ratio, based on a randomization 
schedule prepared by an independent biostatistician, who was not involved in the day-to-day conduct of 
the study.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
  
  
 
 
  
 
 
 
 
 
  
 
 
 
  
 
  
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Masking and Unmasking 
Treatment assignments will be masked to the Investigators, site staff involved in the clinical study, the 
Sponsor team members involved in the day-to-day oversight of the clinical study, the Medical Monitor, the 
employees of the 
 
 
 administrating the study for the Sponsor, and the study 
subjects. The unmasked site designee will not perform any other study activities except handling study 
medication. 
If unmasking of a subject becomes critical to the subject’s safety, the Principal Investigator must authorize 
such decision. If possible, such decision should be first consulted with both the study Sponsor and the 
Medical Monitor. The study treatment assignment of a subject should be unmasked via the IRT system. 
In a situation when the IRT system is not accessible, the unmasking can be achieved via scratch-off portion 
of the study kit label located in the source documentation. The Sponsor and the Medical Monitor must be 
notified within 24-hours following an emergency unmasking of any subject. 
5. Sample Size and Power Considerations 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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Justification of Non-inferiority Margin 
The results of the Phase 2 trial “Dolomites,” NCX-470-17001 demonstrated that all tested concentrations 
of NCX 470 (0.021%, 0.042%, and 0.065%) QD met the primary efficacy endpoint of non-inferiority to 
latanoprost 0.005% QD for reduction from baseline in mean diurnal IOP at Day 28. In pre-specified 
secondary efficacy analyses, NCX 470 0.065% was superior to latanoprost for mean IOP reduction from 
baseline at all 3 time points (8 AM, 10 AM and 4 PM) on Day 28, with the difference reaching up to 1.4 
mmHg. Mean IOP reduction from baseline at the 3 time points across Days 7, 14 and 28 ranged from 7.6 
to 9.8 mmHg for NCX 470 0.065% compared with 6.3 to 8.8 mmHg for latanoprost. 
6. Data Preparation 
Study data will primarily be recorded on the electronic Case Report Forms (eCRFs) supplied by 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data Preparation for the Interim Adaptive Dose Selection 
Interim Adaptive Analysis was conducted when at least 30 subjects were randomized in each arm and 
completed the study through the Week 2 Visit. All assessments, AEs, protocol deviations and concomitant 
medications for the subjects through Week 2 were required to be entered by the site. Adverse event coding, 


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serious adverse event (SAE) EDC reconciliation, and key data points related to the following eCRF data 
was reviewed and cleaned by 
 
• 
Intraocular Pressure 
• 
Conjunctival Hyperemia 
• 
Adverse Events/Serious Adverse Events 
• 
End of Study (Subject discontinuation) 
• 
Pachymetry 
• 
Demographics 
• 
Protocol Deviations 
Upon confirmation that all required data was entered and there were no outstanding concerns in the data 
for the interim analysis, approval signature was obtained from 
 
. and from Nicox Ophthalmics, Inc. 
for 
 to perform a data cut of the data in EDC. Approval for the masked EDC data cut and the unmasked 
 
 cut required approval by at least 2 authorized representatives of Nicox, including the 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
, or if 
one of these personnel were not available, other members of Nicox executive management 
 
 
 
 
 may sign these approvals. 
 
Input Data for Final Analysis 
When all prerequisites for database lock have been met, including Sponsor approval, the database will be 
locked. Following database lock, approval will be obtained from the Sponsor to unmask the study. Once 
the study has been unmasked, unmasked 
 
 will be sent to 
. Any changes to the 
 
 
 databases after data have been locked can only be made with the approval of the Sponsor in 
consultation with 
.  
Final analysis will be carried out after the following have occurred: 
• 
Database lock has occurred, including receipt of all final 
 
, with written authorization 
provided by appropriate 
 and Sponsor personnel. 
• 
Protocol deviations have been identified and status defined (major/minor deviations). 
• 
Analysis populations have been determined. 
• 
Randomized treatment codes have been unmasked. 
 
Output Data for Final Analysis 
Data from EDC and 
 will be transferred to 
 and incorporated into standard formats 
following the 
 
 
 
 
 Data will then be mapped to analysis datasets using 
the 
 
 
 
).  Both 
 
 
 
 will be used to create the subject 
listings, while all tables and figures will be based on the 
 
 
 will follow the 
 
 
 
 and will be implemented using the 
 
 
 
 
 and the 
 
 
 
 
. 
 
 
 
 
 


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l and will be implemented using 
 
 
 
 
 
 
 
 
 
 will be validated using 
 
 
 
 
 
. Any discrepancies in the validation 
will be noted in reviewer’s guides accompanying the final data transfers. 
Define.xml will be created for 
 
 
 
 
 
 
 
 
 
7. Analysis Populations 
Four different populations will be used in the analysis: an intent-to-treat (ITT) population, a modified ITT 
(mITT) population, a per protocol (PP) population, and a safety population. 
7.1.1 
Intent-To-Treat (ITT) Population 
The ITT population will include all randomized subjects. Demographics, baseline characteristics, and 
efficacy variables will be analyzed using the ITT population. These analyses will be performed on an as-
randomized basis. 
7.1.2 
Modified Intent-To-Treat (mITT) Populatio\ 
The modified ITT population is a subset of the ITT population excluding subjects with missing data due to 
COVID-19. Efficacy variables will be analyzed using the mITT population for sensitivity analyses. These 
analyses will be performed on an as-randomized basis. 
7.1.3 
Per Protocol (PP) Population 
The PP population will include all randomized subjects who received study medication, who had at least 
one follow-up visit and who had no major protocol deviations during the 3-month treatment period. 
Demographics, baseline characteristics, and selected efficacy variables (refer to Table 2) will be analyzed 
using the PP population, in addition to the ITT and mITT populations. The PP analyses will be performed 
on an as-treated basis.  
Two classifications of protocol deviations may be made. One for classifying GCP violations and a separate 
classification of protocol deviations for determining exclusions to the PP Population. Classifications may 
be discussed at the same time, however classifying GCP violations and classifications for exclusions from 
the PP Population will be independent of each other. Approval of protocol deviation classifications will be 
sought only for the exclusions from the PP Population. 
7.2.3.1 PROTOCOL DEVIATIONS 
All protocol deviations will be classified to determine the PP Population. Classifications will be determined  
programmatically in ADaM, where possible, or by the Medical Monitor and Sponsor in consultation from 
various members of the study team. The final PP population will be determined and approved by Nicox 
prior to database lock. The Medical Monitor, Sponsor, and lead biostatistician are required to approve all 
protocol deviation classifications prior to database lock and unmasking of treatment arms. A programmed 
protocol deviation listing and a listing of prohibited prior and concomitant medications will be provided to 
ensure thorough protocol deviation review.  


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7.1.4 
Safety Population 
The safety population will include all randomized subjects who received at least one dose of the study 
medication during the 3-month treatment period and will be used for the safety analyses. All safety 
variables will be analyzed on an as-treated basis using the safety population. 
8. General Statistical Considerations 
 
Unit of Analysis 
The unit of analysis in this study will be the study eye for efficacy analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. The safety summaries will be 
performed for study and fellow eyes separately, as applicable.  
Non-ocular assessments, including disposition, demographics, baseline characteristics, medical history, 
concomitant medications, study drug exposure, and AEs, will be summarized at the subject level. Ocular 
assessments will be summarized at the eye level.  
 
IOP Unit of Analysis and Baseline IOP Definition 
IOP will be measured at the 8 AM 
 
 
 for Screening and  
 
 at other visits), 10 AM 
 
 
 
for Screening and  
 
 at other visits), and 4 PM 
 
 
 for Screening and  
 
 at other 
visits) time points at the Eligibility 1, Eligibility 2, Week 2, Week 6, and Month 3/Exit Visits. At Screening 
IOP is measured only once, at any one of the 3 time points.  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Baseline time-matched IOP will be calculated as 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
Baseline mean diurnal IOP will be calculated as: 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 


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The mean diurnal IOP values that are an average of 2 time points will be referred to as “mean diurnal IOP 
2” and the values that are an average of 3 time points will be referred to as “mean diurnal IOP 3”.  
For the changes from baseline (follow-up minus baseline), more extreme negative numbers indicate results 
in favor of the active treatment arm. However, the primary estimand will only be met if the upper bounds of 
the 95.1% CI around the change from baseline mean difference is less than or equal to 1.5 for all time 
points and less than or equal to 1.0 for 4 or more timepoints. 
 
Baseline Definition for Variables Other Than IOP 
Baseline is defined as the last measurement prior to the first administration of study drug. Change from 
baseline will be calculated as follow-up visit minus baseline visit. 
 
Missing or Inconclusive Data Handling 
8.4.1 
Missing Efficacy Data Handling 
Missing data for the primary efficacy analysis in the ITT population will be imputed using MI. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 f 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Due to ongoing recruitment and enrollment during the COVID-19 pandemic, two additional sensitivity 
analyses will be conducted. 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.4.2 
Missing or Inconclusive Dates 
Partial or missing dates, where complete dates are required to flag data as treatment-emergent or for prior 
and/or concomitant with treatment, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Partial/missing start date:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Partial/missing end date:  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
The original dates will be displayed in data listings and the imputed dates will be used in derivations only 
(study day, treatment-emergence status, etc.). 
 
Data Analysis Conventions 
All data analysis will be performed by 
 after the study is completed and the database has been locked 
and released for unmasking. Statistical programming and analyses will be performed using 
 
 
 
 
. Outputs will be provided in rich text format (RTF) for tables and portable document format 
(PDF) for tables, listings, and figures using landscape orientation.  


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All study data will be listed by subject ID, visit (as applicable), and eye (as applicable) based on all 
randomized subjects unless otherwise specified. Additional data listings will be provided as described in 
the sections for the data analyses.  
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, SD, standard error (SE) (for efficacy analyses only), median, minimum, and maximum. Minima and 
maxima will be reported with the same precision as the raw values; means and medians will be presented 
to one additional decimal place than reported in the raw values. Standard deviations and SEs will be 
presented to two additional decimal places than reported in the raw values. Summaries for discrete 
variables will include frequency counts and percentages. All percentages will be rounded to one decimal 
place (i.e., XX.X%).   
All statistical tests will be two-sided with a significance level of 0.049 (α = 0.049), unless otherwise specified. 
All p-values will be rounded to four decimal places; p-values less than 0.0001 will be presented as 
“<0.0001”; p-values greater than 0.9999 will be presented as “>0.9999.” 
For efficacy analyses, unscheduled visits and early termination visits will be mapped to scheduled visits if 
they fall into the scheduled visit windows. If there is more than 1 assessment that falls into a scheduled visit 
window after the mapping, the assessment at original scheduled visit will be used.  
For safety analyses, unscheduled visits will be excluded from analyses and early termination visits will be 
combined with Month 3/Exit Visits for analyses. Event-based data (AEs, concomitant medications, etc.) will 
be listed by date and summarized regardless of visit types.  
 
 
 
 
 
 
 
 
 
, this treatment group will not be presented on 
efficacy tables, but will be on the majority of dispositional, numbered 14.1, and safety tables numbered 
14.3.  An All NCX 470 group will be added as applicable.  
9. Disposition of Subjects 
Analysis populations, study completion, discontinuation from the study, reasons for discontinuation from 
the study, subjects with any protocol deviations, subjects with major deviations, and subjects with minor 
deviations will be summarized for all randomized subjects using number of subjects and percentages. 
Reasons of withdrawal include: AE, lost to follow-up, Physician decision, Sponsor or Institutional Review 
Board (IRB) decision, protocol violation, study termination by Sponsor, withdrawal by subject, 
 
 
 
 
 subject discontinued due to adaptive design, and other. COVID-19 relationship to reasons 
for study discontinuation and relationship to protocol deviations will be listed and summarized. Subject 
dispositions and registration information will also be listed. 
The total number of screened subjects with the number and percentage of screen failure subjects will be 
summarized. The reasons for screen failure, both related to COVID-19 and unrelated, will be displayed with 
the percentages calculated using total number of screen failures as the denominator. Screen failed 
subjects, both related to COVID-19 and unrelated, with their reason for screen failure will be listed.   


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In addition, subject listings will be provided that include informed consent date, inclusion and exclusion 
criteria violations, and exclusions from the PP population. Details of the study randomization, including 
randomization date and time, randomized treatment and actual treatment, and stratification, will also be 
included within a subject listing.  
The number and percentage of subjects with any deviation, classified as major or minor for PP Population 
exclusions and for GCP, will be summarized for each protocol deviation category by treatment group for all 
randomized subjects. The following protocol deviation categories will be summarized: 
  
 
 
  
  
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 A subject listing will be provided that includes the date 
of the deviation, the deviation category, the deviation description, and the classification of whether the 
deviation was judged to be major or minor for PP Population exclusion and GCP violations in a masked 
review prior to database lock.   
10. Demographics and Baseline Characteristics 
The demographic variables collected in this study include age, age category (>=18 to <65, >=65, and >= 
75 years), sex, race, ethnicity, and iris color measured at Eligibility 2 Visit. Subjects who record more than 
one race will be grouped into a single category denoted as multi-racial. Demographic variables will be 
summarized for the ITT population and the PP population, separately. 
Age will be reported in years and calculated using the following formula: 
Age = (Informed Consent Date – Date of Birth) / 365.25, truncated as an integer. 
The following baseline variables for study eyes will be summarized for the ITT and PP population, 
separately:  
• 
Time-Matched Baseline IOP at 8 AM, 10 AM, and 4 PM 
• 
Baseline mean diurnal IOP 2 (average of 8 AM, and 4 PM) 
• 
Baseline mean diurnal IOP 3 (average of 8 AM, 10 AM, and 4 PM)  
• 
Central corneal thickness  
• 
Cup-to-disc ratio (horizontal) 
• 
Cup-to-disc ratio (vertical) 
• 
BCVA 
• 
Conjunctival hyperemia per 
 
 
 
 
 
 
 
• 
PGA or NO-donating PGA at screening 
• 
Number of IOP-lowering medications at screening  
• 
EDC and IRT Stratification Categories 


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Baseline characteristics will be summarized by descriptive statistics and with a 95% confidence interval for 
continuous variables only.  
Gonioscopy and manifest refraction assessments will be performed at Screening Visit and the results will 
be presented in subject data listings for all randomized subjects. Additionally, all demographic information 
will be presented on a subject data listing for all randomized subjects. 
11. Medical History and Concomitant Medications 
 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA), 
 
 
Ocular medical history and non-ocular medical history will be summarized at the subject level based on 
the safety population, separately. If a subject reports the same preferred term (PT) multiple times within 
the same system organ class (SOC), the subject will only be counted once for the SOC. As with the PT, if 
a subject reports multiple conditions within the same PT, that subject will only be counted once for the PT. 
Ocular medical histories will be included on subject data listings sorted by treatment, subject, eye (both 
eyes, then study eye, then fellow eye) and ascending dates. Non-ocular medical histories will be included 
on subject data listings sorted by treatment, subject, and ascending dates. Summaries of SOCs and PTs 
will be sorted in descending frequency by the NCX 470 0.1% arm.  
 
Prior and Concomitant Medications 
All prior and concomitant medications will be coded using World Health Organization Drug Dictionary 
(WHODrug; Global B3, March 2020) and summarized to the therapeutic drug class (Anatomical Therapeutic 
Chemical 
  
) and preferred name. If the 
  classification is not provided, the next 
lowest classification that is provided in the coding dictionary will be used. The preferred name will be defined 
as the active ingredient; if the active ingredient is not provided or includes more than two ingredients (e.g., 
multivitamins) then the drug name will be summarized as the preferred name. Any uncoded terms will be 
summarized under the 
 classification and preferred name of “Uncoded.” 
Ocular prior and concomitant medications will be summarized separately at subject level using the safety 
population. Medications will be tabulated for each treatment group using number of subjects and 
percentages. Subjects may have more than one medication per 
 text. At each level of subject 
summarization, a subject will be counted once if he/she reports one or more medications. Prior medications 
will be defined as mediations with an end date prior to the first dose of study drug. Concomitant medications 
will be defined as medications with an ongoing status or with an end date on/after the first dose of study 
drug.  
Non-ocular prior and concomitant medications will be summarized by subject using the Safety population. 
Summaries of 
 classification and preferred names will be sorted in descending frequency by the NCX 
470 0.1% arm. 


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All prior and concomitant medications will be included on subject data listings sorted by eye (both eyes, 
then study eye, then fellow eye), prior and/or concomitant status, and ascending dates. IOP lowering 
medication will be indicated on listings and summarized on the baseline characteristics table for IOP 
lowering medications used prior to randomization. 
A list of prohibited concomitant medications will be created to aid in the review of protocol deviations (see 
section 7.2.3.1 of this SAP). A Sponsor approved list of preferred names and/or 
 classifications will be 
used to determine prohibited concomitant medications. 
12. Treatment Exposure  of Study Drug and Compliance 
The study medication is expected to be administered one drop in each eye by the subject or caregiver, at 
8 PM   hours starting the evening of Eligibility 2 Visit to the evening prior to the subject’s last study visit. 
Subject diaries are entered into EDC to capture treatment exposure and to calculate compliance. The 
Eligibility 2 Visit is the expected date of the first dose and should be used as Day 1 for all calculations. 
Treatment Exposure will be defined as the number of days that the subject was exposed to study treatment 
as calculated using the formula:  
Treatment Exposure (days) = Date of Last Dose – Date of First Dose + 1. 
Expected Treatment Exposure will be defined as the number of days that the subject was supposed to be 
exposed to study treatment as calculated using the formula: 
Expected Treatment Exposure (days) =  
[(Date of Last Visit or Last Diary, whichever later) – Date of Eligibility 2 (Day 1) in EDC System], + 1 if 
later date is from the subjects’ diary. 
Compliance of study drug is calculated as:  
100 * (Number of Days with Study Drug Taken) / (Expected Treatment Exposure). 
In addition, compliance will also be summarized by treatment using the number and percentage of subjects 
in category of 
 
Descriptive summary statistics by treatment will be presented for treatment exposure, expected treatment 
exposure, and compliance in the ITT and safety population. Diary data will be listed for all randomized 
subjects. A listing will be produced with tallies of the number of days with study drug taken, number of days 
without study drug taken, treatment exposure, expected treatment exposure, and compliance for each 
subject. 
13. Efficacy Analyses 
All primary and secondary efficacy variables, along with the planned analysis methods for those variables, 
are given in Table 2. These analyses will be performed for the ITT population for all efficacy variables and 
PP population for selected efficacy variables. The ITT population will be used for all efficacy subgroup 
analyses. Note that each subject will have one eye designated as the study eye. Only study eyes will be 


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evaluated for all of the efficacy measures, except that, fellow eyes will also be evaluated separately for the 
analysis of the primary efficacy endpoint.  
An analysis of covariance (ANCOVA) model with fixed-effect terms for baseline time-matched IOP and 
treatment as the main effect will be performed.  
To check the appropriateness of the ANCOVA model, and additional ANCOVA will be run with the added 
treatment-by-baseline interaction term added to the model.  
The LS mean of NCX 470 0.1% and latanoprost 0.005% will be obtained from the ANCOVA model with 
fixed-effect terms for baseline time-matched IOP and treatment. The NCX 470 0.1% group will be compared 
with the latanoprost 0.005% group by computing a two-sided 95.1% CI around the differences between the 
LS mean of the NCX 470 0.1% group and the LS mean of the latanoprost group. The differences between 
treatment groups will be calculated as NCX 470 0.1% minus latanoprost 0.005%. For each comparison, the 
two-sided p-values will also be presented.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
All efficacy variables will be summarized by treatment descriptively.  
 
 




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Primary Analysis 
The primary efficacy variable is the change from baseline in time-matched IOP of the 8 AM and 4 PM time 
points to Week 2, Week 6, and Month 3 visits, calculated as time-matched IOP at follow-up visit minus 
baseline IOP. Baseline is based on Eligibility 1 and Eligibility 2 Visit measurements (see Section 8.3). 
Listings with the individual measurements and the “base” unit for both eyes will be produced, and the mean 
diurnal IOP average of 2 (8 AM and 4 PM) and 3 (8 AM, 10 AM, and 4 PM) time points will be on a separate 
listing. The primary analysis will be based on the study eyes for the ITT population using MI to impute 
missing data.  
The primary efficacy assessment is the non-inferiority analysis of the difference in the treatment effect 
between each NCX 470 0.1% and latanoprost 0.005% in change from baseline in time-matched IOP to the 
follow-up visits (Week 2, Week 6, and Month 3), based on study eyes for the ITT population using MI to 
impute missing data.  
An analysis of covariance (ANCOVA) model with fixed-effect terms for baseline time-matched IOP and 
treatment as the main effect will be performed.  
The LS mean of the NCX 470 0.1% treatment groups and latanoprost will be obtained from the ANCOVA 
model. NCX 470 0.1% group will be compared with the latanoprost group by computing a two-sided 95.1% 
CI around the differences between the LS mean of the NCX 470 0.1% treatment groups and the LS mean 
of the latanoprost group. The differences between treatment groups will be calculated as NCX 470 0.1% 
dose minus latanoprost 0.005% dose. For each comparison, the two-sided p-values will also be presented.  
Additionally, the equality of baseline time-matched IOP between NCX 470 0.1% and latanoprost 0.005% 
will be tested using a two-sample t-test. For the change from baseline in time-matched IOP, one-sample t-
tests will be performed for all treatment groups to test whether the change from baseline is significantly 
different from zero within the treatment group. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 


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The following example line of code will be added to the proc mi for the control-based MCMC 
imputations: 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
   
  
 
 
    
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
  
    
  
  
 
 
    
 
 
 
 
 
 


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Sensitivity Analyses 
To assess the robustness of the primary analysis results, sensitivity analyses will be performed based on 
the PP population with observed data and MI similar to the primary endpoint. Sensitivity analyses will also 
be performed on the ITT population using observed data and a tipping point analysis. Also, for the ITT 
population using 
 
. COVID-19 related missingness with be investigated with similar 
randomized treatment-based and control-based imputation methods as the primary analysis in the ITT 
population. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For the sensitivity analyses, the statistical analysis method will be similar to the primary analysis as 
described in Section 13.1. 
 
Secondary Analyses 
Secondary efficacy variables include: 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
The statistical analysis method will be similar to the primary analysis as described in Section 13.1, but 
imputations and 1-sample t-tests will not be performed to test whether the change from baseline is 
significantly different from zero within any treatment group. Secondary analyses will be conducted in the 
ITT and PP populations with observed data only. 
 
Exploratory Analyses 
Exploratory efficacy variables include: 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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For numbers and proportion outputs, Fisher’s exact test (two-sided p-values) will be used to test the pair-
wise differences between the NCX 470 0.1% and latanoprost at each visit. 




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The number and percentages of subjects with the TEAEs listed below will be summarized by SOC, PT, and 
treatment separately. If a subject reports the same PT multiple times within the same SOC, that subject will 
only be counted once for the SOC. As with the PT, if a subject reports multiple conditions within the same 
PT, that subject will only be counted once for the PT.  
• 
Ocular TEAEs 
• 
Non-ocular TEAEs 
• 
Ocular serious TEAEs 
• 
Non-ocular serious TEAEs 
• 
Ocular TEAEs leading to study drug withdrawal 
• 
Non-ocular TEAEs leading to study drug withdrawal 
• 
Ocular TEAEs by maximal severity 
• 
Non-ocular TEAEs by maximal severity 
• 
Ocular TEAEs by strongest relationship to study drug  
• 
Non-ocular TEAEs by strongest relationship to study drug  
All TEAEs, all serious TEAEs, and TEAEs leading to study drug withdrawal will be presented in subject 
data listings. Listings will be sorted by subject, eye (both eyes, then study eye, then fellow eye events), 
then non-ocular events, by ascending dates. Tables will be sorted by the descending frequencies of the 
SOC and PTs in the all NCX 470 group.  
 
Best-Corrected Visual Acuity 
Best-corrected visual acuity (BCVA) 
 
will be assessed at the Screening Visit, and at the 8 AM time point during the Eligibility 1, Eligibility 2, Week 
2, Week 6, and Month 3/Exit visits. The logarithm of the minimum angle of resolution (logMAR) BCVA will 
be summarized by treatment at each visit using continuous summaries, including change from baseline, for 
both the study eyes and the fellow eyes. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination will be performed for eyelid, conjunctiva, cornea, lens, iris/pupil, and 
anterior chamber in both eyes at the Screening Visit, and at the 8 AM time point during the Eligibility 1, 
Eligibility 2, Week 2, Week 6, and Month 3/Exit visits. 
The results (normal, abnormal [not clinically significant], abnormal [clinically significant]) for each parameter 
at each visit will be summarized by treatment using number of subjects and percentages in each result 
category, for the study eyes and the fellow eyes separately. Percentages will be based on the number of 
specific eyes with non-missing assessments at the given visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Anterior Chamber 
Anterior chamber cells and flare will be assessed in both eyes at the Screening Visit, and at the 8 AM time 
point during the Eligibility 1, Eligibility 2, Week 2, Week 6, and Month 3/Exit visits. The results below will be 
summarized by treatment at each visit by number of subjects and percentages in each result category, for 
the study eyes and the fellow eyes separately. Percentages will be based on the number of specific eyes 
with non-missing assessments at the given visit.   
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
   
  
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Conjunctival Hyperemia 
Conjunctival hyperemia, measured by the 
 
 
 
 
 
 will be assessed in 
both eyes at the Screening Visit, and at the 8 AM time point during the Eligibility 1, Eligibility 2, Week 2, 
Week 6, and Month 3/Exit visits. 
The redness grades 
 
 
 
 
 
 
 
 will be summarized by treatment at each visit using 
continuous summaries, including change from baseline, for both the study eyes and the fellow eyes.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilated Ophthalmoscopy Examination 
A dilated ophthalmoscopy examination of the vitreous, retina, macula, choroid, optic nerve, and cup-to-disc 
will be performed in both eyes at the Screening Visit and the 4 PM time point at the Month 3/Exit Visit. The 
results (normal, abnormal [not clinically significant], abnormal [clinically significant]) for each parameter at 
each visit will be summarized by treatment using number of subjects and percentages in each result 
category, for study eyes and fellow eyes separately. Percentages will be based on the number of specific 


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eyes with non-missing assessments at the given visit.  
 
 
 
 
 
 
 
 
 
 
 
 
  
In addition, cup-to-disc ratios (horizontal and vertical) will be assessed in both eyes at the Screening Visit 
and the 4 PM time point at the Month 3/Exit Visit. The results will be summarized by treatment at each visit 
using continuous summaries, including change from screening, for the study eyes and the fellow eyes 
separately. 
 
Pachymetry 
Pachymetry assessment will be performed at the Screening Visit and the 4 PM time point at the Eligibility 
2, Week 2 (for subjects participating in the adaptive phase only), and Month 3/Exit Visits for both eyes. 
There will be 
readings of central corneal thickness in each eye at each visit. The 
 
 will be used as central corneal thickness value for summaries.  
The central corneal thickness values measured in microns (μm) will be summarized by treatment at each 
visit using continuous summaries, including change from baseline, for the study eyes and the fellow eyes 
separately. 
 
Intraocular Pressure 
IOP measurements are taken according to Section 8.3 of this SAP and the “base” unit is used for the safety 
analyses. Baseline will be the time-matched baseline which is an average of the Eligibility 1 and Eligibility 
2 “base” measurements.  
The number and percentage of subjects with a  
  mmHg increase from baseline,  
  mmHg increase 
from baseline, and 
 
 
 
 increase from baseline at any point after randomization in study 
eye, fellow eye, or either eye by visit and time point, and at any post-baseline time points of the study will 
be summarized by treatment.  
 
Pupil Size 
Pupil size or pupil diameter in mm will be assessed at the Screening Visit, and at 8 AM time point during 
the Eligibility 1, Eligibility 2, Week 2, Week 6, and Month 3/Exit visits. Pupil size (mm) will be summarized 
by treatment at each visit using continuous summaries, including change from baseline, for both the study 
eyes and the fellow eyes. 
 
Visual Field 
The visual field examination will be completed at the Screening Visit and at the 8 AM time point at the Month 
3/Exit Visit. The results (
 
 
 
 
 
 
 
]) at each 
visit will be summarized by treatment using number of subjects and percentages in each result category, 
for study eyes and fellow eyes separately. Percentages will be based on the number of specific eyes with 
non-missing assessments at the given visit. Visual field reliability (
 
 
 
 
 
 
 
 
) will also be summarized with the number of subjects and percentages with “Yes” or 
“No.”  


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Iris Color 
Iris Color will be assessed for both eyes at Screening, and at the 8 AM time point during the Eligibility 2 and 
Month 3/Exit visits. The Eligibility 2 assessment will be listed and summarized on the demographics outputs 
while the additional assessments of iris color will be on a separate listing and table, noting any changes 
from Eligibility 2 on the listing.  
 
Urine Pregnancy Test 
Urine pregnancy test results will be provided in a data listing. 
15. Interim Analyses 
A planned unmasked interim adaptive analysis was performed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
. 
The adaptive dose selection occurred per the interim analysis SAP, resulting in the following events: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
No other interim analyses are planned. 


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Determination of the Alpha Spending Function 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
16. Changes from Protocol-Stated Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
  
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
Analyses related to COVID-19 have been added as the study enrolled subjects during the COVID-19 
pandemic. Additionally a mITT population has been added to exclude subjects who have missing data 
related to COVID-19. 
Multiple exploratory and subgroup analyses have been added to support the varying interests of the 
Sponsor. Statistical methods are explained in sections 13.4 and 13.5.  




















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