Clinical trial NCT03657797
Conditions: Glaucoma, Open-Angle Hypertension, Ocular
Sponsor: Nicox Ophthalmics, Inc.
Start date: 2018-08-01; Completion date: 2019-08-23
Enrollment: 656 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this clinical study is to evaluate the safety and efficacy of NCX 470 ophthalmic solution in lowering intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma. Three different concentrations of NCX 470 ophthalmic solution (0.021%, 0.042%, and 0.065%) will be compared to latanoprost 0.005% ophthalmic solution.

Detailed description:

Arms: arm 1: NCX 470 Ophthalmic Solution, 0.021% dosed once daily for 4 weeks arm 2: NCX 470 Ophthalmic Solution, 0.042% dosed once daily for 4 weeks arm 3: NCX 470 Ophthalmic Solution, 0.065% dosed once daily for 4 weeks arm 4: Latanoprost Ophthalmic Solution, 0.005% dosed once daily for 4 weeks
Interventions: intervention 1: NCX 470 intervention 2: Latanoprost 0.005%
Intervention descriptions: intervention 1: NCX 470 Ophthalmic Solution intervention 2: Latanoprost 0.005% Ophthalmic Solution

Protocol documents:
Prot_000.pdf: 
















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LIST OF FIGURES 
FIGURE 1: NCX-470-17001 STUDY DESIGN ............................................................................................... 25 
LIST OF TABLES 
TABLE 1: DURATION OF WASHOUT PERIOD FOR IOP-LOWERING MEDICATIONS ............................................. 26 
TABLE 2: TIMES AND EVENTS SCHEDULE ..................................................................................................... 59 
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LIST OF ABBREVIATIONS 
ACE 
Angiotensin-converting Enzyme 
AE 
Adverse Event 
AEs 
Adverse Events 
ALT 
Argon Laser Trabeculoplasty 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
BCVA 
Best Corrected Visual Acuity 
BP 
Blood Pressure 
CI 
Confidence Interval 
COV 
Close Out Visit 
CRA 
Clinical Research Associate 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
CTA 
Clinical Trial Agreement 
DBP 
Diastolic Blood Pressure 
DMP 
Data Management Plan 
EDC 
Electronic Data Capture 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
 
 
 
 
logMAR 
Logarithm of Minimum Angle Resolution 
LS 
Least Square 
MI 
Multiple Imputations 
MIG 
Minimally Invasive Glaucoma 
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MMP 
Monitoring Management Plan 
mmHg 
Millimeters of Mercury 
ND 
Not Done 
NO 
Nitric Oxide 
OAG 
Open-Angle Glaucoma 
OHT 
Ocular Hypertension 
PGA 
Prostaglandin Analog 
PGF2α 
Prostaglandin F2α 
PI 
Principal Investigator 
PP 
Per Protocol 
QD 
Quaque Die (once daily) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SDV 
Source Data Verification 
SLT 
Selective Laser Trabeculoplasty 
SMP 
Safety Management Plan 
TM 
Trabecular Meshwork 
TEAE 
Treatment Emergent Adverse Event 
US 
United States 
VA 
Visual Acuity 
vs. 
Versus 
WHO 
World Health Organization 
 
Note: the first occurrence of some abbreviations is not spelled out in the document (e.g., units of 
measure). 
 
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1. INTRODUCTION 
1.1 
Background and Rationale 
Glaucoma is a leading cause of blindness worldwide (Jonas, 2017).  Globally it has been 
estimated that 57.5 million people were affected by primary open-angle glaucoma (POAG) 
in 2015, with this number projected to rise to 65.5 million by 2020 (Kapetanakis, 2016).  
Intraocular pressure (IOP) is the primary risk factor for glaucoma, and lowering IOP to 
prevent optic nerve injury is currently the only proven effective treatment (Jonas, 2017).  
Topical PGAs, such as bimatoprost, are considered as the mainstay of treatment due to 
their efficacy and safety in lowering IOP (Daka, 2014).  Clinical trials reported greater 
reduction in IOP in subjects with OAG or OHT with bimatoprost 0.03% compared with 
either travoprost 0.004% or latanoprost 0.005% in some instances, and equivalence among 
the three treatments in others (Parrish, 2003; Gandolfi, 2001).  All treatments presented an 
acceptable safety profile although lower incidences of conjunctival hyperemia have been 
reported with latanoprost 0.005% than with the other PGAs (Canadian Agency for Drugs 
and Technologies in Health, 2015; Daka, 2014). 
Nicox is developing NCX 470, a nitric oxide (NO)-donating bimatoprost prostaglandin 
analog, as a new therapy for lowering IOP in patients with OAG or OHT. When exposed to 
esterases in the eye, NCX 470 is cleaved into its active metabolites, the prostamide 
bimatoprost, which in turn is converted to bimatoprost acid, a prostaglandin F2α receptor 
agonist, and into 6-(nitrooxy)-hexanoic acid, a NO-donating moiety. The active metabolites 
of NCX 470 include bimatoprost, the active ingredient in LUMIGAN®, (NDAs 021275 and 
022184), and 6-(nitrooxy)-hexanoic acid which leads to the release of NO. Another NO-
donating PGA (VYZULTA™, latanoprostene bunod ophthalmic solution, 0.024%), also 
discovered and invented by Nicox, received US FDA (Food and Drug Administration) 
approval in November 2017 for the reduction of IOP in patients with OAG or OHT 
(NDA 207795). 
Bimatoprost and NO provide robust IOP-lowering activity by concomitantly activating two 
independent 
mechanisms: 
uveoscleral 
outflow 
and 
trabecular/Schlemm’s 
canal 
conventional outflow facilities (Woodward, 2010; Cavet, 2014). Nitric oxide donors relax the 
TM and increase aqueous humor outflow (Gabelt, 2011; Heyne, 2013; Cavet, 2014).  As a 
result, NO modulates IOP through the conventional pathway.  In contrast, bimatoprost acts 
by increasing the outflow of aqueous humor primarily through the uveoscleral pathway 
(Krauss, 2004). 
The additive effect of a NO donor and a prostaglandin F2α receptor agonist has been 
confirmed with latanoprostene bunod, a dual-acting NO-donating latanoprost developed for 
the reduction of IOP in patients with OAG or OHT (Meideiros, 2016; Weinreb, 2016).  This 
approach is supported by the nonclinical data package compiled for NCX 470, as well as 
the publicly available data for bimatoprost. 
NCX 470 exhibited potent and effective IOP-lowering activity in three ocular hypertensive 
animal models (Impagnatiello, 2015). Nonclinical pharmacology studies in well-established 
animal models of glaucoma and OHT have demonstrated that the IOP-lowering efficacy of 
NCX 470 is greater than that of equimolar doses of bimatoprost.  In particular, in transient 
ocular hypertensive rabbits, known to respond poorly to PGF2α analogs and prostamides, 
NCX 470 lowers IOP likely via NO release.  Additionally, an equimolar dose of NCX 470 at 
0.042% lowers IOP more effectively than bimatoprost at 0.03% in ocular normotensive 
dogs at 12 hours post dose, as well as in laser-induced ocular hypertensive non-human 
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9. PROTOCOL COMPLIANCE 
Subjects who experience major protocol deviations will have all their data excluded from 
the Per Protocol (PP) analysis.  The list of major protocol deviations, as well as minor 
protocol deviations, will be finalized prior to database lock. 
In order to correctly identify and document protocol deviations, protocol deviations will be 
categorized as follows: 
• 
Minor Deviation: Deviation considered to not impact the primary efficacy 
outcome of the study (i.e., does not affect the study results). 
• 
Major Deviation: Deviation considered to impact the primary efficacy outcome of 
the study (i.e., affects the study results). 
All deviations will be recorded by the site and classified by the Sponsor.  
 
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10. ADVERSE EVENTS 
10.1 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to 
have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal 
(investigational) product.  Lack of efficacy will be reported as a treatment failure, not as an 
AE. 
10.2 
Severity of Adverse Event 
The severity of an AE should be categorized as mild, moderate or severe per Investigator’s 
judgment with the following scale in consideration: 
• 
Mild: Awareness of a sign or symptom that does not interfere with the subject’s 
usual activities or is transient, resolved without treatment and with no sequelae. 
• 
Moderate: interferes with the subject’s usual activities, and or requires symptomatic 
treatment. 
• 
Severe: symptom(s) causing severe discomfort and significant impact of the 
subject’s usual activities and requires treatment. 
10.3 
Causal Relationship with Study Medication 
A determination of the relationship between an AE and the study medication must be 
made by the Investigator for each AE. The following terms to evaluate the causality of the 
AE with the study drug should be used: 
 
• 
Unrelated: a simultaneous disease, a simultaneous treatment or any other known 
cause is clearly responsible for the safety event and the AE is not related to the 
study medication. 
 
• 
Unlikely: on the basis of the available knowledge regarding the subject’s history, 
the disease process, the timing of the safety event in relation to the administration 
of the study medication and the mode of action of study medication, a relation 
between the study medication and the safety event is unlikely, but cannot be totally 
excluded.  
 
• 
Possible: this relation exists when the safety event follows the reasonable 
chronological sequence from the moment of the study medication administration, 
but when the safety event could also have been caused by the clinical condition of 
the subject or by other treatment administered to the subject.  
 
• 
Probable: this relation exists when the safety event follows a reasonable 
chronological sequence from the moment of the study medication administration, 
corresponds to a known effect of the study medication, is confirmed by the 
observation of an improvement upon discontinuation of the study medication 
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administration, and therefore the study medication is the most probable of all the 
causes.  
 
• 
Definite: this relation exists when the safety event follows a reasonable 
chronological sequence from the moment of the study medication administration, 
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 and through the Exit 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, and up to 
30 days following the most recent study drug administration (for a subject who exited the 
study early or after normal study termination) must immediately be reported to the company 
representing Nicox, and recorded on the appropriate forms.  All subjects with an SAE must 
be followed up and the outcomes reported. Subjects must be followed until complete 
healing or stabilization or blood tests are back to normal or up to 30 days after the end of 
the study treatment, whichever occurs first.  The Investigator must supply the company 
representing Nicox with any additional requested information (e.g., autopsy reports and 
final medical reports). 
In the event of an SAE, the Investigator must: 
1) Notify Sponsor’s Primary Contact for Study Related Matters and SAEs immediately 
(see contact information on Page 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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12. EMERGENCY PROCEDURES 
12.1 
Emergency Contact Procedure 
 
In case of any Safety Event including an SAE, the first person to contact is: 
 
 
 
 
The secondary contact is the study Medical Monitor: 
 
 
  
 
 
 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to cope with medical emergencies during the study.  Each subject will receive the 
Investigator’s emergency contact information (to call if needed).   
12.2 
Procedure in Case of Pregnancy 
If a pregnancy occurs during the study, pregnancy itself is not regarded as an AE unless 
there is a suspicion that the study medication may have interfered with the effectiveness of 
a contraceptive medication. 
If a female subject becomes pregnant during the study, the subject will be withdrawn from 
the study immediately.  However, any pregnancies must be followed up, and their 
outcomes must be reported to Nicox or to the company representing Nicox (i.e., mother 
and fetus(es) must be followed up at least until the birth of the infant and one month after 
the birth of the infant). Follow-up will include course, duration, outcome of the pregnancy 
and the health of the infant, as applicable. 
If the outcome of pregnancy is:  
• 
Elective abortion without complications: it must be documented and reported to 
Nicox or to the company representing Nicox, but it should not be handled as an AE.   
• 
Any spontaneous miscarriage or abortion for medical reasons or congenital 
anomaly or birth defect: it must be documented and handled as a SAE and full 
details will be requested.   
Any complications during pregnancy must be recorded as AEs and may constitute SAEs if 
they fulfill any of the specified criteria for a SAE.  
 
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13. STUDY MANAGEMENT 
13.1 
Monitoring 
Site monitoring is conducted to assess that subject protection, study procedures, study 
drug administration, and data collection processes meet protocol, ICH, GCP, and 
regulatory guidelines/requirements.   
Before the study starts, the company representing Nicox will visit/call the investigational 
sites to: 
• 
Determine the adequacy of the facilities, 
• 
Discuss with the Investigator(s), and other personnel involved in the study, about 
their responsibilities with regard to protocol adherence, and also about Sponsor’s 
responsibilities. 
During the study, a monitor from the company representing Nicox will monitor the study on 
a periodic basis by having regular contacts with the investigational sites, including on-site 
visits, to: 
• 
Provide information and support to the Investigator(s), 
• 
Confirm that facilities and investigational site staff remain acceptable, 
• 
Ensure that the investigational site study team is adhering to the protocol, including 
verifying the accuracy of data recorded in the eCRF and that the study medication 
logs are being maintained. 
Any detected non-compliance with the approved study protocol, GCP, or any applicable 
regulatory requirements will be fully documented by the monitor. During the monitoring 
visits, the Investigator and clinical study staff should be available for questions, verification 
of data from the source documentation, and possible correction to the eCRF. 
Following each monitoring visit, the Investigator will be sent a follow up letter detailing any 
actions required by either the investigational site staff or the monitor.  Any actions must, 
wherever possible, be addressed immediately, or by the next scheduled monitoring visit. 
The monitor and the CRO’s clinical operations team will be reachable between visits if the 
Investigator, or other study staff at the site, needs information and advice. 
13.2 
Source Documents 
Each participating site will maintain appropriate medical and research records for this trial, 
in compliance with ICH E6(R2) GCP Section 4.9, and regulatory and institutional 
requirements for the protection of subject confidentiality. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source documents may include, but are not limited to, a subject’s medical records, hospital 
charts if any, clinic charts if any, the Investigator’s subject study files, pharmacy dispensing 
records, recorded data from automated instruments, as well as the results of diagnostic 
tests such laboratory tests. 
 
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13.8 
Training of Staff 
The Principal Investigator will maintain records of all individuals at their site involved in the 
study (medical, nursing, and other staff).  The Principal Investigator will ensure that 
appropriate training relevant to the study is given to all of the study staff, and that any new 
information of relevance to the performance of this study is forwarded to the staff involved.  
The Principal Investigator must inform the monitor, in a timely manner, of any change in the 
study site staff. 
13.9 
Changes to the Protocol 
Neither the Investigator nor the site staff may implement any changes to the protocol 
without approval by Nicox and prior review and documented approval/favorable opinion 
from the IRB of a protocol amendment, except where necessary to eliminate immediate 
hazards to study subjects, or when the changes involve only logistical or administrative 
aspects of the study (e.g., change in monitors, change of telephone numbers).  If a protocol 
amendment requires a change to a particular site's Informed Consent Form, then Nicox or 
the company representing Nicox and the site's IRB must be notified.  Approvals of the 
revised Informed Consent Form by Nicox or the company representing Nicox, and the IRB 
are required before the revised form is used. 
Nicox or the company representing Nicox will distribute amendments and new versions of 
the protocol to each Principal Investigator(s) and site study staff for review and any 
applicable training.   
 
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14.  ADMINISTRATIVE, LEGAL, AND ETHICAL ASPECTS 
14.1 
Conduct of the Trial 
The trial will be conducted according to the protocol, the ICH Consolidated Guideline for 
Good Clinical Practice (ICH GCP E6 (R2) - March 2018), and the applicable regulatory 
requirements.  
14.2 
Ethical Principles 
The study has to be conducted in accordance with the principles of the Declaration of 
Helsinki (1964), as amended or clarified by the General Assembly of the World Medical 
Association (World Medical Association Declaration of Helsinki, last amended October 
2013). 
14.3 
Health Authorities and Institutional Review Board (IRB)  
This study is to be conducted in accordance with IRB regulations (U.S. 21 CFR Part 56). 
The study protocol and subject informed consent form must be submitted to the appropriate 
properly constituted IRB.  The approval from the IRB must refer to the exact protocol title 
and number, and identify all documents reviewed and their corresponding versions.  A list 
of the IRB review board members as well as a statement of compliance with GCP and 
applicable laws and regulations should be also provided.  Copies of all IRB 
correspondence with the Investigator should be given to the company representing Nicox. 
The company representing Nicox is to be notified immediately if the responsible IRB has 
been disqualified or if proceedings leading to disqualification have begun. 
The Principal Investigator is also responsible for providing the IRB with safety reports of 
any unexpected SAEs from any clinical study conducted with the study medication, as 
dictated by the IRB requirements.  These safety reports will be provided to the Principal 
Investigator by the company representing Nicox. 
The Principal Investigator is responsible for informing the IRB of any amendment to the 
protocol.  In addition, the IRB must approve all materials used to recruit subjects for the 
study.  Either the Principal Investigator, or the company representing Nicox, must submit 
progress reports to the IRB according to the IRB requirements and local regulations and 
guidelines.  The Principal Investigator must also provide the IRB with any reports of 
Serious Adverse Events from the study site, as dictated by the IRB requirements. 
14.4 
Subject Information and Consent 
It is the responsibility of the Investigator to obtain written and signed informed consent prior 
to enrollment into the study (i.e., at the Screening Visit) and before any procedure related 
to the trial is performed.   
The methods of obtaining and documenting informed consent and the contents of the ICF 
will comply with ICH GCP guidelines, the requirements of 21 CFR Part 50 “Protection of 
Human Subjects”, the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements. 
The Investigator or their designee must fully explain and adequately inform the subject of 
the purpose of the study prior to entering a subject into the clinical trial or performing any 
trial-specific procedures.  
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Once the subject fully agrees to participate in this study, written ICF must be documented 
by the subject’s personally dated signature and the personally dated signature of the 
informing Investigator/designated person conducting the informed consent discussion.  The 
subject will receive one copy and the original ICF will be filed in the subject study file on 
site. 
The dates when the written informed consent was obtained for the subject and when the 
subject withdraws or exits the study, must be documented in the subject source documents 
so that it is known if the subject is currently participating in a clinical study. 
In signing the ICF, a subject accepts direct access to their data by Nicox, the company 
representing Nicox, monitor, auditor, and Health Authority representatives. 
14.5 
Confidentiality Regarding Trial Subjects Data 
In order to maintain subjects’ privacy, all study materials will identify subjects in a fully 
anonymized manner. The Investigator will grant the company or its designated 
representatives, or regulatory authorities the right to access subject’s original medical 
records for verification of the data gathered in the study. Subject’s confidentiality will be 
maintained and will not be made publically available unless mandated by applicable laws 
and regulations. 
14.6 
Archiving at the End of the Study 
After the close-out visit at each site, the study is considered completed.  A copy of the final 
completed CRFs will be stored in the Investigator's archives for up 2 years following the 
final approval of the last marketing authorization, together with all the other site study-
specific documents (including Investigator’s site file).  Neither of these is ever transferred to 
the Sponsor. 
All study-related materials must be stored in a secure manner and must remain available 
upon request from Nicox or any Health Authority. 
 
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15. PUBLICATION POLICY 
The institutions, investigators, and all study personnel shall regard all study data as 
confidential until analyses and review of the analyses are performed by Nicox.   
The institutions and investigators participating in this trial shall have no right to publish or 
present the results of this study without the prior written consent of Nicox. 
 
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16. REFERENCES 
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ophthalmic use: a review of the comparative clinical effectiveness and cost-effectiveness. 
2015 July 30. 
Cavet ME, Vittitow JL, Impagnatiello F, Ongini E, Bastia E. Nitric oxide (NO): An emerging 
target for the treatment of glaucoma. Invest Ophthalmol Vis Sci. 2014;55:5005-15. 
Daka Q, Trkulja V. Efficacy and tolerability of mono-compound topical treatments for 
reduction of intraocular pressure in patients with primary open angle glaucoma or ocular 
hypertension: an overview of reviews. Croat Med J. 2014;55:468-80. 
Gabelt BT, Kaufman PL, Rasmussen CA. Effect of nitric oxide compounds on monkey 
ciliary muscle in vitro. Exp Eye Res. 2011;93:321-7. 
Gandolfi S, Simmons ST, Strum R, Chen K, VanDenburgh AM, Bimatoprost Study Group 
3. Three-month comparison of bimatoprost and latanoprost in patients with glaucoma and 
ocular hypertension. Adv Ther. 2001 May-Jun;18(3):110-21. 
Heyne GW, Kiland JA, Kaufman PL, Gabelt BT. Effect of nitric oxide on anterior segment 
physiology in monkeys. Invest Ophthalmol Vis Sci. 2013;54:5103-10. 
Impagnatiello F, Toris CB, Batugo M, Prasanna G, Borghi V, Bastia E, et al. Intraocular 
pressure-lowering activity of NCX 470, a novel nitric oxide-donating bimatoprost in 
preclinical models. Invest Ophthalmol Vis Sci. 2015;56:6558-64. 
Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) 
Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results 
of the First International Workshop. Am J Ophthalmol 2005;140:509-16. 
Jonas JB, Aung T, Bourne, RR, Bron AM, Ritch R, Panda-Jonas S.  Glaucoma. Lancet 
2017 Nov 11;309(10108):2183-93. 
Kapetanakis VV, Chan MP, Foster PJ, Cook DG, Owen CG, Rudnicka AR. Global 
variations and time trends in the prevalence of primary open angle glaucoma (POAG): a 
systematic review and meta-analysis. Br J Ophthalmol 2016;100:86-93. 
Krauss AHP, Woodward DF. Update on the mechanism of action of bimatoprost: a review 
and discussion of new evidence. Surv Ophthalmol. 2004;49 (suppl 1):S5-11. 
Li T, Lindsley K, Rouse B, Hong H, Shi Q, Friedman DS, et al. Comparative effectiveness 
of first-line medications for primary open-angle glaucoma: a systematic review and network 
meta-analysis. Ophthalmology. 2016 Jan;123(1):129-40. 
Medeiros FA, Martin KR, Peace J, Scassellati SB, Vittitow JL, Weinreb RN. Comparison of 
latanoprostene bunod 0.024% and timolol maleate 0.5% in open-angle glaucoma or ocular 
hypertension: the LUNAR Study. Am J Ophthalmol. 2016;30223-9. 
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Parrish RK, Palmberg P, Sheu WP, for the XLT Study Group. A comparison of latanoprost, 
bimatoprost, and travoprost in patients with elevated intraocular pressure: a 12-week, 
randomized, masked-evaluator multicenter study. Am J Ophthalmol. 2003 May;135(5):688-
703. 
Weinreb RN, Aung T, Medeiros FA. The pathophysiology and treatment of glaucoma: a 
review. JAMA. 2014 May 14;311:1901-11. 
Weinreb RN, Sforzolini BS, Vittitow J, Liebmann J. Latanoprostene bunod 0.024% versus 
timolol maleate 0.5% in subjects with open-angle glaucoma or ocular hypertension: the 
APOLLO study. Ophthalmology. 2016 May;123(5):965-73. 
Woodward DF, Krauss AHP, Nilsson SFE. Bimatoprost effects on aqueous humor 
dynamics in monkeys. J Ophthalmol. 2010;23:926192. 
 
Nicox Ophthalmics, Inc., NCX-470 Ophthalmic Solution





















SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
 A Phase 2, Randomized, Multicenter, Masked, Parallel-Group, Dose 
Response Study Evaluating the Safety and Efficacy of NCX 470 (3 
doses: 0.021%, 0.042%, and 0.065%) vs. Latanoprost 0.005% in 
Subjects with Open-Angle Glaucoma or Ocular Hypertension 
Sponsor:  
 Nicox Ophthalmics, Inc. 
Protocol Number: 
NCX-470-17001 
Author:  
 
 
 
Date:  
September 23, 2019 
Version: 
Final 2.0 
  
NCT03657797




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Table of Contents 
1. 
Introduction............................................................................................................................... 6 
2. 
Study Objectives ...................................................................................................................... 6 
2.1 Study Endpoints ....................................................................................................................... 6 
2.1.1 
Efficacy Endpoints ............................................................................................................ 6 
2.1.2 
Safety Endpoints .............................................................................................................. 6 
2.2 Primary Hypotheses ................................................................................................................. 7 
3. 
Study Design and Procedures ................................................................................................. 8 
3.1 General Study Design .............................................................................................................. 8 
3.2 Schedule of Visits and Assessments ..................................................................................... 10 
4. 
Study Treatments ................................................................................................................... 10 
4.1 Method of Assigning Subjects to Treatment Groups ............................................................. 10 
4.2 Masking and Unmasking ........................................................................................................ 10 
5. 
Sample Size and Power Considerations ................................................................................ 10 
6. 
Analysis Populations .............................................................................................................. 11 
7. 
General Statistical Considerations ......................................................................................... 11 
7.1 Unit of Analysis....................................................................................................................... 11 
7.2 Missing Data Handling ........................................................................................................... 11 
7.3 IOP Values for Analysis ......................................................................................................... 11 
7.4 Baseline Definition for Variables Other Than IOP.................................................................. 12 
7.5 Data Analysis Conventions .................................................................................................... 12 
8. 
Disposition of Subjects ........................................................................................................... 13 
9. 
Demographics and Baseline Characteristics ......................................................................... 13 
10. 
Medical History and Concomitant Medications ...................................................................... 13 
10.1 Medical History ....................................................................................................................... 13 
10.2 Prior and Concomitant Medications ....................................................................................... 14 
11. 
Efficacy Analyses ................................................................................................................... 14 
11.1 Primary Analysis .................................................................................................................... 17 
 
 
 
 
12. 
Safety Analyses ..................................................................................................................... 22 
12.1 Exposure Duration of Study Drug and Compliance ............................................................... 22 
12.2 Adverse Events ...................................................................................................................... 22 
12.3 Best-Corrected Visual Acuity (Early Treatment of Diabetic Retinopathy Study [ETDRS]) .... 23 


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12.4 Slit-Lamp Biomicroscopy Examination ................................................................................... 23 
12.5 Conjunctival Hyperemia ......................................................................................................... 23 
12.6 Dilated Ophthalmoscopy Examination ................................................................................... 23 
12.7 Anterior Chamber ................................................................................................................... 24 
12.8 Pachymetry ............................................................................................................................ 24 
12.9 Vital Signs .............................................................................................................................. 24 
12.10 
Clinical Laboratory Tests and Urine Pregnancy Test..................................................... 25 
12.11 
Intraocular Pressure ....................................................................................................... 25 
13. 
Interim Analyses ..................................................................................................................... 25 
14. 
Changes from Protocol-Stated Analyses ............................................................................... 25 
15. 
Changes from Statistical Analysis Plan ................................................................................. 25 
16. 
References ............................................................................................................................. 25 
17. 
Appendix Schedule of Clinical Assessments/Procedures ..................................................... 27 
18. 
List of Tables and Listings...................................................................................................... 29 
18.1 List of Tables .......................................................................................................................... 29 
18.2 List of Listings......................................................................................................................... 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity  
CI 
Confidence Interval 
CSR 
Clinical Study Report 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat  
 
 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LS 
Least Squares 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
PDF 
Portable Document Format 
PP 
Per Protocol  
PT 
Preferred Term 
QD 
Once Daily 
RTF 
Rich Text Format 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
 
 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 
 
 




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Safety assessments will include  
o Rate of discontinuation from study 
o Adverse events (AEs)  
 
       as well as changes in the following: 
o IOP 
o Slit-lamp biomicroscopy 
o Conjunctival hyperemia 
o Dilated ophthalmoscopy 
o Pachymetry 
o Best-corrected visual acuity (BCVA) 
o Vital signs 
o Non-fasting clinical laboratory tests 
o Urine pregnancy tests for females of child-bearing potential 
 
2.2 
Primary Hypotheses 
The primary hypotheses are: 
 
• Testing NCX 470 ophthalmic solution, 0.021% non-inferior to latanoprost 
ophthalmic solution, 0.005%. 
 
H0: 
The difference between study eyes treated with NCX 470 0.021% and 
latanoprost 0.005% (NCX 470 – latanoprost) in the mean diurnal IOP 
change from baseline at the Week 4 Visit, is ≥ 1.5 mmHg. 
Ha: 
The difference between study eyes treated with NCX 470 0.021% and 
latanoprost 0.005% (NCX 470 – latanoprost) in the mean diurnal IOP 
change from baseline at the Week 4 Visit, is < 1.5 mmHg. 
 
NCX 470 0.021% will be non-inferior to latanoprost if the null hypothesis (H0) is 
rejected (i.e., the upper limit of the two-sided 95% CI around the differences 
between the LS mean of NCX 470 0.021% and the LS mean of the latanoprost 
group [NCX 470 – latanoprost] is < 1.5 mmHg). If NCX 470 0.021% is non-inferior 
to latanoprost, then the superiority of the NCX470 0.021% to latanoprost will be 
tested. NCX 470 0.021% will be superior to latanoprost if the p-value for the testing 
treatment difference is <= 0.05 and the LS mean difference in change from 
baseline at Week 4 visit (NCX470 – latanoprost) is < 0. 
 
• Testing NCX 470 ophthalmic solution, 0.042% non-inferior to latanoprost 
ophthalmic solution, 0.005%. 
 
H0: 
The difference between study eyes treated with NCX 470 0.042% and 
latanoprost 0.005% (NCX 470 – latanoprost) in the mean diurnal IOP 
change from baseline at the Week 4 Visit, is ≥ 1.5 mmHg. 


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Ha: 
The difference between study eyes treated with NCX 470 0.042% and 
latanoprost 0.005% (NCX 470 – latanoprost) in the mean diurnal IOP 
change from baseline at the Week 4 Visit is <1.5 mmHg. 
 
NCX 470 0.042% will be non-inferior to latanoprost if the null hypothesis (H0) is 
rejected (i.e., the upper limit of the two-sided 95% CI around the differences 
between the LS mean of NCX 470 0.042% and the LS mean of the latanoprost 
group [NCX 470 – latanoprost] is < 1.5 mmHg). If NCX 470 0.042% is non-inferior 
to latanoprost, then the superiority of the NCX470 0.042% to latanoprost will be 
tested. NCX 470 0.042% will be superior to latanoprost if the p-value for the testing 
treatment difference is <= 0.05 and the LS mean difference in change from 
baseline at Week 4 visit (NCX470 – latanoprost) is < 0. 
 
 
• Testing NCX 470 ophthalmic solution, 0.065% non-inferior to latanoprost 
ophthalmic solution, 0.005%. 
 
H0: 
The difference between study eyes treated with NCX 470 0.065% and 
latanoprost 0.005% (NCX 470 – latanoprost), in the mean diurnal IOP 
change from baseline at the Week 4 Visit, is ≥ 1.5 mmHg. 
Ha: 
The difference between study eyes treated with NCX 470 0.065% and 
latanoprost 0.005% (NCX 470 – latanoprost), in the mean diurnal IOP 
change from baseline at the Week 4 Visit, is < 1.5 mmHg. 
 
NCX 470 0.065% will be non-inferior to latanoprost if the null hypothesis (H0) is 
rejected (i.e., the upper limit of the two-sided 95% CI around the differences 
between the LS mean of NCX 470 0.065% and the LS mean of the latanoprost 
group [NCX 470 – latanoprost] is < 1.5 mmHg). If NCX 470 0.065% is non-inferior 
to latanoprost, then the superiority of the NCX470 0.065% to latanoprost will be 
tested. NCX 470 0.065% will be superior to latanoprost if the p-value for the testing 
treatment difference is <= 0.05 and the LS mean difference in change from 
baseline at Week 4 visit (NCX470 – latanoprost) is < 0. 
 
Multiple comparison adjustment will not be applied given that it is a Phase 2 study. 
 
3. Study Design and Procedures 
3.1 
General Study Design 
 
This is a randomized, multicenter, masked, parallel-group, dose-response phase 2 clinical 
study. This study will be conducted in approximately 20 sites in the United States. Up to 
10 will be added based on enrollment rates. Approximately 550 subjects will be screened 
and 420 will be randomized. 
 
 


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Subjects will be assessed for initial eligibility at the Screening Visit (Figure 1). Subjects 
currently being treated with an IOP-lowering medication (pretreated) will be required to 
discontinue their IOP-lowering medication during a washout period which will occur 
between the Screening Visit and the Eligibility 1 Visit. The length of the washout period 
will be determined based on the type of IOP-lowering medication used by the subject. 
Treatment-naïve subjects’ Eligibility 1 Visit will be scheduled a minimum of 5 days after 
the Screening Visit to allow review of clinical laboratory results. 
 
Successful washout and IOP-based eligibility for all subjects will be determined at the 
Eligibility 1 Visit (Day -7 to -3) and the Eligibility 2 Visit (Day 1) with diurnal IOP 
measurements at 8 AM, 10 AM, and 4 PM at both visits. The baseline IOP for all study 
analyses will be based on the study eye mean diurnal IOP from the Eligibility 1 and 
Eligibility 2 Visits. Subjects meeting eligibility requirements will be randomized. Study 
medication will be dispensed at the end of the Eligibility 2 Visit. 
Subjects will be randomized in a 1:1:1:1 ratio to receive NCX 470 or latanoprost one 
drop in both eyes, QD in the evening: 
• NCX 470 ophthalmic solution, 0.021% 
• NCX 470 ophthalmic solution, 0.042% 
• NCX 470 ophthalmic solution, 0.065% 
• Latanoprost ophthalmic solution, 0.005% 
 
Both eyes will be treated for the duration of the study. The study eye will be the eye with 
the highest baseline IOP value or the right eye if both eyes of a subject have the same 
IOP value at baseline. The contralateral eye will be considered as the fellow eye. 
 






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3 readings of IOP. The means or the medians (i.e. the time-matched IOP values) will be 
the ‘base’ values for the calculation of mean diurnal IOP values and IOP analyses. 
  
Mean diurnal IOP value for a specific visit will be calculated as an average of IOP values 
from the three timepoints (8 AM, 10 AM, and 4 PM) for the specific visit.   
 
Baseline mean diurnal IOP will be calculated as an average of the mean diurnal IOP 
values at the Eligibility 1 and Eligibility 2 Visits.   
 
Time-matched baseline IOP will be calculated as an average of the IOP values at the 
8 AM time point from the Eligibility 1 and Eligibility 2 visits for the 8 AM time point of each 
post-baseline visit; an average of the IOP values at the 10 AM time point from the 
Eligibility 1 and Eligibility 2 visits for the 10 AM time points of each post-baseline visit; and 
an average of the IOP values at the 4 PM time point from the Eligibility 1 and Eligibility 2 
visits for the 4 PM time point of each post-baseline visit. 
7.4 
 Baseline Definition for Variables Other Than IOP 
Baseline is defined as the last measurement prior to the first administration of study drug. 
Change from baseline will be calculated as follow-up visit minus baseline visit. 
7.5 
Data Analysis Conventions 
All data analysis will be performed 
 after the study 
is completed and the database has been locked. Statistical programming and analyses 
will be performed using SAS® Version 9.4 or higher. Outputs 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. Additional data listings will be provided 
as described in the sections for the data analyses.  
 
Summaries for continuous and ordinal variables will include the number of observations 
(n), arithmetic mean, standard deviation (SD), standard error (SE),  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. SDs will be presented to two additional decimal places than 
reported in the raw values. Summaries for discrete variables will include frequency counts 
and percentages.  All percentages will be rounded to one decimal place (i.e., XX.X%).   
 
All statistical tests will be two-sided with a significance level of 0.05 (α = 0.05), unless 
otherwise specified. All p-values will be rounded to four decimal places; p-values less 
than 0.0001 will be presented as “<0.0001”; p-values greater than 0.9999 will be 
presented as “>0.9999.” 
 
For efficacy analyses, unscheduled visits and early termination visits will be mapped to 
scheduled visits if they fall into the scheduled visit windows. If there are more than 


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1 assessment that  fall into a scheduled visit window afer the mapping, the assessment 
at original scheduled visit will be used.  
 
For safety analyses, Unscheduled Visits will be excluded from analyses and early 
termination visits will be combined with Exit Visits for analyses.    
8. Disposition of Subjects 
Analysis populations, study completion, discontinuation from the study, reasons for 
discontinuation from the study, subjects with any protocol deviations, subjects with major 
deviations, and subjects with minor deviations will be summarized for all randomized 
subjects using number of subjects and percentages. Reasons of withdrawal include: AE, 
lost to follow-up, Investigator decision, Sponsor or Institutional Review Board (IRB) 
decision, protocol violation, study termination by Sponsor, withdrawal by subject, IOP 
greater than 36 mmHg, and other.    
9. Demographics and Baseline Characteristics 
The demographic variables collected in this study include age, age category (>=18 to 
< 65, >=65, >= 75 years), sex, race, ethnicity and iris color.  Subjects who record more 
than one race will be grouped into a single category denoted as multi-racial. Demographic 
variables will be summarized for the ITT population and the PP population, separately. 
 
Age will be reported in years and calculated using the following formula: 
Age = (Informed consent date – Date of birth) / 365.25 truncated as an integer. 
 
The following baseline variables for study eyes will be summarized for the ITT and PP 
population, separately:  
• Baseline mean diurnal IOP  
• Central corneal thickness  
• Cup to disc ratio (horizontal) 
• Cup to disc ratio (vertical) 
• BCVA 
• Conjunctival hyperemia 
 
 
Visual field and gonioscopy assessments will be performed at Screening Visit. The results 
will be presented in subject data listings.  
10. Medical History and Concomitant Medications 
10.1 Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA), Version 21.0. 
 
Ocular medical history and non-ocular medical history will be summarized at the subject 
level based on the safety population, separately.  If a subject reports the same preferred 
term (PT) multiple times within the same system organ class (SOC), the subject will only 
be counted once for the SOC.  As with the PT, if a subject reports multiple conditions 
within the same PT, that subject will only be counted once for the PT.   


























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and Human Services: Food and Drug Administration.  Federal Register Vol. 61, July 
17, 1996, page 37320. (E3)