Clinical trial NCT04675242
Conditions: Blepharitis
Sponsor: Nicox Ophthalmics, Inc.
Start date: 2020-12-14; Completion date: 2021-06-30
Enrollment: 224 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, randomized, double-masked, placebo-controlled, Phase 2b trial evaluating the safety and efficacy of NCX 4251 (fluticasone propionate nanocrystal) Ophthalmic Suspension 0.1% QD for the treatment of acute exacerbations of blepharitis.

Detailed description:

Arms: arm 1: NCX 4251 Ophthalmic Suspension arm 2: Vehicle of NCX 4251 Ophthalmic Suspension
Interventions: intervention 1: NCX 4251 intervention 2: Placebo
Intervention descriptions: intervention 1: NCX 4251 Ophthalmic Suspension, 0.1% dosed once daily intervention 2: Vehicle of NCX 4251 Ophthalmic Suspension dosed once daily

Protocol documents:
Prot_000.pdf: 
NCX-4251-02 version 4.0; 24-Mar-2021 
Page 1 of 74 
Nicox Ophthalmics, Inc. 
4721 Emperor Blvd., Durham, North Carolina 27703  USA 
Compound: 
NCX 4251 
Study Number: 
NCX-4251-02 
Study Title: 
A Multi-Center, Randomized, Double-Masked, Placebo-Controlled, Phase 2b Study  
Evaluating the Safety and Efficacy of NCX 4251 (Fluticasone Propionate Nanocrystal) 
Ophthalmic Suspension, 0.1% QD for the Treatment of Acute Exacerbations of Blepharitis 
(Mississippi) 
PROTOCOL 
Version # 4.0 
Released on 24-March-2021 
Clinical Development Phase: 
2b 
Sponsor: 
Nicox Ophthalmics, Inc. 
4721 Emperor Blvd. 
Durham, North Carolina 27703 – USA 
CONFIDENTIAL 
This document contains confidential information, which is not to be divulged in any way 
unless previously authorized by Nicox Ophthalmics, Inc. 
NCT04675242 




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NCX-4251-02 version 4.0; 24-Mar-2021 
 
Page 3 of 74 
 
CONTACT INFORMATION 
 
Protocol Identification 
A Multi-Center, Randomized, Double-Masked, Placebo-Controlled, Phase 2b Study Evaluating 
the Safety and Efficacy of NCX 4251 (Fluticasone Propionate Nanocrystal) Ophthalmic 
Suspension, 0.1% QD for the Treatment of Acute Exacerbations of Blepharitis (Mississippi) 
Version #4.0 released on 24-March-2021 
 
 
Sponsor: 
Nicox Ophthalmics, Inc. 
4721 Emperor Blvd. 
Durham, NC 27703 USA 
 
Sponsor Contact: 
José L. Boyer, PhD– Vice President, Head of Research and Development 
Mobile: 
1-919-423-0747 
Email: 
boyer@nicox.com 
 
 
Company Representing the Sponsor: 
  
  
 
 
 
 
 
  
 
Primary Contact for Study Related Matters and SAEs: 
 
 
 
 
 
 
Medical Monitor: 
 
 
  
 
 
 
 
 




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Page 5 of 74 
TABLE OF CONTENTS 
Page 
CONTACT INFORMATION ......................................................................................................... 3 
PROTOCOL HISTORY TABLE .................................................................................................... 4 
TABLE OF CONTENTS ................................................................................................................ 5 
LIST OF ABBREVIATIONS.......................................................................................................... 8 
STUDY OUTLINE / PROTOCOL SYNOPSIS ............................................................................ 10 
1.
INTRODUCTION ......................................................................................................... 20 
1.1 
Background and Rationale................................................................................... 20 
1.2 
Study Background ............................................................................................... 21 
1.3 
Potential Risks and Benefits to Human Subjects ................................................. 23 
1.3.1 
Results of NCX-4251-01 ........................................................................ 23 
1.3.1 
Risks Associated with Other Ophthalmic or Topical Dermal 
Steroids ................................................................................................... 23 
2.
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 25 
2.1 
Study Objectives .................................................................................................. 25 
2.2 
Study Endpoints ................................................................................................... 25 
2.3 
Efficacy Evaluations ............................................................................................ 25 
2.4 
Safety Evaluations ............................................................................................... 26 
2.5 
Review of Safety Data by Medical Monitor ........................................................ 26 
3.
STUDY DESIGN .......................................................................................................... 27 
3.1 
Overall Study Design........................................................................................... 27 
4.
SUBJECT SELECTION ............................................................................................... 28 
4.1 
Number of Subjects and Sites .............................................................................. 28 
4.2 
Subject Population Characteristics ...................................................................... 28 
4.3 
Inclusion Criteria ................................................................................................. 28 
4.4 
Exclusion Criteria ................................................................................................ 28 
5.
CONCOMITANT MEDICATION(S) .......................................................................... 31 
5.1 
Previous and Concomitant Medication(s) ........................................................... 31 
5.2 
Prohibited Medication(s) and Procedures ............................................................ 31 
6.
STUDY SUPPLIES ....................................................................................................... 32 
6.1 
Description of Study Medication ......................................................................... 32 
6.2 
Packaging of the Study Medication ..................................................................... 32 
6.3 
Labeling of the Study Medication ....................................................................... 32 


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6.4 
Storage of the Study Medication ......................................................................... 32 
6.5 
Accountability of Study Medication .................................................................... 33 
6.6 
Assigning Subjects to Treatment ......................................................................... 33 
6.7 
Emergency Subject Unmasking ........................................................................... 33 
6.8 
Study Medication Dispensing and Collection ..................................................... 34 
6.9 
Instructions for Eyelid Scrubs ............................................................................. 34 
6.10 
Instructions for Use and Application of Study Medication ................................. 34 
6.11 
Compliance with Eyelid Scrubs and Study Medication ...................................... 35 
6.12 
Return of Study Medication by the Clinical Sites ............................................... 35 
6.13 
Other Study Supplies ........................................................................................... 35 
7.
STUDY PROCEDURES BY VISIT ............................................................................. 36 
7.1 
Screening Visit (Day -14 to -7) ........................................................................... 36 
7.2 
Baseline/Day 1 Visit ............................................................................................ 37 
7.3 
Day 4 (± 1 day) Visit ........................................................................................... 38 
7.4 
Day 8 (± 1 day) and Day 11 (± 1 day) Visits ....................................................... 38 
7.5 
Day 15 (- 1 day) Visit .......................................................................................... 39 
7.6 
Day 29 (± 2 days)/Exit Visit ................................................................................ 40 
7.7 
Unscheduled Visits .............................................................................................. 40 
8.
SCREEN FAILURES, COMPLETION AND DISCONTINUATION ........................ 42 
8.1 
Subject Screen or Eligibility Failures .................................................................. 42 
8.2 
Subject Completion ............................................................................................. 42 
8.3 
Subject Early Discontinuation ............................................................................. 42 
8.4 
Subject Lost to Follow-up ................................................................................... 42 
8.5 
Study Termination ............................................................................................... 43 
9.
PROTOCOL COMPLIANCE ....................................................................................... 44 
10.
ADVERSE EVENTS .................................................................................................... 45 
10.1 
Adverse Event Definition .................................................................................... 45 
10.2 
Severity of Adverse Event ................................................................................... 45 
10.3 
Causal Relationship with Study Medication........................................................ 45 
10.4 
Serious Adverse Events ....................................................................................... 46 
10.5 
Adverse Event Reporting..................................................................................... 46 
10.6 
Serious Adverse Event Reporting ........................................................................ 47 
11.
STATISTICAL CONSIDERATIONS AND METHODS OF ANALYSIS ................. 48 
11.1 
Determination of Sample Size and Power Calculations ...................................... 48 
11.2 
Analysis Population ............................................................................................. 49 


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11.3 
Data Display ........................................................................................................ 49 
11.4 
Collection and Derivation of Efficacy Assessments ........................................... 49 
11.5 
Hypothesis and Methods of Analysis .................................................................. 50 
11.5.1 Efficacy Analyses ................................................................................................ 50 
11.5.2 Safety Analyses ................................................................................................... 51 
11.5.3 Interim Analysis .................................................................................................. 52 
12.
EMERGENCY PROCEDURES ................................................................................... 53 
12.1 
Emergency Contact Procedure ............................................................................ 53 
12.2 
Procedure in Case of Pregnancy .......................................................................... 53 
13.
STUDY MANAGEMENT ............................................................................................ 54 
13.1 
Monitoring ........................................................................................................... 54 
13.2 
Source Documents ............................................................................................... 54 
13.3 
Source Data Verification ..................................................................................... 55 
13.4 
Completion of Electronic Case Report Forms ..................................................... 55 
13.5 
Data Management ................................................................................................ 55 
13.6 
Audits and Inspections......................................................................................... 55 
13.7 
Access to Source Data ......................................................................................... 55 
13.8 
Training of Staff .................................................................................................. 56 
13.9 
Changes to the Protocol ....................................................................................... 56 
14.
ADMINISTRATIVE, LEGAL, AND ETHICAL ASPECTS ....................................... 57 
14.1 
Conduct of the Trial ............................................................................................. 57 
14.2 
Ethical Principles ................................................................................................. 57 
14.3 
Health Authorities and Institutional Review Board (IRB) .................................. 57 
14.4 
Subject Information and Consent ........................................................................ 57 
14.5 
Confidentiality Regarding Trial Subjects Data.................................................... 58 
14.6 
Archiving at the End of the Study ....................................................................... 58 
14.7 
Coordinating Investigator .................................................................................... 58 
15.
PUBLICATION POLICY ............................................................................................. 59 
16.
REFERENCES .............................................................................................................. 60 
APPENDIX 1: TIME AND EVENTS TABLE ............................................................................. 62 
APPENDIX 2: METHODS OF CLINICAL EVALUATION ...................................................... 64 
APPENDIX 3: GENERAL INSTRUCTIONS FOR COMPLETION OF SAE FORMS ............. 73 






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STUDY OUTLINE / PROTOCOL SYNOPSIS 
 
Title 
A Multi-Center, Randomized, Double-Masked, Placebo-Controlled, Phase 2b 
Study Evaluating the Safety and Efficacy of NCX 4251 (Fluticasone Propionate 
Nanocrystal) Ophthalmic Suspension, 0.1% QD for the Treatment of Acute 
Exacerbations of Blepharitis (Mississippi) 
Study No. 
NCX-4251-02 
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 to the 
site of the inflammation at the eyelid margin. Nicox Ophthalmics, Inc. (Nicox) 
developed a novel formulation and route of delivery consisting of applying 
NCX 4251 directly to the eyelids designed to minimize the intraocular exposure to 
fluticasone. 
The safety and tolerability of NCX 4251 ophthalmic suspension, 0.1% in subjects 
with an acute exacerbation of blepharitis and signs and symptoms of dry eye 
disease was evaluated in a multi-center, randomized, double-masked, placebo-
controlled, two-cohort, phase 2 study (NCX-4251-01). In Cohort 1 of the study, 
15 subjects with ongoing active signs and symptoms of blepharitis evidenced by 
elevated eyelid discomfort, eyelid redness and eyelid debris accompanied by 
concurrent signs and symptoms of dry eye were randomized to NCX 4251 
ophthalmic suspension 0.1% or placebo (2:1 ratio, 10 subjects on NCX 4251 and 
5 subjects on placebo). Subjects additionally performed daily eyelid scrubs with 
baby shampoo and were treated once daily (QD) for 14 days, followed by a 14-day 
eyelid scrubs only safety follow-up period. In Cohort 2, 21 subjects were 
randomized to NCX 4251 Ophthalmic Suspension 0.1% twice daily (BID) or 
placebo BID (1:1 ratio) and performed daily lid scrubs with baby shampoo and 
were treated for 14 days, followed by a 14-day eyelid scrubs only safety follow-up 
period. The interim analysis performed on Cohort 1 indicated that NCX 4251 and 
the new route of administration were well tolerated, and that no clinically relevant 
intraocular pressure (IOP) elevations were observed in the study. Although the 
study was not powered for efficacy, changes in magnitude of clinical relevance 
were observed in signs and symptoms of blepharitis and dry eye. 
 
 
 
 
 
 
 
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, 2012). While generally not sight-threatening, blepharitis can induce 


CONFIDENTIAL 
NCX-4251-02 version 4.0; 24-Mar-2021 
 
Page 11 of 74 
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).  
Even though the treatment of chronic blepharitis remains controversial, palpebral 
neutral shampoo cleaning has been the most widely accepted medical therapy in the 
U.S., followed by the use of antibiotic, or combination of antibiotic and steroid 
ointments. Short courses of topical steroids have been found beneficial for 
symptomatic relief in cases with clinically significant ocular inflammation in acute 
exacerbations of all forms of blepharitis (Lindsley et al, 2012; 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 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 tri-fluorinated corticosteroid of medium potency (class III) 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 
is thought to be its 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. 
FP is marketed for the treatment of asthma (Flovent® HFA, NDA 021433, Advair® 
DISKUS®, NDA 021077), rhinitis (Flonase® NDA 020121), and atopic dermatitis 
(Cutivate®, NDA 021152).   
Nicox is developing NCX 4251 for the treatment of acute exacerbations of 
blepharitis to address the current unmet medical need. 
Study Period 
Q4 2020 to Q4 2021 
Study Phase  
Phase 2b 






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Page 14 of 74 
7) 
have a history of IOP elevation with steroid use (i.e., steroid responder); 
8) 
unable or unwilling to discontinue the use of contact lenses from Screening to 
Day 29/Exit Visit; 
9) 
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 15 Visit; 
10) cosmetic eyelash procedures (e.g., eyelash curling) from the Screening Visit up 
to the Day 15 Visit, or a history of permanent/semi-permanent eye make-up 
procedure (e.g., eyelash extensions / false eyelashes, eyelash tinting, eyeliner 
tattooing) within 30 days of the Screening Visit or planned procedure during 
the study period; 
11) have permanent punctal plugs or history of nasolacrimal obstruction; 
12) have a history of ocular surgical intervention within 6 months prior to the 
Screening Visit or any planned ocular procedure during the study period; 
13) have known hypersensitivity to fluticasone propionate, to any other component 
of the study medication, or to ophthalmic diagnostic dyes 
 
 
14) use strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, 
atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, 
saquinavir, ketoconazole, telithromycin); 
15) unable or unwilling to discontinue use of any non-diagnostic ophthalmic 
treatments (topical, intraocular or systemic) including topical autologous serum 
eyedrops, artificial tears and ocular lubricants. Subjects should not have used 
artificial tears or ocular lubricants for at least 24 hours prior to the Screening 
Visit, and for at least 30 days for all other ophthalmic medications; 
16) 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 routine 
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; 
17) have a history of meibomian gland probing within 3 months prior to the 
Screening Visit; 
18) use of any corticosteroid agent or anabolic steroid within 30 days of the 
Screening Visit or during the study treatment period; 
19) use of isotretinoin or any other retinoids within 12 months of the Screening 
Visit; 
20) have any uncontrolled systemic disease or debilitating disease (e.g., 
cardiovascular disease, hypertension, diabetes, cystic fibrosis) in the opinion of 
the Investigator; 
21) have thyroid ophthalmopathy, rosacea or seborrheic dermatitis; 
22) have any auto-immune disease (e.g., rheumatoid arthritis, lupus, Sjogren’s, 
graft-versus-host disease (GVHD)). Note: Patients with controlled, mild 
rheumatoid arthritis without any other component (e.g., psoriatic) are allowed 






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Page 17 of 74 
a two-sided significance level of 0.025 using a two-sample t-test. 
The study will be considered a success and NCX 4251 will be claimed to be 
superior to placebo in the proportion of subjects with complete cure (score =0) in 
the composite (sum) of Eyelid Margin Redness, Eyelid Debris, and Eyelid 
Discomfort at Day 15 if the primary endpoint is demonstrated to be statistically 
significant in favor of NCX 4251. 
Statistical inference will be made on the two secondary endpoints only if the 
primary endpoint demonstrates statistical significance in favour of NCX 4251.  
Multiplicity correction within the two secondary efficacy endpoints will be 
completed using Hochberg’s procedure.  
 
Summaries for continuous variables will include the sample size, mean, standard 
deviation, standard error, median, minimum, and maximum. Summaries for 
discrete variables will include frequency counts and percentages. The Baseline 
measure will be defined as the last non-missing measure prior to initiation of study 
treatment.  Baseline value will be the last non-missing measure prior to initiation 
of study treatment.  Analyses will be completed on the study eye and fellow eye 
separately.  Additional analyses may be completed using both eyes within a model 
accounting for the correlation between eyes within a subject and will be detailed in 
the formal statistical analysis plan. 
 
 
 
Efficacy analyses 
Complete cure (score =0) in the composite (sum) of Eyelid Margin Redness, 
Eyelid Debris, and Eyelid Discomfort will be summarized using discrete summary 
statistics (frequency counts and percentages) as well as two-sided 95% Clopper-
Pearson confidence intervals by treatment group. The primary efficacy analyses 
will test the difference in the proportion of study eyes with complete cure in the 
composite score between NCX 4251 Ophthalmic Suspension and placebo at Day 
15 using a generalized estimating equation model with complete cure as the 
response, treatment as a fixed effect and baseline composite score as a covariate.  
The, marginal proportions and difference in proportions along with the 
corresponding two-sided 95% Confidence Intervals (CIs) and p-value will be 
presented. 
Secondarily, differences (NCX 4251 Ophthalmic Suspension minus placebo) 
between treatment groups will be summarized using difference in proportions, 95% 
asymptotic confidence intervals around the differences in proportions, and 
Pearson’s chi-squared test. 
 
  
 
 
 
 
 
 


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Page 18 of 74 
 
 
  
 
 
 
 
 
 
 
 
 
Secondary endpoints will be summarized using continuous summary statistics (n, 
mean, standard deviation, standard error, median, minimum, and maximum) as 
well as two-sided 95% t-distribution confidence intervals around the mean by 
treatment group. The primary analysis of the secondary endpoints will employ a 
linear model with mean change from baseline in Eye Dryness evaluated on the 
VAS and mean change from baseline in Fluorescein Staining of the inferior cornea 
at Day 15 as the response and baseline eye dryness as a covariate.  Least squared 
means and differences between treatment groups, along with corresponding 95% 
CIs and p-values will be presented. 
 
 
 
 
 
 
 
 
 
 
 
Safety analyses 
Adverse events (AEs) will be coded using the MedDRA dictionary. The safety 
analysis will summarize treatment emergent ocular and systemic AEs for all 
treated subjects, using discrete summaries at the subject and event level by system 
organ class and preferred term for each treatment group. 
A treatment-emergent AE (TEAE) is defined as an AE that occurred on or after the 
treatment was initiated.  Ocular TEAEs by treatment group: NCX 4251 0.1% and 
placebo will be summarized, by relationship to study drug, and by severity. Non-
ocular TEAEs will be summarized by treatment group as follows: non-ocular 
TEAEs, by relationship to study, and by severity. Serious AEs (SAEs), AEs 
resulting in study drug discontinuation, and deaths will be presented in data 
listings.  
Other ocular safety data including visual acuity, slit-lamp biomicroscopy, IOP, and 
dilated ophthalmoscopy will be summarized by treatment group and visit using 


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Page 19 of 74 
descriptive statistics. 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.  


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Page 20 of 74 
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 and dry eye disease by topical application directly to the site of the inflammation at 
the eyelid margin.  Nicox Ophthalmics, Inc. (Nicox) developed a novel formulation and route 
of delivery consisting of applying NCX 4251 directly to the eyelids designed to minimize the 
intraocular exposure to fluticasone. 
The safety and tolerability of NCX 4251 (fluticasone propionate nanocrystal) ophthalmic 
suspension, 0.1% in subjects with an acute exacerbation of blepharitis and signs and symptoms 
of dry eye disease was evaluated in a multi-center, randomized, double-masked, placebo-
controlled, two-cohort, phase 2 study (NCX-4251-01). In Cohort 1 of the study, 15 subjects 
with ongoing active signs and symptoms of blepharitis evidenced by elevated eyelid 
discomfort, eyelid redness and eyelid debris accompanied by concurrent signs and symptoms 
of dry eye were randomized to NCX 4251 ophthalmic suspension 0.1% or placebo (2:1 ratio, 
10 subjects on NCX 4251 and 5 subjects on placebo). Subjects additionally performed daily 
eyelid scrubs with baby shampoo and were treated QD for 14 days, followed by a 14-day 
eyelid scrubs only safety follow-up period. In Cohort 2, 21 subjects were randomized to 
NCX 4251 Ophthalmic Suspension 0.1% BID or placebo BID (1:1 ratio) and performed daily 
lid scrubs with baby shampoo and were treated for 14 days, followed by a 14-day eyelid scrubs 
only safety follow-up period. The interim analysis performed on Cohort 1 indicated that 
NCX 4251 and the new route of administration were well tolerated, and that no clinically 
relevant IOP elevations were observed in the study. Although the study was not powered for 
efficacy, changes of magnitude of clinical relevance were observed in signs and symptoms of 
blepharitis and dry eye. 
 
 
 
 
 
 
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, 2012). 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 


CONFIDENTIAL 
NCX-4251-02 version 4.0; 24-Mar-2021 
 
Page 21 of 74 
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 combination of antibiotic and steroid ointments. Short courses of 
topical steroids have been found beneficial for symptomatic relief in cases with clinically 
significant ocular inflammation in acute exacerbations of all forms of blepharitis (Lindsley et 
al, 2012; 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, 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 tri-fluorinated corticosteroid of medium potency (class III) 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 is thought to be its 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.  FP is marketed for the treatment 
of asthma (Flovent® HFA, NDA 021433, Advair® DISKUS®, NDA 021077), rhinitis (Flonase® 
NDA 020121), and atopic dermatitis (Cutivate®, NDA 021152).   
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 and the first-in-human clinical study performed with 
NCX 4251 can be found in the Investigator Brochure. 
Description of the Study Medication 
The study medication is a sterile, isotonic, buffered ophthalmic aqueous suspension containing 
NCX 4251 (fluticasone propionate nanocrystals) 0.1%. For further detail see Section 6.1. 


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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 is a multi-center, randomized, double-masked, placebo-controlled, 
Phase 2b study evaluating the safety and efficacy of NCX 4251 (fluticasone propionate 
nanocrystals) Ophthalmic Suspension, 0.1% QD for the treatment of acute exacerbations of 
blepharitis.  
The study design is the same as that used during the QD-dosing cohort of NCX-4251-01. 
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 
and skin formulations for decades. It is therefore most appropriate to use topical local 
applications of fluticasone propionate in the indication of blepharitis. A dosing paradigm has 
been developed by Nicox in order to apply NCX 4251 with an applicator directly at the site of 
the signs and symptoms of blepharitis, namely on the upper and lower eyelids as well as on the 
lower eyelid margin.  
Justification of the Dose Selection for NCX 4251 Ophthalmic Suspension 
Traditionally blepharitis has been treated by topical ocular steroids such as dexamethasone 
0.1% or loteprednol etabonate 0.5%. However, this route of administration results in a minimal 
dose being delivered to the site of the disease origin, the margin of the eyelid. With NCX 4251, 
the drug will be delivered directly to the site of the disorder. The starting dose was selected 
based on the combination of NCX 4251 potency compared to commonly used ophthalmic 
steroids and optimized target delivery to the eyelid margin. 
 
 
 
 
Based on similar efficacy but a higher incidence of 
adverse reactions with BID dosing, QD dosing has been selected for future development. 
Justification of the Placebo Control  
As there is currently no FDA-approved therapy specifically indicated for blepharitis and lack 
of efficacious standard of care, the use of a placebo control is justified. The placebo 
formulation is the vehicle of NCX 4251 Ophthalmic Suspension.   
Selection of the Study Population 
A total of approximately 200 male and female adults with a documented history of blepharitis 
for at least 6 months and who are currently experiencing an acute exacerbation of blepharitis in 
both eyes will be randomized in this clinical study conducted in the U.S. 


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1.3 
Potential Risks and Benefits to Human Subjects 
1.3.1 Results of NCX-4251-01 
To date, the safety and efficacy of NCX 4251 (fluticasone propionate) Ophthalmic Suspension 
has been evaluated in one dose-escalation Phase 2 trial (NCX-4251-01) in which 10 subjects 
received NCX 4251 0.1% QD, 5 subjects received placebo QD, 10 subjects received 
NCX 4251 0.1% BID, and 11 subjects received placebo BID. The results of NCX-4251-01 
indicated that efficacy in reducing the signs and symptoms of blepharitis (i.e., lid debris, eyelid 
redness, eyelid discomfort) and in temporarily relieving the signs and symptoms of dry eye 
disease were not enhanced with BID application of NCX 4251 relative to QD application; 
however, the proportion of subjects experiencing ocular adverse events was increased with 
BID application. 
 
 
 
 
 
 
 
 
1.3.1 Risks Associated with Other Ophthalmic or Topical Dermal Steroids  
As with other ophthalmic steroids, adverse reactions with NCX 4251 (fluticasone propionate) 
Ophthalmic Suspension may include elevated IOP, which may be associated with optic nerve 
damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary 
ocular infection from pathogens including herpes simplex, and perforation of the globe where 
there is thinning of the cornea or sclera (McGhee et al, 2002). 
These same risks pertain to NCX 4251 (fluticasone propionate) Ophthalmic Suspension which 
will be applied to the eyelid margins. Specifically, raised IOP and glaucoma have been 
associated with use of periorbital corticosteroids for dermatological conditions such as 
blepharitis and eczema (Garrot and Walland, 2004; Cubey 1976). 
Local adverse reactions which have been reported infrequently with topical (dermal) 
corticosteroids, and which may occur more frequently with higher potency corticosteroids 
include irritation, folliculitis, acneiform eruptions, hypopigmentation, perioral dermatitis, 
allergic contact dermatitis, secondary infection, skin atrophy, striae, and miliaria (Fluticasone 
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, 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 


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have no effect on HPA axis function and did not cause skin thinning even when used 
extensively over widespread, severe inflammatory disease (Herbert, 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 eyelid redness, ocular 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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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
The objective of this clinical study is to evaluate the safety and efficacy of NCX 4251 
Ophthalmic Suspension, 0.1% vs. placebo for the treatment of the signs and symptoms of an 
acute exacerbation of blepharitis. 
2.2 
Study Endpoints 
The following endpoints will be collected in the course of the study: 
 Signs and symptoms of blepharitis (Eyelid Debris, Eyelid Margin Redness and Eyelid 
Discomfort) 
 Eye Dryness using the Visual Analog Scale (VAS) 
 
 
 
 
 Corneal 
 Staining (Fluorescein 
 
 
 
 
 
 Ocular signs (as assessed by slit-lamp biomicroscopy) 
 IOP 
 Fundus assessments 
 BCVA 
 AEs 
2.3 
Efficacy Evaluations 
Primary Efficacy Endpoint 
 
Proportion of subjects with Complete Cure (Score 0) in each of the following: Eyelid Margin 
Redness, Eyelid Debris, and Eyelid Discomfort at the Day 15 Visit. 
Secondary Efficacy Endpoint 
 
Mean change from baseline in the Eye Dryness Symptoms using the VAS at the Day 15 Visit; 
 
Mean change from baseline in Fluorescein Staining of the inferior cornea at the Day 15 Visit. 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 


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2.4 
Safety Evaluations 
 The incidence of treatment emergent ocular and systemic AEs; 
 BCVA, IOP, ocular signs (as assessed by slit lamp biomicroscopy), and fundus 
assessments. 
2.5 
Review of Safety Data by Medical Monitor 
A review of the ocular and systemic safety data from each subject will be performed on an 
ongoing basis by the Medical Monitor. A subject may be discontinued from the study at any 
time for safety-related reasons at the discretion of the Principal Investigator, and/or a joint 
decision of the Medical Monitor and Sponsor, or for the reasons referenced in but not limited 
to Section 8.3. 
 


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3. 
STUDY DESIGN 
3.1 
Overall Study Design 
This is a multi-center, randomized, double-masked, placebo-controlled, Phase 2b study.  
Subjects will be assessed for initial eligibility at the Screening Visit (Day -14 to -7).  Eligible 
adult subjects with a documented 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 may be randomized into the study. 
A total of approximately 300 subjects will be screened such that 200 eligible subjects will be 
randomized in a 1:1 ratio to receive NCX 4251 Ophthalmic Suspension, 0.1% or placebo for 
both eyelids, QD. 
 
 
 
Study medication will be applied via a sterile applicator to the upper and lower eyelids and 
lower eyelid margin of both eyes once daily in the morning for 14 days. Subjects will also 
perform daily scrubs of the upper and lower eyelids of both eyes using diluted baby shampoo 
on a cotton swab prior to the application of the study medication. 
Study visits will be as follows: Screening (Day -14 to -7), Baseline/Day 1, Day 4 (± 1 day), 
Day 8 (± 1 day), Day 11 (± 1 day), Day 15 (- 1 day), and Day 29/Exit (± 2 days; follow up 
visit). 
Following the Screening Visit and prior to Baseline/Day 1 Visit, subjects will continue their 
previous routine for cleaning of eyelids that they were using prior to the Screening Visit. Both 
eyes will be treated from the Baseline/Day 1 Visit through the day prior to the Day 15 Visit. 
 
 
. From the Day 15 Visit through the day prior to the 
Day 29/Exit Visit, subjects will continue performing the eyelid scrubs.  
Study medication will be self-administered topically in the morning. 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 29/Exit 
Visit (± 2 days). The duration of subject participation (from the Screening Visit to the Exit 
Visit) is approximately 6 weeks. The overall study duration is estimated to be approximately 
12 months from the first subject enrolled until completion of the last subject. 


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4. 
SUBJECT SELECTION  
4.1 
Number of Subjects and Sites 
This study will be conducted at approximately 5 to 10 sites in the U.S. Additional sites may be 
added based on enrollment rates. Overall, approximately 300 subjects will be screened and 
200 subjects will be randomized into the study. 
4.2 
Subject Population Characteristics 
The target population in this study will be adult men and women with a documented history of 
blepharitis for at least 6 months and who are experiencing an acute exacerbation of blepharitis. 
4.3 
Inclusion Criteria 
Prior to inclusion in the study, each subject must fulfill all of the following criteria: 
1) be at least 18 years of age; 
2) have a documented history of blepharitis of at least 6 months; 
3) be currently experiencing signs and symptoms of blepharitis defined as a minimum score 
of ‘1’ for each of Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort 
 
at both the Screening and Baseline/Day 1 Visits.  
4) have a Best Corrected Visual Acuity (BCVA) of +0.60 logMAR (approximately 20/80 
Snellen) or better in each eye as measured using an ETDRS chart with the subject wearing 
their habitual correction or with pinhole refraction; 
5) be able to perform eyelid scrubs with diluted baby shampoo and apply study medication 
satisfactorily, in the opinion of the Investigator; 
6) if female, must either be incapable of pregnancy because of hysterectomy, bilateral tubal 
ligation, or bilateral oophorectomy, or be post-menopausal (have been amenorrheic for at 
least 2 years) or must use an effective method of birth control for the duration of the study. 
Female subjects of childbearing potential must have a negative urine pregnancy test and 
not be breastfeeding or planning a pregnancy; 
7) be able to provide written informed consent and sign the HIPAA form to participate in the 
study, in accordance with the International Council for Harmonisation (ICH) Good 
Clinical Practice (GCP) guidelines and local regulations, before initiating any study-
related procedures; and 
8) be able and willing to comply with treatment and all study procedures  
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
1) have an Eyelid Debris score of 3 or have cylindrical collarettes in either eye; 
2) have clinically significant abnormality of the eyelids or lashes (e.g., entropion, 
ectropion) other than blepharitis, or have a history of lagophthalmos or trichiasis; or 
have had eyelid surgery (including blepharoplasty) within 4 years of the Screening 
Visit. Eyelid surgery performed >4 years prior to the Screening Visit is permitted 
provided there is normal apposition of the eyelids upon closure and that there is no 


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residual lagophthalmos, no distortion of the lid margin and no abnormal lid function 
resulting in potentially increased exposure of the ocular surface; 
3) have received an injection of Botulinum toxin (Botox or equivalent) in the periocular area 
within 3 months prior to the Screening Visit; 
4) have any current or recurrent ocular infections (bacterial, viral or fungal), active ocular 
inflammation other than blepharitis or dry eye (i.e., follicular conjunctivitis, iritis) or 
preauricular lymphadenopathy; 
5) have current or recurrent diagnosis of ulcerative keratitis, specifically any epithelial loss 
greater than punctate keratitis (e.g., confluent epithelial loss or any infiltrates); 
6) have been diagnosed with glaucoma or ocular hypertension, or have an IOP > 21 mmHg at 
the Screening Visit or Baseline/Day 1 Visit; 
7) have a history of IOP elevation with steroid use (i.e., steroid responder); 
8) unable or unwilling to discontinue the use of contact lenses from Screening to Day 29/Exit 
Visit; 
9) 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 15 Visit; 
10) cosmetic eyelash procedures (e.g., eyelash curling) from the Screening Visit up to the 
Day 15 Visit, or a history of permanent/semi-permanent eye make-up procedure (e.g., 
eyelash extensions / false eyelashes, eyelash tinting, eyeliner tattooing) within 30 days of 
the Screening Visit or planned procedure during the study period; 
11) have permanent punctal plugs or history of nasolacrimal obstruction;  
12) have a history of ocular surgical intervention within 6 months prior to the Screening Visit 
or any planned ocular procedure during the study period; 
13) have known hypersensitivity to fluticasone propionate, to any other component of the study 
medication, or to ophthalmic diagnostic dyes 
 
14) use strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, 
clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, 
telithromycin); 
15) unable or unwilling to discontinue use of any non-diagnostic ophthalmic treatments 
(topical, intraocular or systemic) including topical autologous serum eyedrops, artificial 
tears and ocular lubricants. Subjects should not have used artificial tears or ocular 
lubricants for at least 24 hours prior to the Screening Visit, and for at least 30 days for all 
other ophthalmic medications; 
16) 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; 
17) have a history of meibomian gland probing within 3 months prior to the Screening Visit; 


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18) use of any corticosteroid agent or anabolic steroid within 30 days of the Screening Visit or 
during the study treatment period; 
19) use of isotretinoin or any other retinoids within 12 months of the Screening Visit; 
20) have any uncontrolled systemic disease or debilitating disease (e.g., cardiovascular disease, 
hypertension, diabetes, cystic fibrosis) in the opinion of the Investigator; 
21) have thyroid ophthalmopathy, rosacea or seborrheic dermatitis; 
22) 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; 
23) 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;  
24) have participated in any drug or device study within 30 days prior to the Screening Visit 
and/or planning to participate in any other study while participating in the current study; 
and 
25) were randomized in the NCX-4251-01 clinical trial. 
 


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5. 
CONCOMITANT MEDICATION(S) 
5.1 
Previous and Concomitant Medication(s) 
All non-ophthalmic medications used in the 3 months prior to the Screening Visit and all 
ophthalmic medications used in the 12 months prior to the Screening Visit must be recorded. 
Additionally, all medications used between the Screening Visit and the Day 29/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 29/Exit Visit subjects must not receive: 
 any non-diagnostic ophthalmic treatments (topical, intraocular or systemic) including 
topical autologous serum eyedrops, artificial tears, ocular lubricants, 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 or 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 the Day 29/Exit Visit. The use of any 
eye make-up (including on the eyelids, eyelid margins, and lashes) is prohibited up to the 
Day 15 Visit. 
Additionally, cosmetic eyelash procedures (e.g. eyelash curling) are prohibited from the 
Screening Visit up to the Day 15 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 29/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 
 Permanent punctal plugs 


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6. 
STUDY SUPPLIES 
6.1 
Description of Study Medication 
NCX 4251 Ophthalmic Suspension, 0.1% is a sterile, isotonic, buffered ophthalmic suspension 
containing 0.1% fluticasone propionate nanocrystals. The inactive ingredients are:
 
 
 
 
  
The placebo comparator is the vehicle of NCX 4251 Ophthalmic Suspension.  
6.2 
Packaging of the Study Medication 
NCX 4251 Ophthalmic Suspension and placebo comparator are supplied as 
 
 
  
Each kit is a carton that contains 
 The kit will be identified by a unique “kit number.” 
The subject will be dispensed one kit after randomization at the end of the Baseline/Day 1 
Visit. 
All study medication will be packaged, labeled, and supplied to the site by the study 
medication supplier under the direction of Nicox. Each kit contains sufficient study medication 
for the duration of the study treatment period. 
6.3 
Labeling of the Study Medication 
All labeling will be in English and will comply with U.S. federal regulations for investigational 
drug product.  
The kit and bottles will be labeled with the following:  
 Sponsor  
 Protocol number 
 Kit number 
 Instructions for use 
 Contents 
 Storage temperature 
 Cautionary statement: “New Drug - Limited by Federal Law to Investigational Use” 
6.4 
Storage of the Study Medication  
It is the site’s responsibility to ensure that all study medication is stored in a secure area and 
administered only to randomized subjects and in accordance with conditions specified in this 
protocol. 
At the site, the study medication will be stored 
  
 in accordance with the conditions specified in the site shipment documentation. 
  
The storage conditions will be indicated on the kit and bottle labeling.   


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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  
Each site will be assigned a 2-digit site ID by the Sponsor or its representative. At the 
Screening Visit, the site will assign a unique 3-digit screening number to each subject and 
record it in the screening log. The site will then assign the subject a unique consecutive Subject 
ID comprised of the 2-digit site ID followed by the 3-digit screening number.  
Subjects must meet all qualification criteria prior to randomization at the Baseline/Day 1 Visit. 
Approximately 100 subjects will be randomly assigned to NCX 4251 0.1% and approximately 
100 subjects will be randomized to placebo 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. During study visits Investigators, the Sponsor, the Medical Monitor, and masked 
CRO personnel interacting with the clinical sites must not be present during the instruction and 
supervision of study medication application. Instruction and supervision of subjects on the 
application of study medication will be performed by unmasked site personnel who will not 
perform any other study assessments. 
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. The Sponsor and the Medical Monitor must be 
notified within 24 hours following an emergency unmasking of any subject. 


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6.8 
Study Medication Dispensing and Collection  
For each subject fulfilling eligibility criteria, the clinical site staff will randomize subjects as 
per the randomization schedule 
 prior to the start of the study. A 
randomization number, which corresponds to a study medication kit number, will be allocated 
to each subject. The study medication kit number corresponds to a unique box containing  
. The randomization and the study medication kit number must be 
allocated only on the day of the first treatment application during Baseline/Day 1. Replacement 
kit numbers will be provided should a dispensed kit become lost or damaged. 
Once all Baseline/Day 1 Visit study procedures have been completed, the site will dispense the 
study medication to the subject. Each subject will be given one kit containing 
 
 
Study medication will be dispensed by the site designee (other than the investigator(s)) at the 
study site. 
Subjects will be instructed to return their study medication 
 to the 
Study Coordinator or another designated individual at the Day 15 Visit. An inventory will be 
conducted by the site.  
Each subject will be given a copy of the study medication dosing and storage instructions. 
6.9 
Instructions for Eyelid Scrubs 
The eyelid scrub procedure must be performed by the subject, prior to the study medication 
application, on both eyes each morning 
 
On study visit days, the subject must not perform eyelid scrubs at home; rather, eyelid scrubs 
will be performed at the site by the subject under the instruction and supervision of unmasked 
site study staff. Study staff will contact the subject the day prior to a scheduled visit to instruct 
the subject not to perform eyelid scrubs the morning of their visit and to bring their study 
supplies to the visit.  
Subjects must perform the eyelid scrubs as instructed using the supplies provided by the study 
site. Each subject will be given a copy of the eyelid scrub instructions. 
6.10 
Instructions for Use and Application of Study Medication 
The study medication must be administered to both eyelids each morning, 
 
 from the Baseline/Day 1 Visit to the day prior 
to the Day 15 Visit. The first study medication application (Baseline/Day 1 Visit) will be 
performed at the site by the subject under the instructions and supervision of site study staff. 
Similarly, at the Day 4, 8, and 11 Visits, application of the study medication will also be 
performed at the site by the subject under the supervision of site study staff. Study staff will 
contact the subject the day prior to a scheduled visit to instruct the subject not to apply study 
medication the morning of their visit and to bring their study medication and study supplies to 
the visit.  
Subjects must apply the study medication as instructed using the supplies provided by the 
study site. 


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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 
 
 
 
 
 
 
 
 
 VAS rulers 
Additional supplies may be provided once discussed and approved by the Sponsor.  
 














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8. 
SCREEN FAILURES, COMPLETION AND DISCONTINUATION 
8.1 
Subject Screen or Eligibility Failures 
Subjects who are screen or randomization failures should not be randomized into the study. 
The reason for screen/randomization failure must be documented. 
8.2 
Subject Completion 
A subject is considered to have completed the study at the end of the Day 29/Exit Visit. 
8.3 
Subject Early Discontinuation 
A subject may be discontinued from the study prior to the final study visit at the discretion of 
the Investigator, Sponsor, and/or IRB. Subjects may also discontinue their participation in the 
study at any time for any reason of their choosing. 
A subject may be discontinued from the study for the following reasons, including but not 
limited to: 
 Serious adverse event  
 Violation of eligibility criteria 
 Lack of compliance with the study procedures 
A subject must be discontinued from the study for the following reasons, including but 
not limited to: 
 If IOP > 36 mmHg in the same eye at two consecutive visits during the Treatment 
Period 
 Withdrawal of consent 
 Subject becoming pregnant in the course of the study 
 Eye infection 
Procedures for Discontinuation 
If a subject is discontinued or withdraws consent, no procedures other than those which may be 
related to the follow-up of AEs will be required. The Investigator will document the reason for 
the subject withdrawal.  
If a subject withdraws their consent during the 14-day Treatment Period, all efforts should be 
taken to complete the Day 15 Visit procedures prior to subject’s exit. 
If a subject is discontinued due to an AE, the status of the AE at the time of discontinuation 
must be documented. 
For any subject that is discontinued due to an AE the Investigator must ensure that adequate 
medical care/treatment will be provided. 
8.4 
Subject Lost to Follow-up 
Subjects who fail to present for a study visit should be contacted in an attempt to have the 
subject comply with the protocol and to return the diary and study medication, if applicable. If 


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a subject cannot be contacted with a minimum of three documented telephone calls followed 
by a certified letter and there is no known reason for withdrawal (e.g., 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 29/ 
Exit must immediately be reported 
 representing Nicox, 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 (Day 15), 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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11. 
STATISTICAL CONSIDERATIONS AND METHODS OF ANALYSIS 
An analysis plan containing detailed statistical methods, including accounting for missing data, 
will be generated and finalized prior to database lock.   
11.1 
Determination of Sample Size and Power Calculations 
The primary objective of this study is to demonstrate that the proportion of subjects with 
complete cure (score =0) in the composite (sum) of Eyelid Margin Redness, Eyelid Debris, and 
Eyelid Discomfort at Day 15 for NCX 4251 treated subjects is statistically superior to placebo 
treated subjects using a 2-sided alpha = 0.05. 
For the complete cure endpoint, 
 approximately 208 
subjects randomized overall (~104 subjects randomized per treatment group, with 94 subjects 
per treatment group completing the Day 15 study time point evaluations) 
 to 
demonstrate statistical superiority to placebo. 
The above analysis assumed a Day 15 time point; 
 
; and a 
two-sided significance level of 5% using a Fisher’s exact test. 
The secondary objective of this study is to demonstrate that mean reduction from baseline in 
Eye Dryness evaluated on VAS and/or Fluorescein Staining of inferior cornea at Day 15 for 
NCX 4251 are statistically superior to placebo using a Hochberg procedure to maintain the 
overall Type I Error rate = 0.05. 
For Eye Dryness endpoint, 
 approximately 124 
subjects randomized overall (~62 subjects per treatment group, with 55 subjects per group 
completing Day 15) 
 to demonstrate statistical superiority to placebo. 
The above analysis assumed a Day 15 time point; 
 
 and a two-sided significance level 
of 0.025 using a two-sample t-test. 
For Fluorescein Staining of inferior cornea, 
, 
approximately 72 subjects randomized overall (~36 subjects per treatment group, with 32 
subjects per group completing Day 15) 
 to demonstrate statistical superiority 
to placebo. 
The above analysis assumed a Day 15 time point;
 
 and a two-sided significance 
level of 0.025 using a two-sample t-test. 
The study will be considered a success and NCX 4251 will be claimed to be superior to 
placebo in the proportion of subjects with complete cure (score =0) in the composite (sum) of 
Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort at Day 15 if the primary 
endpoint is demonstrated to be statistically significant in favor of NCX 4251. 
Statistical inference will be made on the two secondary endpoints only if the primary endpoint 
demonstrates statistical significance in favor of NCX 4251.  Multiplicity correction within the 
two secondary efficacy endpoints will be completed using Hochberg’s procedure. 
 


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11.2 
Analysis Population 
 Intent-to-Treat Population: The intent-to-treat (ITT) population includes all randomized 
subjects. Subjects in the ITT population will be analyzed as randomized. 
 Per-Protocol Population: 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. 
 Safety Population: 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. 
11.3 
Data Display 
Summaries for continuous variables will include the sample size, mean, standard deviation, 
standard error, median, minimum, and maximum. Summaries for discrete variables will 
include frequency counts and percentages. The Baseline measure will be defined as the last 
non-missing measure prior to initiation of study treatment. Analyses will be completed on the 
study eye and fellow eye separately. 
 
 
 
 
 
 
11.4 
Collection and Derivation of Efficacy Assessments 
For both eyes, eyelid signs and symptoms (Eyelid Margin Redness, Eyelid Debris, Eyelid 
Discomfort) will be assessed. 
The primary efficacy endpoint is the complete cure (score = 0) in the composite (sum) of 
Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort at Day 15. The primary efficacy 
analyses of the primary efficacy endpoint will be conducted in the ITT population; intercurrent 
events handled in the following manner for each measure comprising the primary endpoint 
(Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort) after which complete cure will 
be determined:  
 
 
 
 
 
 
 
 
 
 




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Secondary endpoints will be summarized using continuous summary statistics (n, mean, 
standard deviation, standard error, median, minimum, and maximum) as well as two-sided 
95% t-distribution confidence intervals around the mean by treatment group. The primary 
analysis of the secondary outcome will employ a linear model with mean change from baseline 
in Eye Dryness evaluated on the VAS and mean change from baseline in Fluorescein Staining 
of the inferior cornea at Day 15 as the response and baseline eye dryness as a covariate. Least 
squared means and differences between treatment groups, along with corresponding 95% CIs 
and p-values will be presented. 
 
 
 
 
  
 
 
 
 
 
Detailed statistical methodology will be provided in the SAP. 
11.5.2 Safety Analyses 
Subject disposition, demographics, and baseline characteristics will be summarized and 
presented in data listings.  
Safety analyses are based on the safety dataset.  The safety dataset will include all subjects who 
receive at least one dose of study medication. 
Adverse events (AEs) will be coded using the MedDRA dictionary. The safety analysis will 
summarize treatment emergent ocular and systemic AEs for all treated subjects, using discrete 
summaries at the subject and event level by system organ class and preferred term for each 
treatment group. 
A treatment-emergent AE (TEAE) is defined as an AE that occurred on or after the treatment 
was initiated.  Ocular TEAEs by treatment group: NCX 4251 0.1% and placebo, will be 
summarized, by relationship to study drug, and by severity. Non-ocular TEAEs will be 
summarized by treatment group as follows: non-ocular TEAEs, by relationship to study, and by 
severity. Serious AEs (SAEs), AEs resulting in study drug discontinuation, and deaths will be 
presented in data listings.  
Other ocular safety data including visual acuity, slit-lamp biomicroscopy, IOP, and dilated 
ophthalmoscopy will be summarized by treatment group and visit using descriptive statistics. 
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. 


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11.5.3 Interim Analysis 
There is no interim analysis planned for this study.  
 


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


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13. 
STUDY MANAGEMENT 
13.1 
Monitoring 
Site monitoring is conducted to assess that subject protection, study procedures, study 
medication application, and data collection processes meet protocol, ICH, GCP, and regulatory 
guidelines/requirements.   
Before the study starts, the Clinical Research Organization (CRO) 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 Clinical Research Associate (CRA) 
 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 CRA. 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 CRA will send the Investigator a follow up letter detailing 
any actions required by the investigational site staff.  Any actions must, wherever possible, be 
addressed immediately, or by the next scheduled monitoring visit. 
The CRA 
 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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13.3 
Source Data Verification 
To ensure that data in the eCRF is accurate and complete and in accordance with subject 
source documents and other source data, source data verification (SDV) will be performed by 
the monitor on eCRFs and SAE and pregnancy related documents as detailed in the Monitoring 
Management Plan (MMP). The SDV consists of a comparison of the source documentation and 
other relevant records to the eCRFs. This will require direct access to all original records for 
each subject. 
It will be verified that documentation of the informed consent is on file for all subjects 
screened whether or not they were randomized into the study. 
13.4 
Completion of Electronic Case Report Forms  
eCRFs must be completed for each subject enrolled in the trial, including screening failures. 
eCRFs should be completed as soon as possible after the subject visit. All eCRFs must be 
checked for consistency, accuracy, and completeness by the responsible Investigator, as well 
as, personally electronically signed and dated.   
13.5 
Data Management 
The study Data Management Plan (DMP) will describe the methods used to collect, check and 
process clinical data, as well as the process for database locks. The DMP will be developed by 
the CRO and approved by Nicox. It will also list the roles and responsibilities of the various 
functions and personnel involved in the data management process. 
The database lock 
 
. 
13.6 
Audits and Inspections 
Authorized representatives of Nicox or the CRO, a regulatory authority, or an IRB may visit 
the site to perform audits or inspections, including source data verification. The purpose of 
such audit or inspection is to systematically and independently examine all study related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the approved protocol, GCP, ICH 
guidelines, and any applicable regulatory requirements. The Investigator must contact Nicox or 
CRO immediately if contacted by a regulatory agency about an inspection at their site. 
The presence of the CRA at the site is mandatory in case of an inspection or audit (at least for 
the SDV audit and the debriefing with the Principal Investigator). Nevertheless, when justified, 
the CRA may be represented by another CRO representative involved in the study (e.g., lead 
CRA).  
13.7 
Access to Source Data 
Nicox, authorized representatives of the CRO, or regulatory authority representatives will be 
allowed to have full and direct access to the various records relating to 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. 


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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 CRA, 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 CRO and the site's IRB 
must be notified. Approvals of the revised Informed Consent Form by Nicox or the CRO, and 
the IRB are required before the revised form is used. 
Nicox or the CRO 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 also be provided. Copies of all IRB correspondence with the 
Investigator should be given to the CRO. 
The CRO 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 
CRO. 
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 CRO, 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 CRO, CRA, 
auditor, and Health Authority representatives. 
14.5 
Confidentiality Regarding Trial Subjects Data 
In order to maintain subjects’ privacy, all study materials will identify subjects in a fully 
anonymized manner. The Investigator will grant the company or its designated representatives, 
or regulatory authorities the right to access subject’s original medical records for verification of 
the data gathered in the study. Subject’s confidentiality will be maintained and will not be 
made publicly available unless mandated by applicable laws and regulations. 
14.6 
Archiving at the End of the Study 
After the close-out visit at each site, the study is considered completed.  A copy of the final 
completed CRFs will be stored in the Investigator's archives for up 2 years following the final 
approval of the last marketing authorization, together with all the other site study-specific 
documents (including Investigator’s site file). Neither of these is ever transferred to the 
Sponsor. 
All study-related materials must be stored in a secure manner and must remain available upon 
request from Nicox or any Health Authority. 
14.7 
Coordinating Investigator 
The coordinating investigator 
 
 


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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 
American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice 
Pattern® Guidelines. Blepharitis. San Francisco, CA: American Academy of Ophthalmology; 
2013. Available at: www.aao.org/ppp. 
Arrúa M, Samudio M, Fariña N, Cibils D, Laspina F, Sanabria R, et al. Comparative study of 
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. 
2006;149:378-82. 
Hosseini K, Lindstrom RL, Foulks G, Nichols KK. A randomized, double-masked, parallel-
group, comparative study to evaluate the clinical efficacy and safety of 1% azithromycin – 
0.1% dexamethasone combination compared to 1% azithromycin alone, 0.1% dexamethasone 
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. 
 




 
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a) Screening Visit may be performed at any time of the day.  
b) Subject-rated eyelid discomfort will be assessed prior to investigator-evaluated eyelid margin redness and eyelid debris  
c) Daily eyelid scrubs will be performed prior to study medication application by the subject when self-administering study treatment. On applicable 
study visit days eyelid scrubs and study medication application will be performed at the site by the subject under the supervision of the study staff. 
d) At the Baseline/Day 1 Visit, study medication is administered by the subject after site confirmation of eligibility and randomization. Subjects will be 
instructed on proper application technique.  
 
 
 
 
 


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APPENDIX 2: METHODS OF CLINICAL EVALUATION 
For all assessments, sites should use the same instrument(s), method and examiner whenever 
possible throughout the study. All ophthalmic assessments will be performed bilaterally.  The 
right eye will be assessed first, then the left eye.  
1. 
URINE PREGNANCY TEST 
Urine pregnancy test is to be conducted on site by study staff per the instructions on the 
pregnancy kit.   
2. 
EYE DRYNESS SCALE USING THE VISUAL ANALOGUE SCALE (VAS) 
Subjects will be asked the following questions regarding ocular discomfort (unrelated to study 
drug instillation). 
 
 
 
 
 
 
 


















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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 


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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. 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A Multi-Center, Randomized, Double-Masked, Placebo-Controlled, 
Phase 2b Study Evaluating the Safety and Efficacy of NCX 4251 
(Fluticasone Propionate Nanocrystal) Ophthalmic Suspension, 0.1% 
QD for the Treatment of Acute Exacerbations of Blepharitis 
(Mississippi) 
Sponsor: 
Nicox Ophthalmics, Inc. 
Protocol Number: 
NCX-4251-02 
Author: 
Date: 
04AUG2021 
Version: 
Final 2.0 
NCT04675242












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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-4251-02, Version 4.0 dated 24 Mar 2021. This SAP describes the final analyses for complete 
data as no interim analyses are planned for this 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  
The objective of this clinical study is to evaluate the safety and efficacy of NCX 4251 Ophthalmic 
Suspension, 0.1% vs placebo for the treatment of the signs and symptoms of an acute exacerbation of 
blepharitis. 
2.1 
Primary Objective 
The primary objective of this clinical study is to evaluate the proportion of subjects with complete cure 
(Score 0) in the composite (sum) score of Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort at 
the Day 15 Visit for NCX 4251 treated subjects compared to placebo. 
2.2 
Secondary Objectives 
The secondary objective of the study is to evaluate the mean change from baseline in Eye Dryness 
evaluated using the Visual Analog Scale (VAS) and Fluorescein Staining of inferior cornea at the Day 15 
Visit for NCX 4251 compared to placebo. 
3. 
Study Variables 
The following will be collected during the course of the study: 
 
Signs and symptoms of blepharitis (Eyelid Debris, Eyelid Margin Redness, and Eyelid Discomfort) 
 
Eye Dryness symptoms using the VAS 
 
 
 
 
 
 
Corneal 
 staining (Fluorescein 
 
 
 
 
 


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Slit-lamp biomicroscopy 
 
Intraocular pressure (IOP) 
Dilated ophthalmoscopy
 
Best-corrected visual acuity (BCVA) 
 
Urine pregnancy tests (for females of childbearing potential) 
 
Adverse Events (AE) 
 
Concomitant Medications 
3.1 
Efficacy Endpoints 
3.1.1 
Primary Efficacy Endpoint 
The primary endpoint for this study is: 
 
Proportion of subjects with Complete Cure (Score 0) in each of the following: Eyelid Margin 
Redness, Eyelid Debris, and Eyelid Discomfort at the Day 15 Visit. 
3.1.2 
Secondary Efficacy Endpoints 
The secondary endpoints for this study are: 
 
Mean change from baseline in the Eye Dryness Symptoms using the VAS at the Day 15 Visit; 
and 
 
Mean change from baseline in Fluorescein Staining of the inferior cornea at the Day 15 Visit. 
3.2 
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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3.4 
Statistical Hypotheses 
The primary objective of this study is to test whether the proportion of subjects with complete cure (Score 
0) in the composite (sum) score of Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort at the 
Day 15 Visit for NCX-4251-treated subjects is statistically superior to placebo-treated subjects using a 
two-sided alpha=0.05.   
The two secondary endpoints will test if the mean reduction from baseline in Eye Dryness evaluated on 
the VAS and/or Fluorescein Staining of inferior cornea at the Day 15 Visit for NCX 4251 is statistically 
superior to placebo. The Hochberg correction for multiple testing will be performed to maintain any overall 
Type I Error rate = 0.05. Statistical inference will be made on the two secondary endpoints only if the 
primary endpoint demonstrates statistical significance in favor of NCX 4251. Exploratory endpoints will 
not be adjusted for multiplicity. 
4. 
Study Design and Procedures 
4.1 
General Study Design 
This is a multi-center, randomized, double-masked, placebo-controlled, Phase 2b study.  Subjects will be 
assessed for initial eligibility at the Screening Visit (Day -14 to -7). Eligible adult subjects with a documented 
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 may be randomized into the study. 
Study medication will be applied via a sterile applicator to the upper and lower eyelids and lower eyelid 
margin of both eyes once daily (QD) in the morning for 14 days. Subjects will also perform daily scrubs of 
the upper and lower eyelids of both eyes using diluted baby shampoo on a cotton swab prior to the 
application of the study medication. 




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personnel who will not perform any other study assessments.
6.
Sample Size and Power Considerations
The sample size was based on the primary endpoint of complete cure (Score 0) in the composite (sum) 
score of Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort at Day 15. For the complete cure 
endpoint, 
, approximately 208 subjects randomized overall (~104 
subjects randomized per treatment group, with 94 subjects per treatment group completing the Day 15 
Visit study time point evaluations) 
 to demonstrate statistical superiority to placebo. 
The above analysis assumes a Day 15 Visit time point, 
 
, and a two-sided 
significance level of 5% using a Fisher’s exact test.  
7. 
Data Preparation 
7.1 
Input Data 
All reported study data will be recorded on the electronic case report forms (eCRFs) 
 
 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 to 
, 
including data entry, performance of edit and validation checks, documentation and resolution of 
data queries, and database lock with written authorization provided by 
 
 
 
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. 
7.2 
Output Data 
Data will be transferred to 
 into standard formats following the Study Data 
Tabulation Model (SDTM). Data will then be mapped to analysis datasets using the Analysis Data Model 


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(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. 
SDTM will follow the SDTM Version 1.7 model and will be implemented using the SDTM Implementation 
Guide Version 3.3 and the most recent SDTM Controlled Terminology version at the initiation of 
programming. ADaM data will follow the ADaM Version 2.1 model and will be implemented using the ADaM 
Implementation Guide Version 1.2. 
 
Any discrepancies in the validation will be noted in reviewer’s guides accompanying the final data transfers. 
Define.xml will be created for SDTM and ADaM using the Define-XML version 2.0 model.
8. 
Analysis Populations 
8.1 
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. 
8.2 
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. 
8.3 
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. 
9. 
General Statistical Considerations 
9.1 
Unit of Analysis 
The unit of analysis for the final analysis in this study will be the study eye, fellow eye for all summaries of 
efficacy and ocular safety assessments performed by eye (visual acuity, slit lamp biomicroscopy, intraocular 
pressure [IOP], dilated ophthalmoscopy).  The study eye will be the eye with the highest composite score in 
Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort before eyelid scrubs at the Baseline/Day 1 
study visit, or the right eye (OD) if both eyes of a subject have the same score at baseline. 
 
 
Additionally, AEs, medical history, and concomitant medications will be presented at the 
subject level.   
. 


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9.2 
Missing or Inconclusive Data Handling 
Efficacy analyses will be based on eyelid signs and symptoms (Eyelid Margin Redness, Eyelid Debris, 
Eyelid Discomfort). These analyses will be based on the ITT population with observed data only. To check 
for robustness of outcomes, 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
All AEs with completely missing onset dates will be considered treatment-emergent. All 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. All 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. 
All AEs missing a relationship will be considered treatment-related. Medications with missing start dates 
will be considered concomitant medications unless (1) the medication start year is prior to the year of the first 
dose of study treatment or (2) the medication start year is the same as the year of first dose of study 
treatment and the medication start month is prior to the month of first dose of study treatment, in which 
case these will be considered prior (and possibly concomitant depending on the end date) medications. 
Medications with missing end dates will be considered concomitant medications unless (1) the medication 
end year is prior to the year of first dose of study treatment or (2) the medication end year is the same as 
the year of first dose of study treatment and the medication end month is prior to the month of first dose of 
study treatment, in which case these will be considered prior medications. In the event that a medication end 
date is prior to the medication start date, the medication end date will be considered as one day after the 
medication start date for the purposes of determining whether this is a prior and/or concomitant medication. 
The actual reported AE onset dates and medication start and end dates, including any unknown portions, 
will be included in the appropriate listings as entered by site personnel. 


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9.3 
Definition of Baseline 
All on-site efficacy assessments including Eyelid signs and symptoms (Eyelid Discomfort, Eyelid Margin 
Redness, and Eyelid Debris) will be conducted 
, therefore the Baseline measure will 
be defined as the last non-missing measure prior to initiation of study treatment. 
9.4 
Data Analysis Conventions 
The final analysis will 
 after the study is completed and the database has been locked 
and released for unmasking.
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 variables (Eyelid 
Margin Redness, Eyelid Debris, and Eyelid Discomfort, along with the composite scores; Fluorescein 
Staining; 
 and VAS Eye Dryness, 
 
  
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 SEMs will be presented 
to two additional decimal places than reported in the raw values. Summaries for discrete and ordinal efficacy 
variables (Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort, along with the composite score) 
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 
confidence intervals (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. 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 separately by study eye and fellow eye. 
Confidence intervals for differences between treatment groups will be two-sided at 95% confidence. The p-
values may also be presented for change from baseline values; however, the study is not powered to show 


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significance for these. 
Unless otherwise specified, summaries will be presented by treatment group and, where appropriate, visit. 
9.5 
Adjustments for Multiplicity 
Statistical inference will be made on the two secondary endpoints only if the primary endpoint demonstrates 
statistical significance in favor of NCX 4251. Multiplicity correction within the two secondary efficacy 
endpoints will be completed using Hochberg’s procedure. 
 
10. 
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 29/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 will be 
summarized. 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, Investigator decision, protocol 
violation, lack of compliance, 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, not 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. 
11. 
Demographic and Pre-treatment Variables 


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11.1 
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 
the following formula: 
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. 
11.2 
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: 
 
Eyelid 
Margin Redness Scale, Eyelid Debris Scale, Conjunctival Redness Scale, 
 
fluorescein staining, 
; 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. 
12. 
Medical History and Concomitant Medications 
12.1 
Medical History 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 
23,1. 
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. 




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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 
A subject listing of treatment exposure will be produced. 
14. 
Efficacy Analyses 
All assessments will be conducted by the Study Eye 
 
   
14.1 
Efficacy Endpoints 
Primary
 
Proportion of subjects who achieve a Complete Cure (score of 0) by Day 15 in all of the following 
scores Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort 
Secondary 
 
Mean change from baseline in the Eye Dryness Symptoms using the VAS at the Day 15 Visit
 
Mean change from baseline in the Fluorescein Staining of the inferior cornea at the Day 15 Visit 
 
14.2 
Eye Assessments Used for the Efficacy Endpoints 
14.2.1 
Eyelid Discomfort 
 Eyelid Discomfort is subject-reported based on a four-point scale 
 
 
 
14.2.2 
Eyelid Margin Redness
After assessing Eyelid Discomfort, the Investigator assesses and grades Eyelid Margin Redness based on 
the following four-point scale: 
 
 
 
 
14.2.3 
Eyelid Debris 
After accessing Eyelid Discomfort and Eyelid Margin Redness, the Investigator assesses and grades Eyelid 
Debris based on the following four-point scale: 
 
 
 


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14.2.4 
Composite Score of Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort 
The composite score of Eyelid Margin Redness, Eyelid Debris, and Eyelid Discomfort is defined as the sum 
across the three measurements at a particular visit. If any of the assessments is missing, the composite 
score will be set to missing. 
14.2.5 
Eye Dryness Symptoms 
  
Eye Dryness Symptoms are self-reported using a 0-100 mm VAS, where 0 = No Discomfort and 100 = 
Maximal Discomfort. 
 
 
14.2.6 
Fluorescein Staining 
Fluorescein staining is Investigator assessed using a 5-point scale (allowing for half interval responses) 
 
 
 
 
 
14.3 
Detailed Description of the Efficacy Analysis 
Complete cure (Score 0) in the composite (sum) of Eyelid Margin Redness, Eyelid Debris, and Eyelid 
Discomfort will be summarized using discrete summary statistics (frequency counts and percentages) as 
well as two-sided 95% Clopper-Pearson CIs by treatment group. The primary efficacy analyses will test the 
difference in the proportion of study eyes with complete cure in the composite score between NCX 4251 
Ophthalmic Suspension and placebo at Day 15 
 
. The marginal 
proportions and difference in proportions along with the corresponding two-sided 95% CIs and p-value will 
be presented. 
Secondarily, differences (NCX 4251 Ophthalmic Suspension minus placebo) between treatment groups will 
be summarized using difference in proportions, 95% asymptotic CIs around the differences in proportions, 
and Pearson’s chi-squared test. Summaries will be presented for the Day 15 Visit 
 
 
Change from baseline in the composite (sum) score of Eyelid Margin Redness, Eyelid Debris, and Eyelid 
Discomfort will be summarized using continuous summary statistics (n, mean, SD, standard error, median, 
minimum and maximum) as well as two-sided 95% t-distribution CIs by treatment group. Additionally, 
differences in mean change from baseline scores (NCX 4251 Ophthalmic Suspension minus placebo) 
between treatment groups will be summarized including 95% t-distribution CIs around the differences in 
mean. Summaries will be presented for the Day 15 Visit as well as each other post-baseline visit. 
 






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15.2 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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. 
 
 
 
 
 
 
 
 
16. 
Safety Analyses 
All safety analyses will be conducted using the Safety population. 
16.1 
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 (TEAEs) 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 with a missing severity will be counted as severe. 
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 


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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. 
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 




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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. 
16.4 
Slit Lamp Biomicroscopy 
The slit lamp examination will be performed prior to any contact assessments and instillation of any drops 
at each specified visit. 
Each structure will be graded 
 
 The following structures will be examined at each visit: cornea, conjunctiva 
 
 anterior chamber, iris, lens, eyelid (other than Eyelid Margin Redness and Eyelid 
Debris), and pupil. 
A subject listing of the slit lamp biomicroscopy parameters will also be produced. 
17. 
Interim Analyses 
There are no planned interim analyses for this study. 
18. 
Changes from Protocol-Stated Analyses 
There are no changes from the protocol-stated analyses. 
19. 
References 
SAS Online documentation (http://support.sas.com/kb/63/038.html). 
20. 
Revision History 
A revision was issued (version 2.0) on August 4, 2021. 
Summary of Changes 
Section # 
Description of Change 
Rationale 
14.3 
Provide clarification on the 
  
 
 
 
21. 
Tables  
The following tables are planned to be included in the final analysis. Tables to be included in the topline 
analysis are highlighted below in bold. 












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Appendix A 
Table 1. Schedule of Visits and Assessments 
 
a) 
Screening Visit may be performed at any time of the day.  
b) 
Subject-rated eyelid discomfort will be assessed prior to investigator-evaluated eyelid margin redness and eyelid debris. 
c) 
Daily eyelid scrubs will be performed prior to study medication application by the subject when self-administering study treatment. On study visit days eyelid scrubs and 
study medication application will be performed by the subject under the supervision of the study staff. 
d) 
At the Baseline/Day 1 Visit, study medication is administered by the subject after site confirmation of eligibility and randomization.  Subjects will be instructed on proper 
application technique.