Clinical trial NCT03926026
Conditions: Blepharitis
Sponsor: Nicox Ophthalmics, Inc.
Start date: 2019-03-18; Completion date: 2019-10-21
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, randomized, double-masked, placebo-controlled, Phase 2 study evaluating the safety and tolerability of NCX 4251 (fluticasone propionate nanocrystal) Ophthalmic Suspension 0.1% QD and BID for the treatment of acute exacerbations of blepharitis. The study will be performed in two sequential dose escalating cohorts.

The study is designed to select the dose(s) of NCX 4251 to advance into the next stage of development, and to assess the safety and tolerability of NCX 4251 Ophthalmic Suspension.

Detailed description:

Arms: arm 1: NCX 4251 Ophthalmic Suspension, 0.1% once daily for 14 days arm 2: Placebo once daily for 14 days arm 3: NCX 4251 Ophthalmic Suspension, 0.1% twice daily for 14 days arm 4: Placebo twice daily for 14 days
Interventions: intervention 1: Fluticasone Propionate intervention 2: Placebo
Intervention descriptions: intervention 1: NCX 4251 Ophthalmic Suspension, 0.1% intervention 2: NCX 4251 Ophthalmic Suspension, 0%

Protocol documents:
Prot_000.pdf: 
NCX-4251-01 version 5.0; 13-Aug-2019 
Page 1 of 81 
Nicox Ophthalmics, Inc. 
15 T.W. Alexander Drive, Durham, North Carolina 27709  USA 
Compound: 
NCX 4251 
Study Number: 
NCX-4251-01 
Study Title: 
A Multi-Center, Randomized, Double-Masked, Placebo-Controlled, Dose-Escalation,  
Phase 2 Study Evaluating the Safety and Tolerability of NCX 4251 (Fluticasone Propionate 
Nanocrystal) Ophthalmic Suspension, 0.1% QD and BID for the Treatment of Acute 
Exacerbations of Blepharitis 
PROTOCOL 
Version # 5.0 
Released on 13-August-2019 
Clinical Development Phase: 
2 
Sponsor: 
Nicox Ophthalmics, Inc. 
15 T.W. Alexander Drive 
Durham, North Carolina 27709 – USA 
CONFIDENTIAL 
This document contains confidential information, which is not to be divulged in any way 
unless previously authorized by Nicox Ophthalmics, Inc. 
NCT03926026


NCX-4251-01 version 5.0; 13-Aug-2019 
Page 2 of 81 
PROTOCOL SIGNATURE PAGE 
Study No.: 
NCX-4251-01 
Title: 
A Multi-Center, Randomized, Double-Masked, Placebo-Controlled, Dose-
Escalation, Phase 2 Study Evaluating the Safety and Tolerability of NCX 4251 
(Fluticasone Propionate Nanocrystal) Ophthalmic Suspension, 0.1% QD and BID 
for the Treatment of Acute Exacerbations of Blepharitis 
APPROVAL OF STUDY PROTOCOL 
Version: Version 5.0 
Release Date: 13-August-2019 
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. 
15 T.W. Alexander Drive, Durham, NC 27709  USA 
On behalf of the Sponsor:  
José L. Boyer, PhD 
13-August-2019 
Vice President, Clinical Development 
Date 
Signature 
Tomas Navratil, PhD 
13-August-2019 
Executive Vice President, Head of 
Development 
Date 
Signature 












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Page 8 of 81 
 
TABLE OF CONTENTS 
 
 
Page 
CONTACT INFORMATION .............................................................................................. 3 
PROTOCOL HISTORY TABLE ........................................................................................ 4 
TABLE OF CONTENTS ..................................................................................................... 8 
LIST OF FIGURES ........................................................................................................... 11 
LIST OF ABBREVIATIONS ............................................................................................ 12 
STUDY OUTLINE / PROTOCOL SYNOPSIS ................................................................ 14 
1. 
INTRODUCTION .............................................................................................. 22 
1.1 
Background and Rationale ......................................................................... 22 
1.2 
Study Background ...................................................................................... 23 
1.3 
Potential Risks and Benefits to Human Subjects ....................................... 24 
2. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 26 
2.1 
Study Objectives ........................................................................................ 26 
2.2 
Study Endpoints ......................................................................................... 26 
2.3 
Efficacy Evaluations .................................................................................. 26 
2.4 
Safety Evaluations ..................................................................................... 27 
 
 
2.6 
Review of Safety Data by Medical Monitor .............................................. 27 
3. 
STUDY DESIGN ............................................................................................... 28 
3.1 
Overall Study Design ................................................................................. 28 
4. 
SUBJECT SELECTION ..................................................................................... 30 
4.1 
Number of Subjects and Sites .................................................................... 30 
4.2 
Subject Population Characteristics ............................................................ 30 
4.3 
Inclusion Criteria ....................................................................................... 30 
4.4 
Exclusion Criteria ...................................................................................... 30 
5. 
CONCOMITANT MEDICATION(S) ................................................................ 33 
5.1 
Previous and Concomitant Medication(s) .................................................. 33 
5.2 
Prohibited Medication(s) and Procedures .................................................. 33 
6. 
STUDY SUPPLIES ............................................................................................ 34 
6.1 
Description of Study Medication ............................................................... 34 
6.2 
Packaging of the Study Medication ........................................................... 34 


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6.3 
Labeling of the Study Medication ............................................................. 34 
6.4 
Storage of the Study Medication ............................................................... 34 
6.5 
Accountability of Study Medication .......................................................... 35 
6.6 
Assigning Subjects to Treatment and Study Masking ............................... 35 
6.7 
Emergency Subject Unmasking ................................................................. 35 
6.8 
Study Medication Dispensing and Collection ........................................... 36 
6.9 
Instructions for Eyelid Scrubs .................................................................... 36 
6.10 
Instructions for Use and Application of Study Medication ....................... 37 
6.11 
Compliance with Eyelid Scrubs and Study Medication ............................ 39 
6.12 
Return of Study Medication by the Clinical Sites ..................................... 39 
6.13 
Other Study Supplies ................................................................................. 39 
7. 
STUDY PROCEDURES BY VISIT .................................................................. 40 
7.1 
Screening Visit (Day -7 to -3) .................................................................... 40 
7.2 
Baseline/Day 1 Visit .................................................................................. 41 
7.3 
Treatment/Day 4 (± 1 day) Visit ................................................................ 42 
7.4 
Treatment/Day 8 (± 1 day) and Day 11 (± 1 day) Visits ........................... 43 
7.5 
Day 14 (- 1 day) ......................................................................................... 43 
7.6 
Day 28/Exit Visit (± 2 days) ...................................................................... 44 
7.7 
Unscheduled Visits .................................................................................... 45 
8. 
SCREEN FAILURES, COMPLETION AND DISCONTINUATION .............. 46 
8.1 
Subject Screen or Eligibility Failures ........................................................ 46 
8.2 
Subject Completion .................................................................................... 46 
8.3 
Subject Early Discontinuation ................................................................... 46 
8.4 
Subject Lost to Follow-up .......................................................................... 46 
8.5 
Study Termination ..................................................................................... 47 
9. 
PROTOCOL COMPLIANCE ............................................................................ 48 
10. 
ADVERSE EVENTS .......................................................................................... 49 
10.1 
Adverse Event Definition .......................................................................... 49 
10.2 
Severity of Adverse Event ......................................................................... 49 
10.3 
Causal Relationship with Study Medication .............................................. 49 
10.4 
Serious Adverse Events ............................................................................. 50 
10.5 
Adverse Event Reporting ........................................................................... 50 
10.6 
Serious Adverse Event Reporting .............................................................. 51 


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11. 
STATISTICAL CONSIDERATIONS AND METHODS OF ANALYSIS ....... 52 
11.1 
Determination of Sample Size and Power Calculations ............................ 52 
11.2 
Analysis Population ................................................................................... 52 
11.3 
Data Display .............................................................................................. 52 
11.4 
Collection and Derivation of Efficacy Assessments .................................. 53 
11.5 
Hypothesis and Methods of Analysis ........................................................ 53 
11.5.1 Hypothesis ................................................................................................. 53 
11.5.2 Efficacy Analysis ....................................................................................... 53 
11.5.3 Safety Analysis .......................................................................................... 54 
11.5.4 Dose Selection Process .............................................................................. 55 
11.5.5 Interim Analysis ......................................................................................... 55 
12. 
EMERGENCY PROCEDURES ......................................................................... 56 
12.1 
Emergency Contact Procedure ................................................................... 56 
12.2 
Procedure in Case of Pregnancy ................................................................ 56 
13. 
STUDY MANAGEMENT ................................................................................. 57 
13.1 
Monitoring ................................................................................................. 57 
13.2 
Source Documents ..................................................................................... 57 
13.3 
Source Data Verification ........................................................................... 58 
13.4 
Completion of Electronic Case Report Forms ........................................... 58 
13.5 
Data Management ...................................................................................... 58 
13.6 
Audits and Inspections ............................................................................... 58 
13.7 
Access to Source Data ............................................................................... 58 
13.8 
Training of Staff ......................................................................................... 59 
13.9 
Changes to the Protocol ............................................................................. 59 
14. 
ADMINISTRATIVE, LEGAL, AND ETHICAL ASPECTS ............................ 60 
14.1 
Conduct of the Trial ................................................................................... 60 
14.2 
Ethical Principles ....................................................................................... 60 
14.3 
Health Authorities and Institutional Review Board (IRB) ........................ 60 
14.4 
Subject Information and Consent .............................................................. 60 
14.5 
Confidentiality Regarding Trial Subjects Data .......................................... 61 
14.6 
Archiving at the End of the Study ............................................................. 61 
15. 
PUBLICATION POLICY .................................................................................. 62 
16. 
REFERENCES ................................................................................................... 63 


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APPENDIX 1: TIME AND EVENTS TABLE – COHORTS 1 & 2 ................................ 65 
APPENDIX 2: METHODS OF CLINICAL EVALUATION .......................................... 67 
APPENDIX 3: GENERAL INSTRUCTIONS FOR COMPLETION OF SAE FORMS . 77 
APPENDIX 4: SUBJECT’S DOSING INSTRUCTIONS ................................................ 79 
 
 
LIST OF FIGURES 
 
FIGURE 1: 
NCX-4251-01 STUDY DESIGN 
29 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AM 
Ante meridiem (before mid-day) 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
BCVA 
Best Corrected Visual Acuity 
BID 
Bis in die (twice daily) 
CI 
Confidence Interval 
COV 
Close Out Visit 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
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 
HDPE 
High Density Polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HPA 
Hypothalamic-Pituitary-Adrenal  
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRT  
Interactive Response Technology 
LDPE 
Low Density Polyethylene 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of Minimum Angle Resolution 
LS 
Least Square 
 
 
MI 
Multiple Imputations 
MMP 
Monitoring Management Plan 
mmHg 
Millimeters of Mercury 
ND 
Not Done 
OAG 
Open-Angle Glaucoma 
OHT 
Ocular Hypertension 
PI 
Principal Investigator 


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PM 
Post meridiem (after mid-day) 
PP 
Per Protocol 
QD 
Quaque Die (once daily) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDV 
Source Data Verification 
SMP 
Safety Management Plan 
TEAE 
Treatment Emergent Adverse Event 
TFBUT 
Tear Film Break Up Time 
U.S. 
United States 
VA 
Visual Acuity 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
 
Note: the first occurrence of some abbreviations is not spelled out in the document (e.g., units of measure). 
 


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STUDY OUTLINE / PROTOCOL SYNOPSIS 
Title 
A Multi-Center, Randomized, Double-Masked, Placebo-Controlled, Dose-
Escalation, Phase 2 Study Evaluating the Safety and Tolerability of NCX 4251 
(Fluticasone Propionate Nanocrystal) Ophthalmic Suspension, 0.1% QD and BID 
for the Treatment of Acute Exacerbations of Blepharitis. 
Study No. 
NCX-4251-01 
Sponsor 
Nicox Ophthalmics, Inc. 
Background and 
Rationale  
NCX 4251 (fluticasone propionate nanocrystal) Ophthalmic Suspension is a sterile, 
preserved, topical ocular suspension of fluticasone propionate nanocrystals 
packaged in multi-dose ophthalmic dropper bottles, and is being developed for the 
treatment of acute exacerbations of blepharitis by topical application directly site of 
the disease at the eyelid margin.  Nicox Ophthalmics, Inc. (Nicox) developed a 
route of delivery composed of applying NCX 4251 directly to the rim of the lower 
and upper lids in order to deliver effective dose to where the disease originates and 
to minimize the intraocular exposure to fluticasone. 
Blepharitis, a chronic inflammatory condition of the eyelid margin, is one of the 
most common ocular disorders seen by ophthalmic practitioners and is recognized 
to have a significant impact on ocular comfort and quality of life (Buchholz, 2006; 
Duncan, 2015).  It often has a chronic manifestation with intermittent exacerbations 
defined by an increase in symptoms. Signs and symptoms of blepharitis include 
burning, itchiness, gritty feeling in the eyes, contact lens intolerance, photophobia, 
redness (telangiectasia), swelling, discomfort and crusting of the eyelid margins 
(Lindsley et al, 2014).  While generally not sight-threatening, blepharitis can 
induce permanent eyelid margin alterations (eyelid notching and scarring, loss of 
eyelashes, in-turning of eyelashes) and even vision loss from superficial 
keratopathy, corneal neovascularization, or ulceration. Chronic blepharitis can also 
lead to destruction of the meibomian gland architecture and closure of the orifices 
by scar tissue (AAO PPP, 2013; Foulks, 2009). 
Blepharitis affects all ages and ethnic groups. While children can develop 
blepharitis, onset is typically during middle age.  Although blepharitis is commonly 
encountered in clinical practice, its true incidence and prevalence in the general 
population has not been well documented apart from some regional studies. In one 
survey, ophthalmologists and optometrists in the United States reported that 37% to 
47% of their patients had evidence of blepharitis (AAO PPP, 2013; Lemp, 2009).   


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NCX-4251-01 version 5.0; 13-Aug-2019 
Page 15 of 81 
Background and 
Rationale 
(continued) 
Even though the treatment of chronic blepharitis remains controversial, palpebral 
neutral shampoo cleaning has been the most widely accepted medical therapy in the 
US, followed by the use of antibiotic, or antibiotic and steroids ointments. Short 
courses of topical steroids have been found beneficial for symptomatic relief in 
cases with clinically significant ocular inflammation in an acute exacerbations of 
all forms of blepharitis (Lindsley et al, 2014; AAO PPP, 2013, Arrua, 2015; 
Pflugfelder, 2014; Jackson, 2008). Topical ocular corticosteroids, including 0.5% 
loteprednol etabonate and 0.1% dexamethasone, in combination with topical ocular 
antibiotics, have been effective in reducing the signs of blepharitis, with some 
differences in safety profile with respect to intraocular pressure (IOP; Pflugfelder et 
al, 2014; Hosseini et al, 2016; Comstock et al, 2017).  No clinical trials have 
evaluated topical ocular steroids applied directly to the eyelid margin; the site of 
blepharitis.  Eyelid margin application may avoid ocular side effects of topical 
ocular corticosteroids, including IOP elevation.  Although fluticasone propionate 
(FP) demonstrates greater activity than other corticosteroids of similar potency in 
vasoconstrictor assays in humans, FP used in the treatment of inhalation, intranasal 
or dermatological disorders demonstrates low potential to cause significant 
suppression of the hypothalamic-pituitary-adrenal (HPA) axis (Spencer and 
Wiseman, 1997; Johnson, 1998; Korting and Schöllmann, 2012).  
FP is a synthetic trifluorinated medium potent (class III) corticosteroid with high 
affinity for the glucocorticoid receptor, high lipophilicity, rapid hepatic 
biotransformation and a favorable benefit/risk ratio (Johnson, 1998; Korting and 
Schöllmann, 2012).  Like other topical dermal corticosteroids, FP has anti-
inflammatory, immunosuppressive, antipruritic, and antiproliferative effects, which 
are thought to be their primary mechanism of action in the treatment of several skin 
disorders (Roeder et al, 2005; Cutivate Lotion US Prescribing Information, 2015).  
FP is a locally active glucocorticoid which has no demonstrable systemic side-
effects when given by the oral or topical routes, as it appears to be extracted totally 
during its 'first pass' from the gut through the liver.  FP has an established 
nonclinical and clinical safety profile as inhalation, nasal, and dermal formulations 
of the drug are marketed for the treatment of asthma (Flovent® HFA, NDA 
021433, Advair® DISKUS®, NDA 021077), rhinitis (Flonase® NDA 020121), and 
atopic dermatitis (Cutivate®, NDA 021152), respectively.   
Overall, there is no general consensus on blepharitis treatment, and currently there 
are no official guidelines or FDA-approved drug products specifically studied for 
this condition. Physicians are looking for treatment to more effectively manage 
patients with blepharitis and prevent its adverse outcomes. Nicox is developing 
NCX 4251 for the treatment of acute exacerbations of blepharitis to address the 
current unmet medical need. 
Study Period 
Q1-Q4 2019 
Study Phase 
Phase 2 














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NCX-4251-01 version 5.0; 13-Aug-2019 
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1.
INTRODUCTION
1.1 
Background and Rationale 
NCX 4251 (fluticasone propionate nanocrystal) Ophthalmic Suspension is a sterile, preserved, 
topical ocular suspension of fluticasone propionate nanocrystals packaged in multi-dose 
ophthalmic dropper bottles, and is being developed for the treatment of acute exacerbations of 
blepharitis by topical application directly to the site of the disease at the eyelid margin.  Nicox 
Ophthalmics, Inc. (Nicox) developed a route of delivery composed of applying NCX 4251 
directly to the lower and upper lids and the rim of the lower eyelid in order to deliver an 
effective dose to where the disease originates and to minimize the intraocular exposure to 
fluticasone. 
Blepharitis, a chronic inflammatory condition of the eyelid margin, is one of the most common 
ocular disorders seen by ophthalmic practitioners and is recognized to have a significant impact 
on ocular comfort and quality of life (Buchholz, 2006; Duncan, 2015).  It often has a chronic 
manifestation with intermittent exacerbations defined by an increase in symptoms. Signs and 
symptoms of blepharitis include burning, itchiness, gritty feeling in the eyes, contact lens 
intolerance, photophobia, redness (telangiectasia), swelling, discomfort and crusting of the 
eyelid margins (Lindsley et al, 2014).  While generally not sight-threatening, blepharitis can 
induce permanent eyelid margin alterations (eyelid notching and scarring, loss of eyelashes, in-
turning of eyelashes) and even vision loss from superficial keratopathy, corneal 
neovascularization, or ulceration. Chronic blepharitis can also lead to destruction of the 
meibomian gland architecture and closure of the orifices by scar tissue (AAO PPP, 2013; 
Foulks, 2009). 
Blepharitis affects all age and ethnic groups. While children can develop blepharitis, onset is 
typically during middle age.  Although blepharitis is commonly encountered in clinical 
practice, its true incidence and prevalence in the general population has not been well 
documented apart from some regional studies. In one survey, ophthalmologists and 
optometrists in the United States reported that 37% to 47% of their patients had evidence of 
blepharitis (AAO PPP, 2013; Lemp, 2009).   
Even though the treatment of chronic blepharitis remains controversial, palpebral neutral 
shampoo cleaning has been the most widely accepted medical therapy in the US, followed by 
the use of antibiotic, or antibiotic and steroids ointments. Short courses of topical steroids have 
been found beneficial for symptomatic relief in cases with clinically significant ocular 
inflammation in an acute exacerbation of all forms of blepharitis (Lindsley et al, 2014; AAO 
PPP, 2013, Arrua, 2015; Pflugfelder, 2014; Jackson, 2008). Topical ocular corticosteroids, 
including 0.5% loteprednol etabonate and 0.1% dexamethasone, in combination with topical 
ocular antibiotics, have been effective in reducing the signs of blepharitis, with some 
differences in safety profile with respect to intraocular pressure (IOP; Pflugfelder et al, 2014; 
Hosseini et al, 2016; Comstock et al, 2017).  No clinical trials have evaluated topical ocular 
steroids applied directly to the eyelid margin; the site of blepharitis.  Eyelid margin application 
may avoid ocular side effects of topical ocular corticosteroids, including IOP elevation.  
Although FP demonstrates greater activity than other corticosteroids of similar potency in 
vasoconstrictor assays in humans, FP used in the treatment of inhalation, intranasal or 
dermatological disorders demonstrates low potential to cause significant suppression of the 


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NCX-4251-01 version 5.0; 13-Aug-2019 
 
Page 23 of 81 
hypothalamic-pituitary-adrenal axis (Spencer and Wiseman, 1997; Johnson, 1998; Korting and 
Schöllmann, 2012).  
FP is a synthetic trifluorinated medium potent (class III) corticosteroid with high affinity for 
the glucocorticoid receptor, high lipophilicity, rapid hepatic biotransformation and a favorable 
benefit/risk ratio (Johnson, 1998; Korting and Schöllmann, 2012).  Like other topical dermal 
corticosteroids, FP has anti-inflammatory, immunosuppressive, antipruritic, and 
antiproliferative effects, which are thought to be their primary mechanism of action in the 
treatment of several skin disorders (Roeder et al, 2005; Cutivate Lotion US Prescribing 
Information, 2015).  Fluticasone propionate is a locally active glucocorticoid which has no 
demonstrable systemic side-effects when given by the oral or topical routes, as it appears to be 
extracted totally during its 'first pass' from the gut through the liver. FP has an established 
nonclinical and clinical safety profile as inhalation, nasal, and dermal formulations of the drug 
are marketed for the treatment of asthma (Flovent® HFA, NDA 021433, Advair® DISKUS®, 
NDA 021077), rhinitis (Flonase® NDA 020121), and atopic dermatitis (Cutivate®, NDA 
021152), respectively.   
Overall, there is no general consensus on blepharitis treatment, and currently there are no 
official guidelines or FDA-approved drug products specifically studied for this condition. 
Physicians are looking for treatment to more effectively manage patients with blepharitis and 
prevent its adverse outcomes. Nicox is developing NCX 4251 for the treatment of acute 
exacerbations of blepharitis to address the current unmet medical need. 
1.2 
Study Background 
Nonclinical and Clinical Studies of NCX 4251 
A summary of all nonclinical studies performed with NCX 4251 can be found in the 
Investigator Brochure. This study is the First-In-Human study performed with NCX 4251 
Ophthalmic Suspension. 
Description of the Study Medication 
The study medication is a sterile, 
ophthalmic aqueous suspension containing 
NCX 4251 (fluticasone propionate nanocrystals) 0.1%. For further detail see Section 6.1. 
Description of the Placebo Comparator 
The placebo comparator is the vehicle of NCX 4251 Ophthalmic Suspension, 0.1%. For further 
detail see Section 6.1. 
Justification of the Study Design  
The proposed study will be the First-In-Human study of NCX 4251 Ophthalmic Suspension. 
This is a multi-center, randomized, double-masked, placebo-controlled, dose-escalation 
Phase 2 study evaluating the safety and tolerability of NCX 4251 (fluticasone propionate 
nanocrystals) Ophthalmic Suspension, 0.1% QD and BID for the treatment of acute 
exacerbations of blepharitis. The study will be performed in two sequential dose escalating 
cohorts. The study design has been selected to select the dose(s) of NCX 4251 to advance into 
the next stage of development. 
Justification of the Route of Delivery 
A reduction in the unwanted, systemic effects of glucocorticoids can be achieved by local 
administration to the site of action. Fluticasone propionate is a potent, locally active 
glucocorticoid which has been administered safely as an intranasal spray, inhaled suspension 




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Page 25 of 81 
propionate cream USP 0.05% US Prescribing Information, 2016). The penetration of 0.005% 
fluticasone propionate ointment through eyelid skin after a single application in vitro has been 
shown to be very small (Tan et al, 2001).  
Additionally, systemic absorption of topical corticosteroids can produce reversible HPA axis 
suppression with the potential for glucocorticosteroid insufficiency after withdrawal from 
treatment. Manifestations of Cushing's syndrome, hyperglycemia, and glucosuria can also be 
produced in some patients by systemic absorption of topical corticosteroids while on treatment. 
However, in patients as young as 3 months, fluticasone propionate 0.05% lotion was shown to 
have no effect on HPA axis function and did not cause skin thinning even when used 
extensively over widespread, severe inflammatory disease (Herbert et al, 2006). 
Specific risks associated with topical ophthalmic products 
There have been reports of bacterial infections associated with the use of multiple-dose 
containers of topical ophthalmic products. These containers had been inadvertently 
contaminated by patients touching the tip of the bottles.  
Benefits 
Glucocorticoids produce a number of beneficial effects on the events involved in inflammation. 
These include inhibition of production of interleukins, inhibition of cellular and protein 
extravasation, inhibition of arachidonic acid generation from phospholipids and a reduction in 
the release of proteases and other enzymes from a number of cell types. The effects are 
cumulative, such that clinical improvement continues over several days or weeks of treatment 
(Harding, 1990). The expected benefits of the application of NCX 4251 Ophthalmic 
Suspension in subjects with blepharitis are the relief of the signs and symptoms of blepharitis 
such as redness, discomfort, itchy eyes, swollen eyes, crusted eyelashes upon awakening, 
watery eyes, gritty, burning or stinging sensation in the eyes. 
For further information, please refer to the Investigator’s Brochure for NCX 4251. 








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scrubs per instructions provided in the study protocol until the day prior to the Day 28/Exit 
Visit.  
Study medication will be self-administered topically in the morning (Cohort 1), or in the 
morning and evening (Cohort 2). Morning eyelid scrubs and morning study medication 
application will be performed by the subject at the clinical site on the days of study visits. 
A subject will be considered as having completed the study after completion of Day 28/Exit 
Visit (± 2 days). The duration of subject participation (from the Screening Visit to the Exit 
Visit) is approximately 5 weeks. The overall study duration is estimated to be approximately 
6 months from the first subject enrolled until completion of the last subject. 
The study design is essentially identical for Cohort 1 and Cohort 2; the main differences are the 
dosing frequency (QD vs. BID) and the randomization ratio (2:1 vs. 1:1). Final statistical 
analyses will be performed after the completion of Cohort 2. 
 
Figure 1: 
NCX-4251-01 Study Design 
 
 




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Page 31 of 81 
3) have any current or recurrent ocular infections (bacterial, viral or fungal), active ocular 
inflammation other than blepharitis (i.e., follicular conjunctivitis, iritis) or preauricular 
lymphadenopathy; 
4) have current or recurrent diagnosis of ulcerative keratitis, specifically any epithelial loss 
greater than punctate keratitis (e.g., confluent epithelial loss or any infiltrates); 
5) have been diagnosed with glaucoma or ocular hypertension, or have an IOP > 21 mmHg at 
the Screening Visit and/or Baseline/Day 1 Visit; 
6) have a history of IOP elevation with steroid use (i.e., steroid responder); 
7) unable or unwilling to discontinue the use of contact lenses from Screening  to 
Day 28/Exit Visit; 
8) use any eye makeup (including on the eyelids, eyelid margins, and lashes) at the Screening 
Visit and unwilling to cease the use of eye make-up up to the Day 14 Visit; 
9) cosmetic eyelash procedures (e.g., eyelash curling) from the Screening Visit up to the Day 
14 Visit, or a history of permanent/semi-permanent eye make-up procedures (e.g., eyelash 
extensions / false eyelashes, eyelash tinting, eyeliner tattooing) within 30 days of the 
Screening Visit or planned procedure during the study period; 
10) have a history of ocular surgical intervention within 6 months prior to the Screening Visit 
or any planned ocular procedure during the study period; 
11) Have permanent punctal plugs or history of nasolacrimal obstruction; 
12) have known hypersensitivity to fluticasone propionate, to any other component of the 
study medication, or to ophthalmic diagnostic dyes (e.g., fluorescein, lissamine green); 
13) use strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, 
clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, 
telithromycin); 
14) unable or unwilling to discontinue use of any non-diagnostic ophthalmic treatments 
(topical, intraocular or systemic) including topical autologous serum eyedrops and 
artificial tears. Subjects should have discontinued use of artificial tears for at least 24 
hours prior to the Screening Visit, and for at least 30 days for all other ophthalmic 
medications; 
15) unable or unwilling to discontinue use of any non-diagnostic ophthalmic procedures 
  
from the Screening Visit through the study 
period. Warm compresses and the subject’s standard of care eyelid scrubs are permitted 
from the Screening Visit through the evening prior to Baseline/Day 1 Visit, and protocol-
specified eyelid scrubs from Baseline/Day 1 through the study period; 
16) have a history of Meibomian gland probing within 3 months prior to the Screening Visit; 
17) use of any corticosteroid agent or anabolic steroid within 30 days of the Screening Visit or 
during the study treatment period; 
18) use of isotretinoin or any other retinoids within 12 months of the Screening Visit; 
19) have any uncontrolled systemic disease or debilitating disease (e.g., cardiovascular 
disease, hypertension, diabetes, cystic fibrosis) in the opinion of the Investigator; 


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20) have any auto-immune disease (e.g., rheumatoid arthritis, lupus, Sjögren’s, graft-versus-
host disease (GVHD)). Note: Patients with controlled, mild rheumatoid arthritis without 
any other component (e.g., psoriatic) are allowed to be included in the study; 
21) have a condition which, in the Investigator’s opinion, may put the subject at increased risk, 
confound study data, or interfere significantly with the subject’s study participation or 
their ability to perform eyelid scrubs and apply the study medication; and 
22) have participated in any drug or device study within 30 days prior to the Screening Visit 
and/or during the period of study participation. 


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5. 
CONCOMITANT MEDICATION(S) 
5.1 
Previous and Concomitant Medication(s) 
All non-ophthalmic medications (with the exception of isotretinoin or any other retinoids) used 
in the 3 months prior to the Screening Visit must be recorded. Additionally, isotretinoin or any 
other retinoids, and all ophthalmic medications used in the 12 months prior to the Screening 
Visit must be recorded. All medications used between the Screening Visit and the Day 28/Exit 
Visit must be recorded. 
Any diagnostic ophthalmic agents administered throughout the study will not be captured in 
the concomitant medication log.  
5.2 
Prohibited Medication(s) and Procedures  
All the prohibited drugs and procedures mentioned below are also listed in Section 4.4 
(“Exclusion Criteria''). 
From the Screening Visit through the Day 28/Exit Visit subjects must not receive: 
• any non-diagnostic ophthalmic treatments (topical, intraocular or systemic) including 
topical autologous serum eyedrops artificial tears or procedures 
 
 other than the eyelid scrubs administered in this trial (note: 
Warm compresses and the subject’s standard of care eyelid scrubs are permitted from 
the Screening Visit through the evening prior to Baseline/Day 1 Visit), 
• strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, 
clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, 
ketoconazole, telithromycin) 
• any corticosteroid or anabolic steroid agents 
• isotretinoin or any other retinoids 
• topical ocular and periocular antibiotics 
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.  
Contact lens use is prohibited from the Screening Visit to Day 28/Exit Visit. The use of any 
eye make-up (including on the eyelids, eyelid margins, and lashes) is prohibited up to the Day 
14 Visit.  
Additionally, cosmetic eyelash procedures (e.g. eyelash curling) are prohibited from the 
Screening Visit up to the Day 14 Visit, and permanent/semi-permanent eye make-up 
procedures (e.g., eyelash extensions / false eyelashes, eyelash tinting, eyeliner tattooing) are 
prohibited up to the Day 28/Exit Visit. 
Additionally, the following are prohibited: 
• Botulinum toxin (Botox or equivalent) injected in the periocular area within 
3 months prior to the Screening Visit 
• Meibomian gland probing within 3 months prior to the Screening Visit 
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6.5 
Accountability of Study Medication 
It is the responsibility of the site to maintain detailed study medication accountability records.   
The study medication will be shipped by the study medication supplier to each study site.  The 
receipt of study medication by the site should be documented. The dispensed and returned 
study medication will be recorded by the site on an inventory log. 
The importance of returning the kit with all bottles dispensed 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 site. 
6.6 
Assigning Subjects to Treatment and Study Masking 
Each site will be assigned a two digit site ID by the Sponsor or its representative. At the 
Screening Visit, the site will assign a unique three digit screening number 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 unique Subject ID comprised of the two digit site ID followed by 
the three digit screening number.  
Once a subjects meets qualification criteria at the Baseline/Day 1 Visit, approximately 15 
subjects in Cohort 1 will be randomly assigned to NCX 4251 0.1% QD or placebo QD in a 2:1 
ratio.  Approximately 20 subjects in Cohort 2 will be randomly assigned to NCX 4251 0.1% 
BID or placebo BID in a 1:1 ratio.  
Subjects will be assigned a randomization number available at that site. No randomization 
numbers will be skipped or omitted. Randomization numbers will be unique across the sites, 
and will correspond with a kit number.  
Randomization will be used to avoid bias in the assignment of subjects to treatment, to increase 
the likelihood that known and unknown subject attributes (e.g., demographics and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons. 
The subjects, investigators, 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. Investigators, the Sponsor, the Medical Monitor, and CRO personnel interacting 
with the clinical sites must not be present at study visits during the preparation of the study 
medication for application. 
A sealed envelope containing the identity of the study medication will be provided for each kit. 
The envelopes will be kept in a secure location at the study site and must not be opened except 
in the case of an emergency. All envelopes must be returned to the Sponsor at the completion 
of the study to confirm that masking has not been broken during the study. 
6.7 
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 must be first consulted with both the 
study Sponsor and the Medical Monitor. Unmasking can be achieved by opening the sealed 
envelope that corresponds to the randomization number assigned to the subject. The Sponsor 






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2. 
 
 
 
    
 
 
  
 
  
  
 
 
 
   
Now proceed with applying the study medication beginning with the right eye:  
10. 
 
 
 
 
  
  
 
 
 
 
  
applicator and tube, apply study medication to the left eye repeating 
Steps 2-16.  
IMPORTANT! THE APPLICATOR SPONGE MUST NOT MAKE CONTACT WITH THE 
SURFACE OF THE EYE OR THE WHITE PART OF THE EYE. The only contact should be 
to the specified areas of the eyelid.  


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6.11 
Compliance with Eyelid Scrubs and Study Medication 
It is important to encourage the subject to be compliant with eyelid scrubs and application of 
study medication. Compliance of both will be captured in a subject diary. 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 the completion of the last subject last visit at the site, 
and only after database lock and following onsite verification by the CRA. 
6.13 
Other Study Supplies 
Sites will also be provided with: 
• Sterile applicators and tubes (for study medication) 
• Baby shampoo, cotton swabs, bottled water, tissues, and capped tubes (for eyelid 
scrubs) 
• Safety scissors (for opening tube packaging) 
• Subject diaries and dosing instructions 
• Early Treatment Diabetic Retinopathy Study (ETDRS) charts and/or illuminator cabinet 
(or replacement bulb with diffuser), if needed 
• Urine pregnancy tests 
• 
 
 
 
 
 
 
 
• Visual Analog Scale (VAS) rulers 
• 
 
 
 
Additional supplies may be provided once discussed and approved by the Sponsor.  
 
















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by a certified letter and there is no known reason for withdrawal (e.g., withdrawal of 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. 
 
 


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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 application 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 application, 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 application, corresponds to a known 
effect of the study medication, is confirmed by the observation of an improvement upon 
discontinuation of the study medication application, and therefore the study medication 
is the most probable of all the causes.  


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• Definite: this relation exists when the safety event follows a reasonable chronological 
sequence from the moment of the study medication application, corresponds to a known 
effect of the category of the studied medication, is confirmed 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. 
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.  


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From the signing of the ICF on the day of the Screening Visit, all AEs 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.   
10.6 
Serious Adverse Event Reporting 
Any SAE occurring from the signing of the ICF on the day of the Screening Visit until Day 28/ 
Exit must immediately be reported
 and recorded on the 
appropriate forms.  All subjects with an SAE must be followed up until complete healing or 
stabilization, or up to 30 days after the end of Treatment Period, whichever occurs first, and the 
SAE outcome reported. 
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 the Primary Contact for Study Related Matters and SAEs immediately (see 
contact information on Page 2 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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Changes or shifts from baseline will also be summarized where appropriate. For assessments 
performed by eye, study eye and fellow eye will be summarized separately. 
11.5.4 Dose Selection Process 
Once this study’s efficacy and safety results become available, the NCX 4251 dose(s) with the 
most favorable efficacy/safety ratio may be advanced into the next stage of development.  
11.5.5 Interim Analysis 
A limited interim analysis, composed of a subset of final analysis will be performed after 
completion of Cohort 1. Details of the interim analysis will be provided in the Statistical 
Analysis Plan.  




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13. 
STUDY MANAGEMENT 
13.1 
Monitoring 
Site monitoring is conducted to assess that subject protection, study procedures, study drug 
application, 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 monitor from the company representing Nicox will monitor the study on a 
periodic basis by having regular contacts with the investigational sites, including on-site 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 and that the study medication logs 
are being maintained. 
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. 
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 
such laboratory tests. 




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the trial (i.e., subject’s data records) 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, and 
all other applicable regulatory requirements. 


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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.  
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 publically 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. 
 


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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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16. 
REFERENCES 
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the efficacy of different treatment option in patients with chronic blepharitis. Arch Soc Esp 
Oftalmol. 2015;90(3):112-8. 
Buchholz P, Steeds CS, Stern LS, Wiederkehr DP, Doyle JJ, Katz LM, Figueiredo FC. Utility 
assessment to measure the impact of dry eye disease. Ocul Surf. 2006 Jul;4(3):155-61. 
Comstock T, DeCory H.  Loteprednol etabonate 0.5%/tobramycin 0.3% compared with 
dexamethasone 0.1%/tobramycin 0.3% for the treatment of blepharitis.  Ocular Immunol 
Inflamm. 2017;25:267-74. 
Cubey RB. Glaucoma following the application of corticosteroids to the skin of the eyelids. 
Brit J Dermatol 1976; 95:207–8. 
Duncan K, Jeng BH. Medical management of blepharitis. Curr Opin Ophthalmol. 2015 
Jul;26(4):289-94. 
Foulks GN. Enhancing our knowledge of blepharitis. Ocul Surf. 2009 Apr;7(2 Suppl):S15-6. 
Jackson WB. Blepharitis; current strategies for diagnosis and management. Can J Ophthalmol. 
2008;43(2):170-9. 
Garrott HM, Walland MJ. Glaucoma from topical corticosteroids to the eyelids. Clin Exp 
Ophthalmol 2004; 32:656–7. 
Harding SM. The human pharmacology of fluticasone propionate. Resp Med. 1990;84:25-9. 
Herbert AA, Friedlander SF, Allen DB, for the Fluticasone Pediatrics Safety Study Group. 
Topical fluticasone propionate lotion does not cause HPA axis suppression. J Pediatr. 
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Hosseini K, Lindstrom RL, Foulks G, Nichols KK. A randomized, double-masked, parallel-
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alone, and vehicle in the treatment of subjects with blepharitis. Clin Ophthalmol. 
2016;10:1495-503. 
Johnson M. Development of fluticasone propionate and comparison with other inhaled 
steroids. J Allergy Clin Immunol. 1998;101;S434-9. 


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Korting HC, Schöllmann C.  Topical fluticasone propionate: intervention and maintenance 
treatment options of atopic dermatitis based on a high therapeutic index.  J Eur Acad Dermatol 
Venereol. 2012;26:133-40. 
Lemp MA, Nichols KK. Blepharitis in the United States 2009: A survey-based prespective on 
prevalence and treatment. Ocular Surf. 2009;7(2, Suppl):S1-S14. 
Lindsley K, Matsumura S, Hatef E, Akpek EK. Interventions for chronic blepharitis. Cochrane 
Database Syst Rev. 2014;5:1-117. 
McGhee C, Dean S, Danesh-Meyer H. Locally administered ocular corticosteroids: benefits 
and risks. Drug Saf. 2002;25:33-55. 
Pflugfelder SC, Karpecki PM, Perez VL.  Treatment of blepharitis: recent clinical trials.  Ocul 
Surf. 2014 Oct;12(4):273-84. 
Roeder A, Schaller M, Schäfer-Korting M, Korting HC.  Safety and efficacy of fluticasone 
propionate in the topical treatment of skin diseases.  Skin Pharmacol Physiol. 2005;18:3-11. 
Spencer CM, Wiseman LR.  Topical fluticasone propionate: a review of its pharmacological 
properties and therapeutic use in the treatment of dermatological disorders.  BioDrugs. 
1997;7:318-34. 
Tan M-H, Lebwohl M, Esser AC, Wei H. The penetration of 0.005% fluticasone propionate 
ointment in eyelid skin. J Am Acad Dermatol. 2001;45(3):392-6. 
United States Prescribing Information for Cutivate Lotion, 2015. 
United States Prescribing Information for Fluticasone Propionate Cream, USP 0.05%. 2016. 


























APPENDIX 3 
CONFIDENTIAL 
NCX-4251-01 version 5.0; 13-Aug-2019 
 
Page 77 of 81 
APPENDIX 3: GENERAL INSTRUCTIONS FOR COMPLETION OF SAE FORMS 
1. As soon as possible, and at the latest within 24 hours of becoming aware of event, complete 
an initial SAE Form.  The SAE Form must be completed with a black ink ball point pen, in 
English and with block capitals to facilitate the readability of the submitted document.  
Please ensure that all sections have been completed. 
2. Evaluate the events of trial subjects and record on the case report form a diagnosis (when 
possible and appropriate) rather than each individual sign and symptom. 
3. Terms such as death, hospitalization or a procedural name are not acceptable event terms. 
• Example: Subject was hospitalized for cholecystectomy due to cholecystitis.  The event 
term would be “Cholecystitis” (not the procedure). 
• Example: “Death” is an outcome not an event term.  The Investigator should report the 
primary cause of death as the SAE term. 
4. All initial SAE reports must have the relationship to study medication documented. 
5. All SAEs will be:  
• Followed to resolution (subject’s health has returned to their  baseline status or all 
variables have returned to normal) or  
• Followed until stabilization of the event has occurred (the Investigator does not expect 
any further improvement or worsening of the event) or  
• The event is followed up to 30 days after last study medication application. 
• Some events do not end, such as metastasis; however, once these events are determined 
by the Principal Investigator to be stable or chronic, the PI may consider the event to be 
resolved or resolved with sequelae. 
6. In case of death: 
• Specify the cause of death (do not use the term “death” and avoid using cardiac arrest 
or respiratory failure if possible. Instead, provide the diagnosis leading to cardiac arrest 
or respiratory failure.)  
• There should be only one SAE with an outcome of death for each subject. 
• For other adverse events that were ongoing at the time of death, enter outcome of these 
events as ‘Ongoing.’ 
• Please submit a copy of the Death Certificate and Autopsy Report (if applicable). 
7. Review all source documents (examples - hospital discharge summary, hospital notes) as 
additional SAEs may be detected.  If there are any questions as to whether you think an 
additional SAE may be present, please contact the Medical Monitor to discuss. 
8. Protect the subject’s identity.  Redact all individually identifiable information (e.g., 
subject’s name, medical record number, social security number and any parent or spouse 


APPENDIX 3 
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NCX-4251-01 version 5.0; 13-Aug-2019 
 
Page 78 of 81 
information such as names and addresses) in the header as well as in the body of the text on 
any supporting documents. 
9. Follow-up SAE form completion instructions: 
• 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. 
• Complete a new SAE Form.  At the top of the first page, tick the follow-up report or 
final report box and fax all pages even if changes were only made to one of the pages  
• Retain the submission confirmation. 
10. In case of mistake on the original initial SAE Form submitted to the SAE contact person, 
correct it, date and sign it and submit it again.  Retain the submission confirmation. 
11. Downgrading/deletion of a previously reported SAE: 
If the Investigator determines a previously reported SAE doesn’t meet serious criteria, a 
Follow-up SAE report should be completed.  Document in the “Event Summary” section a 
brief explanation of why the Investigator determined the event to not be serious (i.e., “it 
was determined that the subject was not hospitalized; therefore, this event does not meet 
serious criteria” or “the event was determined to be past medical history”) 
12. File original forms in the Case Report Form (CRF) of the subject. 
13. Inform the IRB per IRB requirements and as required by local regulations. 
 






APPENDIX 4 
CONFIDENTIAL 
NCX-4251-01 version 5.0; 13-Aug-2019 
 
Page 81 of 81 
 
 
 
 
  
 
  
IMPORTANT! THE APPLICATOR SPONGE MUST NOT MAKE CONTACT WITH THE 
SURFACE OF THE EYE OR THE WHITE PART OF THE EYE. The only contact should be 
to the specified areas of the eyelid.  
 

SAP_001.pdf: 
FINAL STATISTICAL ANALYSIS PLAN FOR NCX 
4251-01 PHASE 2 CLINICAL STUDY 
A Multi-Center, Randomized, Double-Masked, Placebo-Controlled, 
Dose-Escalation, Phase 2 Study Evaluating the Safety and 
Tolerability of NCX 4251 (Fluticasone Propionate Nanocrystal) 
Ophthalmic Suspension, 0.1% QD and BID for the Treatment of Acute 
Exacerbations of Blepharitis 
Sponsor:  
Nicox Ophthalmics, Inc. 
Protocol Number: 
NCX-4251-01 
Author:  
Date:  
05 November 2019 
Version: 
Final 2.0 
NCT03926026


Protocol NCX-4251-01 SAP, Version 2.0 
A Multi-Center, Randomized, Double-Masked, Placebo-Controlled, Dose-Escalation, Phase 2 Study 
Evaluating the Safety and Tolerability of NCX 4251 (Fluticasone Propionate Nanocrystal) 
Ophthalmic Suspension, 0.1% QD and BID for the Treatment of Acute Exacerbations of Blepharitis 
Protocol Number: 
NCX-4251-01 
Final 2.0 
Version: 
Date: 
05 November 2019 
Statistical Analysis Plan Approval 
Prepared by: 
Reviewed by: 
Approved by: 
Approved by: 
 
 
 
 
 
 
Jose L. Boyer, PhD 
Vice President, Clinical Development 
Nicox Ophthalmics, Inc. 
Tomas Navratil, PhD 
Date 
Date 
Date 
Date 
Executive Vice President and Head of Development 
Nicox Ophthalmics, Inc. 
05 November 2019 
Confidential & Proprietary 
Page 2 of 38 




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Table of Contents 
1 
Introduction............................................................................................................................... 7 
2 
Study Objectives ...................................................................................................................... 7 
2.1 Study Variables ........................................................................................................................ 7 
2.2 Efficacy Endpoints .................................................................................................................... 8 
2.3 Safety Endpoints ...................................................................................................................... 9 
2.4 Exploratory Variables ............................................................................................................... 9 
2.5 Statistical Hypotheses ............................................................................................................ 10 
3 
Study Design and Procedures ............................................................................................... 10 
3.1 General Study Design ............................................................................................................ 10 
3.2 Schedule of Visits and Assessments ..................................................................................... 11 
4 
Study Treatments ................................................................................................................... 11 
4.1 Method of Assigning Subjects to Treatment Groups ............................................................. 11 
4.2 Masking and Unmasking ........................................................................................................ 11 
5 
Sample Size and Power Considerations ................................................................................ 12 
6 
Data Preparation .................................................................................................................... 12 
6.1 Input Data ............................................................................................................................... 12 
6.2 Output Data ............................................................................................................................ 12 
7 
Analysis Populations .............................................................................................................. 13 
7.1 Intent-to-Treat......................................................................................................................... 13 
7.2 Per Protocol............................................................................................................................ 13 
7.3 Safety ..................................................................................................................................... 13 
8 
General Statistical Considerations ......................................................................................... 13 
8.1 Unit of Analysis....................................................................................................................... 13 
8.2 Missing or Inconclusive Data Handling .................................................................................. 13 
8.3 Definition of Baseline ............................................................................................................. 14 
8.4 Data Analysis Conventions .................................................................................................... 14 
8.5 Adjustments for Multiplicity ..................................................................................................... 15 
9 
Disposition of Subjects ........................................................................................................... 16 
10 
Demographic and Pre-treatment Variables ............................................................................ 16 
10.1 Demographic Variables .......................................................................................................... 16 
10.2 Baseline Characteristics ......................................................................................................... 17 
11 
Medical History and Concomitant Medications ...................................................................... 17 
11.1 Medical History ....................................................................................................................... 17 
11.2 Concomitant Medications ....................................................................................................... 17 
12 
Dosing Compliance and Treatment Exposure ....................................................................... 18 




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19 
Revision History ..................................................................................................................... 28 
20 
Tables to Be Included In the Final Analysis ........................................................................... 29 
21 
Listings ................................................................................................................................... 35 
22 
Appendix A ............................................................................................................................. 37 
 
 
 




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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-4251-01, version 5.0 dated 13 Aug 2019. 
 
 
 
 
 
 
 
the combined analyses for Cohort 1 and Cohort 2 analysed together will be 
covered in the body of this “Final Statistical Analysis Plan for NCX 4251-01 Phase 2 Clinical Study” and 
carried out following database lock and unmasking of the Cohort 2 portion of the NCX 4251-01 study. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline, titled Guidance for Industry: Statistical 
Principles for Clinical Trials, and the most recent ICH E3 Guideline, titled 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. 
2 
Study Objectives 
Primary Objective 
The primary objective of this clinical study is to select the dose(s) of NCX 4251 to be advanced into the 
next stage of development. 
Secondary Objectives 
The secondary objectives of the study are to assess the safety and tolerability of the study medication 
applied once daily (QD) and twice daily (BID). 
2.1 
Study Variables 
The following will be collected in the course of the study: 
• 
Eyelid signs and symptoms (Eyelid Debris, Eyelid Margin Redness, and Eyelid Discomfort) 
• 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
• 
Intraocular pressure (IOP) 
• 
Dilated ophthalmoscopy 
• 
Best-corrected visual acuity (BCVA) 
• 
Urine pregnancy tests (for females of childbearing potential) 
• 
Adverse Events (AE) 
2.2 
Efficacy Endpoints 
The efficacy endpoints are the following for Cohort 1 and 2. 
 
 
 
 
• 
Mean change from baseline in composite (sum) score of Eyelid Margin Redness, Eyelid Debris, 
and Eyelid Discomfort 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
2.3 
Safety Endpoints 
The safety endpoints include the following: 
• 
The incidence of treatment-emergent ocular and systemic AEs 
• 
BCVA, IOP, ocular signs (as assessed by slit lamp biomicroscopy), and fundus assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.5 
Statistical Hypotheses 
There are no formal hypotheses in this early phase study. 
3 
Study Design and Procedures 
3.1 
General Study Design 
This is a multi-center, randomized, double-masked, placebo-controlled, dose-escalation study consisting of 
two cohorts, Cohort 1 and Cohort 2 studied sequentially. Each cohort consists of two arms, placebo and 
NCX 4251 Ophthalmic Suspension 0.1%. Approximately 15 subjects in Cohort 1 will be randomized in a 
2:1 ratio (NCX 4251:placebo) and will receive study medication QD. 
 
Approximately 20 subjects in Cohort 
2 will be randomized in a 1:1 ratio and will receive study medication BID. Screening of eligible subjects for 
Cohort 2 will commence after the interim analysis from the Cohort 1 is conducted. 
In each cohort, subjects will be assessed for initial eligibility at the Screening Visit (Day -7 to -3). Eligible 
adult subjects with a history of blepharitis and who are experiencing an acute exacerbation of blepharitis 
defined as a minimum score of ‘1’ (on a 4-point scale) for each of Eyelid Margin Redness, Eyelid Debris, 
and overall Eyelid Discomfort 
 at both the Screening and 
Baseline/Day 1 Visits will be randomized into the study. 
For both Cohorts 1 and 2, study visits will be as follows: Screening (Day -7 to -3), Baseline/Day 1, Day 4 (± 
1 day), Day 8 (± 1 day), Day 11 (± 1 day), Day 14 (- 1 day; last day of treatment), and Day 28/Exit (± 2 
days; follow-up visit). 
Following the Screening Visit prior to Baseline/Day 1 Visit, subjects will continue their previous routine for 
cleaning of eyelids that they were using prior to Screening Visit. Both eyes will be treated from the 
Baseline/Day 1 Visit through Day 14 Visit. The study eye will be the eye with the highest composite score 
before eyelid scrubs at Baseline/Day 1 or the right eye (OD) if both eyes of a subject have the same score 
at baseline. The contralateral eye will be considered as the fellow eye. After the Day 14 Visit, subjects will 
continue using the eyelid scrubs per instructions provided in the study protocol until the day prior to the Day 
28/Exit Visit. 
Study medication will be self-administered topically in the morning (Cohort 1), or in the morning and evening 
(Cohort 2). Morning eyelid scrubs and morning study medication application will be performed by the subject 
at the clinical site on the days of study visits under supervision of the study personnel. 
A subject will be considered as having completed the study after completion of Day 28/Exit Visit (± 2 days). 
The duration of subject participation (from the Screening Visit to the Exit Visit) is approximately 5 weeks. 


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The overall study duration is estimated to be approximately 6 months from the first subject enrolled until 
completion of the last subject. 
The study design is essentially identical for Cohort 1 and Cohort 2; the main differences are the dosing 
frequency (QD vs. BID), the randomization ratio (2:1 vs 1:1), 
 
 
3.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided in Appendix A. 
4 
Study Treatments 
4.1 
Method of Assigning Subjects to Treatment Groups 
At the Screening Visit, subjects who provide verbal and written informed consent will be assigned a unique 
5-digit subject ID, which consists of the 2-digit site number plus a unique 3-digit screening number 
(beginning with 001 within each site). A subject must meet all qualification criteria at the Baseline/Day 1 
Visit to be randomized. Approximately 15 subjects in Cohort 1 will be randomly assigned to NCX 4251 0.1% 
QD or placebo QD in a 2:1 ratio. Approximately 20 subjects in Cohort 2 will be randomly assigned to NCX 
4251 0.1% BID or placebo BID in a 1:1 ratio. Study drug will be randomly assigned using a (2:1 for Cohort 
1, 1:1 for Cohort 2) assignment ratio, which is stratified by site. Sequentially numbered study drug kits will 
be provided to each investigational site, in accordance with the site-specific randomized study drug kit list, 
which consists of sequential 4-digit kit ID numbers. Subjects who meet all eligibility criteria will be 
randomized by assignment of the lowest 4-digit study drug kit number available at their investigational site. 
If a randomized subject is discontinued from the study for any reason, their randomized study drug kit 
number will not be reassigned. A back-up block of treatments will be available at each site to be used for 
study treatment replacement.  
The 5-digit subject ID will be used to identify subjects in all datasets and listings for this study.  
4.2 
Masking and Unmasking 
The study statistician will generate the complete randomized study drug kit list. The subject, Sponsor, 
Investigators, and study staff will be masked during the randomization process and throughout the study. 
 
.  
If unmasking of a subject becomes critical to the subject’s safety, the Principal Investigator must authorize 
such decision. If possible, such decision must be first consulted with both the study Sponsor and the Medical 
Monitor. Unmasking can be achieved by opening the sealed envelope that corresponds to the 
randomization number assigned to the subject. The Sponsor and the Medical Monitor must be notified 
within 24 hours following an emergency unmasking of any subject. 


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5 
Sample Size and Power Considerations 
The sample size was not calculated to yield pre-stated power for a specific efficacy analysis; instead, the 
sample size in this early phase study will assist in obtaining estimates from which to power future studies. 
6 
Data Preparation 
6.1 
Input Data 
All reported study data will be recorded on the eCRF 
 
. Only the Principal Investigator and authorized study staff according to 
the Delegation of Responsibilities log are entitled to make entries in the eCRF.  
After data are entered into the clinical study database, electronic edit checks and data review will be 
performed. All data validation specifications and procedures are detailed in the Data Validation Manual as 
a separate document. When the database has been declared to be complete and accurate, the database 
will be locked. Any changes to the database after data have been locked can only be made with the approval 
of the Sponsor 
  
All analyses outlined in this document will be carried out after the following have occurred: 
• 
All data management requirements are met according 
standard operating procedures, 
including data entry, performance of edit and validation checks, documentation and resolution of 
data queries, and database lock with written authorization provided by 
 
Sponsor personnel. 
• 
Protocol deviations have been identified and status defined (major/minor deviations). 
• 
Analysis populations have been determined. 
• 
Randomized treatment codes have been unmasked. 
Please note that the database must be locked and all protocol deviations adjudicated as either major or 
minor prior to unmasking. 
6.2 
Output Data  
Data will be transferred to 
 and incorporated into standard formats following the Study Data 
Tabulation Model (SDTM). Data will then be mapped to analysis datasets using the Analysis Data Model 
(ADaM).  Both SDTM- and ADaM-formatted data will be used to create the subject listings, while all tables 
and figures will be based on the ADaM-formatted data.  
 
 
 
 
  
 


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7 
Analysis Populations 
7.1 
Intent-to-Treat 
The intent-to-treat (ITT) population includes all randomized subjects. All efficacy analyses will be performed 
on the ITT population, and subjects will be analyzed as randomized. 
7.2 
Per Protocol 
The per-protocol (PP) population includes subjects in the ITT population who do not have significant 
protocol deviations likely to seriously affect the efficacy measures of the study. Protocol deviations will be 
assessed prior to database lock and unmasking. Subjects in the PP population will be analyzed as treated. 
The t-test analyses on the composite score of eyelid margin redness, eyelid debris, and eyelid discomfort 
will be conducted using the PP population as an additional analysis to assess efficacy when subjects strictly 
comply with the protocol. In the event that the ITT and PP populations are the same, this analyses will not 
be performed. 
7.3 
Safety 
The Safety population includes all randomized subjects who have received at least one dose of the 
investigational product. Subjects in the Safety population will be analyzed as treated. 
8 
General Statistical Considerations 
8.1 
Unit of Analysis 
The unit of analysis for the final analysis in this study will be the study eye, fellow eye, and both eyes for all 
summaries of efficacy and ocular safety assessments performed by eye (VA, SLE, IOP, dilated 
ophthalmoscopy). The study eye will be the eye with the highest composite score in Eyelid Margin Redness, 
Eyelid Debris, and Eyelid Discomfort 
at the Baseline/Day 1 study visit, or the right eye 
(OD) if both eyes of a subject have the same score at baseline. The contralateral eye will be considered as 
the fellow eye; however, no analyses will be conducted specifically for the contralateral eyes. Instead as 
stated above, analyses by both eyes will be conducted given the bilateral nature of the dosing and the 
inclusion criteria requiring both eyes to qualify. Additionally, AEs, medical history, and concomitant 
medications will be presented at the subject level.  
8.2 
Missing or Inconclusive Data Handling 
Efficacy analyses will be primarily based on the ITT population with observed data only. To check for 
robustness of outcomes, missing data will be imputed using last time consistent (pre- and post-eyelid scrub) 
observation carried forward for the composite endpoint analysis by eye.  
AEs with completely missing onset dates will be considered treatment-emergent. AEs with a missing month 
and day of onset will be considered treatment-emergent unless the onset year is prior to the year of first 
dose of study treatment. AEs with a missing day of onset will be considered treatment-emergent unless (1) 
the onset year is prior to the first dose of study treatment or (2) the onset year is the same as the year of 
first dose of study treatment and the onset month is prior to the month of first dose of study treatment. AEs 




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Statistical programming and analyses will be performed using SAS® Version 9.4 or higher. Output will be 
provided in rich text format (RTF) for tables and portable document format (PDF) for tables, listings, and 
figures using landscape orientation. All study data will be listed by subject, treatment, and visit (as 
applicable) based on all randomized subjects unless otherwise specified. 
Change from baseline will be provided as summaries for continuous and ordinal efficacy (Eyelid Margin 
Redness, Eyelid Debris, and Eyelid Discomfort, along with the composite scores; 
 
 
 
. Summaries for continuous variables 
will include the number of observations (n), arithmetic mean, standard deviation (SD), standard error of the 
mean (SEM), 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 standard errors of the mean will be presented to two 
additional decimal places than reported in the raw values. Summaries for discrete and ordinal efficacy 
(Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort, along with the composite score) variables 
will include frequency counts and percentages. All percentages will be rounded to one decimal place (i.e., 
XX.X%). For continuous variables, the differences between active treatment groups and placebo will be 
calculated as Active – Placebo using descriptive statistics and two-sample Student’s t-distribution CIs and 
p-values. Within one group, change from baseline will be calculated as Follow-up Visit – Baseline using 
descriptive statistics and one-sample Student’s t-distribution CIs and p-values; differences in mean change 
from baseline scores between treatment groups will be summarized including 95% t-distribution CIs around 
the differences in mean. Summaries will be presented for each post-baseline visit. These summaries will 
be completed separately for the pre-scrub and post-scrub assessments. For discrete variables, binomial 
proportions and Clopper-Pearson CIs will be used to compare follow-up visit to baseline within each 
treatment group; Fisher’s Exact Test will be used to compare the categorical endpoints between treatment 
groups. 
All assessments will be summarized by study eye, fellow eye, and by both eyes, unless specifically stated. 
When the assessments need to be presented in both eyes, for continuous variables, between group CIs 
and p-values will come from a mixed effects linear model for each post-baseline visit 
Confidence intervals (CI) for differences between treatment groups will be two-sided at 95% confidence.  
P-values may also be presented for change from baseline values, however the study is not powered to 
show significance for these. 
Unless otherwise specified, summaries will be presented by treatment group and, where appropriate, visit.  
8.5 
Adjustments for Multiplicity 
No adjustments for multiplicity will be made for this early phase study.  


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9 
Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized, completed the study, and discontinued from the study. Subjects who complete the Day 28/Exit 
Visit will be considered study completers. Disposition will be summarized by treatment group and for all 
subjects. 
The total number of screened subjects with the number and percentage of screen failure subjects. The 
reasons for screen failure will be displayed with the percentages calculated using total number of screen 
failures as the denominator. The number of subjects in each of the analysis populations (ITT, PP, and 
Safety) will be displayed by treatment and percentages will be calculated using randomized subjects as the 
denominator. 
The number and percentage of subjects prematurely discontinued from the study and the reasons for study 
discontinuation will be summarized by treatment group for all randomized subjects. The reasons for study 
discontinuation that will be summarized include: AE, lost to follow-up, physician decision, protocol violation, 
study terminated by Sponsor, withdrawal by subject, and other. A subject listing will be provided that 
includes the date of and reason for premature study discontinuation and masking/unmasking information. 
The number and percentage of subjects with major protocol deviations will be summarized by treatment 
group for all randomized subjects. The protocol deviations that will be summarized include: informed 
consent, inclusion/exclusion and randomization, test article/study drug instillation and assignment at site, 
improper protocol procedures at site (missed, repeated, no per protocol), site’s failure to report serious 
adverse event (SAE)/AE, visit out of window, subject’s non-compliance with test article/study drug, subject’s 
use of prohibited concomitant medication, subject’s failure to follow instructions, and other. A subject listing 
will be provided that includes the date of the deviation, the deviation code, the deviation description, and 
the classification of whether the deviation was judged to be major or minor. 
In addition, subject listings will be provided that include informed consent date, inclusion and exclusion 
criteria violations, and exclusions from each population. 
10 Demographic and Pre-treatment Variables 
10.1 Demographic Variables 
The demographic variables collected in this study include age, gender (including childbearing potential for 
female subjects), race, and ethnicity. 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 and Safety 
populations, separately. 
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics.  Age will 
also be categorized as follows:  <65 years and ≥65 years.  Age will be reported in years and calculated 
using the following formula: 


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Age = (Informed Consent Date – Date of Birth) / 365.25, truncated as an integer 
The number and percentage of subjects will be presented, overall and by treatment, for age category, 
gender, race, and ethnicity.   
A subject listing that includes all demographic variables will be provided. 
10.2 Baseline Characteristics 
 
 
The following screening visit assessments will be summarized by study eye and all eyes using 
the appropriate set of statistics in the ITT population: 
 
 BCVA; 
 Eyelid 
Margin Redness Scale, Eyelid Debris Scale, 
, 
 
 slit lamp biomicroscopy 
eyelid, conjunctiva, cornea, lens, iris, pupil, and anterior chamber assessments; 
 
IOP; and dilated ophthalmoscopy vitreous, retina, macula, choroid, and optic nerve assessments along with 
cup-to-disc ratio in the horizontal and vertical dimensions. Further details about these assessments are 
given later in the SAP.  
A subject listing that includes all pre-treatment variables will be provided. 
11 Medical History and Concomitant Medications 
11.1 Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 22.0. 
Non-ocular medical history will be summarized using discrete summary statistics and presented by 
treatment group at the subject and event level by System Organ Class (SOC) and Preferred Term (PT) 
using the ITT population. Ocular medical history will be similarly summarized at the subject level. If a subject 
reports the same PT multiple times within the same SOC, that PT will only be reported once within that 
SOC. As with the PT, if a subject reports multiple conditions within the same SOC, that SOC will only be 
reported once.  
Listings of medical history will be generated separately for ocular and non-ocular data. 
11.2 Concomitant Medications 
Concomitant medications will be coded using World Health Organization (WHO) Drug Dictionary (Global 
B3, March 2019) and summarized to the therapeutic drug class (Anatomical Therapeutic Chemical [ATC] 
4 classification) and preferred name. If the ATC 4 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) 


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then the drug name will be summarized as the preferred name. Any uncoded terms will be summarized 
under the ATC classification and preferred name of “Uncoded.” 
Concomitant medications are defined as those medications listed as having been taken (1) prior to initiation 
of study drug administration and continuing for any period of time following the first administration of study 
drug or (2) at any time following the first administration of study drug. 
Concomitant medications will be summarized using the ITT population separately for ocular and non-ocular 
data. Medications will be tabulated for each treatment group using frequencies and percentages. Subjects 
may have more than 1 medication per ATC text. At each level of subject summarization, a subject will be 
counted once if he/she reports 1 or more medications. Percentages will be based on the number of subjects 
in each treatment group. Listings of prior and concomitant medications will be generated separately for 
ocular and non-ocular medications. 
12 Dosing Compliance and Treatment Exposure 
12.1 Dosing Compliance 
Dosing compliance (% compliance) will be assessed by calculating the number of actual doses received 
and comparing that to the number of expected doses as follows: 
Compliance (%) = 100% × Number of doses received
Number of expected doses 
The number of doses received will be determined through a review of the subject diary and the in-office 
applications. The number of expected doses is 14 for subjects assigned to Cohort 1 and 28 for subjects 
assigned to Cohort 2. 
 
 
Dosing compliance (%) will be summarized with continuous descriptive statistics for each treatment group, 
using the ITT population. The compliance category defined above will be summarized with discrete 
summary statistics.  
A subject listing of dosing compliance, including eyelid scrub data, will also be produced. 
12.2 Treatment Exposure 
Extent of treatment exposure for completed or discontinued subjects will be calculated in days using the 
following: 
Extent of Exposure (days) = (Date of Last Dose – Date of Baseline/Day 1 Visit) + 1 
Extent of treatment exposure for subjects who were lost to follow-up will be calculated in days using the 
following: 
Extent of Exposure (days) = (Date of Last Recorded Visit – Date of Baseline/Day 1 Visit) + 1 




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13.3 Eyelid Assessments 
13.3.1 
 EYELID DISCOMFORT 
Eyelid Discomfort is subject-reported based on a four-point scale with responses of 0 = No 
eyelid discomfort, 1 = Mild 
 
, 2 = Moderate 
 
 
, and 3 = Severe 
 
. 
13.3.2 
 EYELID MARGIN REDNESS 
After assessing eyelid discomfort, the Investigator assesses and grades eyelid margin redness based on 
the following scale: 0 = None: 
 1 = Mild: 
 
 2 = Moderate: 
 and 3 = Severe: 
 
 
13.3.3 
 EYELID DEBRIS 
After accessing eyelid discomfort and eyelid margin redness, the Investigator assesses and grades eyelid 
debris based on the following scale: 0 = None: 
1 = Mild: 
 
 2 = Moderate: 
 3 = Severe: 
 
 








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15 Safety Analyses 
All safety analyses will be conducted using the Safety population. 
15.1 Adverse Events 
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.  
Treatment-emergent adverse events (TEAE) are defined as any event that occurs or worsens on or after 
the day that randomized study treatment is initiated. Adverse events recorded in the eCRF which began 
prior to treatment will not be included in the summary tables but will be included in the AE data listings. 
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 
Adverse events missing severity will be counted as severe. 


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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 application 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 application, 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 application, corresponds to a known effect of the study 
medication, is confirmed by the observation of an improvement upon discontinuation of the study 
medication application, 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 application, corresponds to a known effect of the category 
of the studied medication, is confirmed by the observation of an improvement upon discontinuation 
of the study medication, and no other reasonable cause exists. 
Treatment-emergent adverse events possibly, probably, or definitely related to study drug will be 
considered treatment-related TEAEs. Any TEAEs with a missing relationship will be considered treatment-
related TEAEs. 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death; 
• 
Results in-subject hospitalization or prolongation of existing hospitalization; 
• 
Results in persistent or significant disability/incapacity; 
• 
Results in a congenital anomaly/birth defect; 
• 
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); or 
• 
Results in a significant and persistent loss or impairment of vision. 


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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. 
An overall summary will be presented that includes the number of events and the number and percentage 
of subjects who experienced at least one AE and TEAE, by treatment group and over all subjects. This 
summary will also include breakdowns of TEAEs further categorized as treatment-related TEAEs, serious 
AEs (SAE), TEAEs leading to early treatment discontinuation, TEAEs leading to death, and TEAEs by 
maximum severity. 
Additional summaries of TEAEs will be provided showing the number of events and the number and 
percentage of subjects who experienced at least one TEAE by treatment group and over all subjects. Ocular  
and Non-ocular TEAEs will be summarized together using discrete summary statistics and presented by 
treatment group at the subject and event level by SOC and PT. If a subject reports the same PT multiple 
times within the same SOC, that PT will only be reported once within that SOC. As with the PT, if a subject 
reports multiple conditions within the same SOC, that SOC will only be reported once. In the summary, 
SOCs will be listed in ascending alphabetical order; PTs will be listed in order of descending frequency for 
all subjects within each SOC.   
Separate summaries will be provided for the following categories of AEs: 
• 
Treatment-Related TEAEs 
• 
TEAEs by Relationship to Study Drug 
• 
TEAEs by Maximal Severity 
The number of subjects with any TEAEs (along with percentages) will be tabulated by SOC and PT within 
each SOC by treatment group. To count the number of subjects with any TEAEs, if a subject has multiple 
TEAEs coded to the same PT within the same SOC, the subject will be counted once under the maximum 
severity. 
All TEAEs will be presented in a subject listing. The TEAEs leading to study treatment discontinuation will 
be listed separately. In addition, all SAEs will be presented in a separate listing. 
15.2 Best Corrected Visual Acuity 
Best corrected visual acuity will be measured by trained personnel prior to slit-lamp examination and dilating 
the eyes with the subject wearing their habitual correction or with pinhole refraction. 
Testing of both eyes is done at a distance of 4 meters from the visual acuity ETDRS (Early Treatment of 
Diabetic Retinopathy Study) chart. The chart should be at a comfortable viewing angle. The right eye (chart 
1) will be tested first then the left eye (chart 2). The eye not being tested will be properly occluded. 
The observed and change from baseline BCVA will be summarized using continuous descriptive statistics 
by visit for each treatment group and for all actively treated subjects. A subject listing of BCVA will be 


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produced. 
 
 
15.3 Intraocular Pressure 
Intraocular pressure will be measured by qualified study site personnel at each specified visit using a 
Goldmann applanation tonometer affixed to a slit lamp and in accordance with the site’s standard practice. 
Two measurements will be obtained, and the mean of the two readings will be calculated and recorded. If 
the first two measurements differ by more than 2 mmHg, a third measurement will be obtained and the 
median IOP will be recorded. 
The IOP values and changes from baseline for each eye (study eye and all eyes) will be summarized using 
continuous descriptive statistics by visit and eye for each treatment group and for all actively treated 
subjects. A subject listing of IOP will also be produced.  
15.4 Slit Lamp Biomicroscopy Examination 
The slit lamp examination will be performed prior to any contact assessments and instillation of any drops 
at each specified visit. 
 
 The following structures will be examined at each visit: eyelid (other than eyelid margin 
redness and eyelid debris), conjunctiva 
 cornea, lens, iris, pupil, and 
anterior chamber. 
A subject listing of the slit lamp biomicroscopy parameters will also be produced. 
 
  
17 Changes from Protocol Stated Analyses 
The protocol describes analyses pooling just the placebo arms from Cohorts 1 and 2; however, the SAP 
includes analyses pooling both the placebo arms from each cohort and the NCX 4251 arms from each 
cohort. 
The protocol describes AE summaries separately for ocular and non-ocular AEs. Given the low number of 
expected AEs overall, the SAP combines summaries of ocular and non-ocular AEs. The separation of AEs 
by SOC will clearly identify which AEs are ocular and which are not. 
18 References 
There are no references for this SAP. 
19 Revision History 
The following revisions were made to version 1.0 of the SAP, after approval of version 5.0 of the study 
protocol.