Clinical trial NCT02978183
Conditions: Allergic Conjunctivitis
Sponsor: Noveome Biotherapeutics, formerly Stemnion
Start date: 2016-12-01; Completion date: 2017-11-01
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy of ST266 ophthalmic drops compared to placebo for the treatment of the signs and symptoms of allergic conjunctivitis.

Detailed description:
The study is a multi-center, double-masked, randomized, placebo-controlled, modified conjunctival allergen challenge (CAC) model. The primary endpoints of ocular itching and conjunctival redness will be evaluated at the subject's final visit. Subjects who meet inclusion criteria will be randomized to one of two treatment groups (1:1). Randomization will be stratified by average post-CAC itching scores at baseline.

Subjects will be evaluated at baseline and on Days 6, 7 and 8.

Arms: arm 1: 1X ST266 dosed 4 times a day for 8 days arm 2: Placebo dosed 4 times a day for 8 days
Interventions: intervention 1: ST266 intervention 2: Saline (0.9% NaCl)
Intervention descriptions: intervention 1: One (1) drop of 1X ST266 ophthalmic eye drops will be administered to each eye 4 times a day for 8 days. intervention 2: One (1) drop of saline ophthalmic eye drops will be administered to each eye 4 times a day for 8 days.

Protocol documents:
Prot_002.pdf: 
CLINICAL TRIAL PROTOCOL: ST266-AC-201/16-100-0005 
 
A Multi-Center, Double-Masked, Randomized, Phase 2 Evaluation of the Effectiveness of 
ST266 Ophthalmic Drops Compared to Placebo for the Treatment of Allergic Conjunctivitis 
Using a Modified Conjunctival Allergen Challenge Model (Ora-CAC®) 
 
NCT02978183 
 
Protocol Date: 13 January 2017 
 
Noveome Biotherapeutics, Inc. 
100 Technology Drive, Suite 200 
Pittsburgh, PA 15219 


ST266 Ophthalmic Drops 
Noveome Biotherapeutics, Inc. 
Clinical Trial Protocol: ST266-AC-201/16-100-0005 
Amendment V3.0/13Jan2017 
CONFIDENTIAL 
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1 CLINICAL TRIAL PROTOCOL: ST266-AC-201/16-100-0005 
Protocol Title: 
A Multi-Center, Double-Masked, Randomized, 
Phase 2 Evaluation of the Effectiveness of ST266 
Ophthalmic Drops Compared to Placebo for the 
Treatment of Allergic Conjunctivitis Using a 
Modified Conjunctival Allergen Challenge Model 
(Ora-CAC®)  
Protocol Number: 
ST266-AC-201/16-100-0005 
Investigational Product Name: 
ST266 Ophthalmic Drops 
IND Number: 
BB-IND 16,170 
Indication Studied: 
Allergic Conjunctivitis 
Development Phase: 
2 
Name of Sponsor: 
Noveome Biotherapeutics, Inc.  
100 Technology Drive, Suite 200 
Pittsburgh, PA 15219 
Contract Research 
Organization: 
Ora, Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico, Suite C, #497 
San Clemente, CA 92673 
 
Date 
Original Protocol: 
31 October 2016 
Amendment: 
13 January 2017 
 
Statement of Compliance with Good Clinical Practice 
This study will be performed in compliance with the ethical principles of the Declaration of Helsinki and 
the International Conference on Harmonization (ICH) Harmonized Tripartite Guideline for Good Clinical 
Practice (GCP). 
Confidentiality Statement 
This protocol is confidential and the information available within it may not be reproduced or otherwise 
disseminated. 


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SPONSOR PERSONNEL 
Chief Medical Officer/Medical 
Monitor: 
 
 
 
 
ORA PERSONNEL 
Medical Monitor: 
  
 
 
Chief Medical Officer: 
 
 
 
Department Vice President: 
 
 
 
Project Lead: 
  
  
 
 
 
 
















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TABLE OF CONTENTS 
1 CLINICAL TRIAL PROTOCOL: ST266-AC-201/16-100-0005.............................1 
2 SYNOPSIS ....................................................................................................................3 
TABLE OF CONTENTS ................................................................................................10 
List of Abbreviations .......................................................................................................13 
3 INTRODUCTION......................................................................................................15 
4 STUDY OBJECTIVES ..............................................................................................17 
5 CLINICAL HYPOTHESES .....................................................................................17 
6 OVERALL STUDY DESIGN ...................................................................................17 
7 STUDY POPULATION ............................................................................................19 
 
Number of Subjects (approximate) ..................................................................19 
7.1
 
Study Population Characteristics .....................................................................19 
7.2
 
INCLUSION CRITERIA ..................................................................................19 
7.3
 
Exclusion Criteria ..............................................................................................20 
7.4
 
Withdrawal Criteria (if applicable) ..................................................................22 
7.5
8 STUDY MEASURES .................................................................................................22 
 
Efficacy Measures ..............................................................................................22 
8.1
 Primary Efficacy Measure(s) ......................................................................22 
8.1.1
 Secondary Efficacy Measure(s) ...................................................................22 
8.1.2
 Criteria for Effectiveness .............................................................................23 
8.1.3
 
Safety Measures ..................................................................................................23 
8.2
 
exploratory Measures ........................................................................................23 
8.3
 
tolerability Measures..........................................................................................24 
8.4
9 STUDY MATERIALS ...............................................................................................24 
 
Study Treatment(s) ............................................................................................24 
9.1
 Study Treatment(s)/ Formulation(s) ...........................................................24 
9.1.1
 Instructions for Use and Administration ...................................................26 
9.1.2
 
Other Study Supplies .........................................................................................27 
9.2
10 STUDY METHODS AND PROCEDURES ............................................................27 
 Subject Entry Procedures ..................................................................................27 
10.1
 Overview ........................................................................................................27 
10.1.1
 Informed Consent .........................................................................................27 
10.1.2
 Washout Intervals ........................................................................................28 
10.1.3
 Procedures for Final Study Entry ...............................................................29 
10.1.4
 Methods for Assignment to Treatment Groups: .......................................29 
10.1.5
 Concurrent Therapies ........................................................................................29 
10.2
 Prohibited Medications/Treatments ...........................................................29 
10.2.1
 Escape Medications ......................................................................................30 
10.2.2
 Special Diet or Activities ..............................................................................30 
10.2.3
 Examination Procedures....................................................................................30 
10.3
Procedures to be performed at each study visit with regard to study 
objective(s) ....................................................................................................30 
 Screening Visit (Day -30 to -3): Informed Consent/Skin 
10.3.1
Test/Washout Period ....................................................................................30 
 Visit 1 (Day -2): Screening/Titration CAC .................................................31 
10.3.2


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 Visit 2a (Day -1): CAC #1 ............................................................................33 
10.3.3
 Visit 2b (Day -1; 4 hours from Visit 2a): CAC #2 .....................................34 
10.3.4
 Visit 3 (Day 1): Baseline CAC/Enrollment/Begin QID Treatment ..........34 
10.3.5
 Visit 4a (Day 6): CAC #1 .............................................................................36 
10.3.6
 Visit 4b (Day 6; 4 hours from Visit 4a): CAC #2 .......................................37 
10.3.7
 Visit 5a (Day 7): CAC #3 .............................................................................38 
10.3.8
 Visit 5b (Day 7; 4 hours from Visit 5a): Duration of Action Efficacy 
10.3.9
CAC (4 Hours Post-Dose) ............................................................................39 
 Visit 6 (Day 8): Onset of Action Efficacy CAC (15 Minutes Post-
10.3.10
Dose) ..............................................................................................................40 
 Schedule of Visits, Measurements and Dosing ................................................42 
10.4
 Refer to Appendix 1 for a schedule of visits and measurements..............42 
10.4.1
 Unscheduled/Early Exit Visits .....................................................................42 
10.4.2
 Compliance with Protocol .................................................................................42 
10.5
 Subject Disposition .............................................................................................43 
10.6
 Completed Subjects ......................................................................................43 
10.6.1
 Discontinued Subjects ..................................................................................43 
10.6.2
 Study Termination .............................................................................................43 
10.7
 STUDY Duration ................................................................................................43 
10.8
 Monitoring and Quality Assurance ..................................................................43 
10.9
11 ADVERSE EVENTS .................................................................................................44 
 Severity ..........................................................................................................44 
11.1.1
 Relationship to Investigational Product .....................................................45 
11.1.2
 Expectedness .................................................................................................46 
11.1.3
 Serious Adverse Events ......................................................................................46 
11.2
 Procedures for Reporting Adverse Events.......................................................47 
11.3
 Reporting a Suspected Unexpected Adverse Reaction .............................47 
11.3.1
 Reporting a Serious Adverse Event ............................................................47 
11.3.2
 Procedures for Unmasking (if applicable) .......................................................48 
11.4
 Type and Duration of the Follow-up of Subjects after Adverse Events ........48 
11.5
12 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES...................48 
 Statistical Analysis Plan .....................................................................................48 
12.1
 Study Populations ...............................................................................................49 
12.2
 Intent-to-Treat Population ..........................................................................49 
12.2.1
 Per-Protocol Population ...............................................................................49 
12.2.2
 Safety Population ..........................................................................................49 
12.2.3
 Statistical Hypotheses ........................................................................................49 
12.3
 Sample Size .........................................................................................................49 
12.4
 Efficacy Analyses ................................................................................................50 
12.5
 Safety Analysis ....................................................................................................50 
12.6
 Interim Analysis .................................................................................................50 
12.7
13 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ...................................51 
 Protection of Human Subjects ..........................................................................51 
13.1
 Subject Informed Consent ...........................................................................51 
13.1.1
 Institutional Review Board (IRB) Approval ..............................................52 
13.1.2


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 Ethical Conduct of the Study ............................................................................52 
13.2
 Subject Confidentiality ......................................................................................52 
13.3
 Documentation ....................................................................................................52 
13.4
 Retention of Documentation ........................................................................52 
13.4.1
 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
13.5
Investigational Product ......................................................................................53 
 Labeling/Packaging ......................................................................................53 
13.5.1
 Storage of Investigational Product .............................................................53 
13.5.2
 Accountability of Investigational Product .................................................53 
13.5.3
 Return or Disposal of Investigational Product ..........................................53 
13.5.4
 Recording of Data on Source Documents and Case Reports Forms (CRFs) 54 
13.6
 Handling of Biological Specimens .....................................................................54 
13.7
 Publications .........................................................................................................54 
13.8
14 REFERENCES ...........................................................................................................55 
Appendix 1 ........................................................................................................................56 
Appendix 2 ........................................................................................................................58 
Appendix 3 ........................................................................................................................66 
Appendix 4 ........................................................................................................................74 
Appendix 5 ........................................................................................................................75 
Appendix 6 ........................................................................................................................79 
Appendix 7 ........................................................................................................................80 
Appendix 8 ........................................................................................................................81 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
AC 
allergic conjunctivitis 
ACCS 
Amnion-derived Cellular Cytokine Solution 
AE 
adverse event 
AMP 
Amnion-derived Multipotent Progenitor 
ANCOVA 
Analysis of Covariance 
BCVA 
best-corrected visual acuity 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIS 
conjunctival inflammation score 
CRF 
case report form 
CRO 
contract research organization 
DHHS 
Department of Health and Human Services 
ECD 
endothelial cell density  
ECG 
Electrocardiogram 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Information Portability and Accountability Act 
IB 
investigators’ brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IND 
investigational new drug application 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
institutional/independent review board 
ITT 
intent to treat 


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IV 
intravenous  
LASIK 
laser in situ keratomileusis 
LOCF 
last observation carried forward 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters of mercury 
NCS 
not clinically significant 
NSAID  
nonsteroidal anti-inflammatory drug 
OD 
right eye 
Ora-CAC® 
conjunctival allergen challenge 
OS 
left eye 
OU 
both eyes 
PHI 
protected health information 
PP 
per protocol 
PRN 
as needed 
QID 
four times a day 
ROPI 
Report of Prior Investigations  
SAE 
serious adverse event 
SAS 
statistical analysis software 
SD 
standard deviation 
SDC 
Statistics and Data Corporation 
SOP 
standard operating procedures 
SUSARs 
suspected unexpected serious adverse reactions 
TEAEs 
treatment-emergent adverse events 
VA 
visual acuity 
 
 


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3 INTRODUCTION 
Allergies affect approximately 15% of the global population and up to 30% of the U.S. 
population (Bielory 2000). Allergic reactions can vary from a mild, self-limiting 
condition to a debilitating condition that significantly impairs the quality of life. Allergic 
conjunctivitis is generally considered a type 1 hypersensitivity reaction, and is the most 
prevalent allergic condition, representing about a third of all allergic disorders.  
The physiologic basis for allergic conjunctivitis is multifactorial and involves both an 
early acute phase triggered by mast cell degranulation and release of histamine and a late 
phase involving various pro-inflammatory mediators (Abelson 2003). Histamine is the 
primary preformed mediator responsible for the typical early phase reaction that triggers 
itching, vasodilation, and vascular leakage leading to ocular redness, chemosis, and 
blepharitis. The early phase response occurs within minutes to hours following allergen 
exposure. The itching associated with the early phase allergic reaction has been shown to 
peak at ~ 5-7 minutes after allergen provocation, which coincides with mast-cell 
degranulation. Mast cells also synthesize and release cytokines, chemokines, and growth 
factors that initiate a cascade of inflammatory events leading to a late-phase reaction 
involving a variety of pro-inflammatory mediators including prostaglandins, leukotrienes, 
cytokines, and interleukins and characterized by recruitment of eosinophils, neutrophils, 
and subsequent lymphocytes and macrophages into the conjunctival tissues (Ciprandi 
1993; Bacon 2000). 
 
Current treatments for allergic conjunctivitis include histamine blockers and mast-cell 
stabilizers, which address early-phase symptoms, and steroids, which address late-phase 
symptoms. Agents that have good efficacy with fewer adverse effects, particularly 
associated with steroids for late-phase symptoms, are warranted.  
 
Amnion-derived Multipotent Progenitor (AMP) cells have a unique secretory profile, 
producing a novel secretome containing many cytokines and growth factors known to be 
involved in wound healing and the inflammatory response. This secretome, known as 
ST266 (formerly Amnion-derived Cellular Cytokine Solution [ACCS], Noveome 
Biotherapeutics, Inc.), has been carefully characterized. Noveome produces ST266 under 
cGMP conditions. Placentas are tested and screened for known infectious agents, and 
conform to all HIPAA requirements. The secreted proteins have been characterized by 
mass spectroscopy, antibody array analysis, and ELISA. Lot release testing of individual 
production lots of ST266 have documented the concentration reproducibility of five 
selected cytokines (PDGF-ββ, VEGF, Angiogenin, TIMP-1, TIMP-2) and MMP-9 
inhibition activity. ST266 may provide a novel treatment option for inflammatory 
conditions, including allergic conjunctivitis (Steed 2008). 
 
ST266 has been shown to be anti-inflammatory, anti-apoptotic, and neuroprotective in 
several animal models, including rats, rabbits, guinea pigs, and mice. ST266 appears to 
reinstate physiologic homeostasis in impaired inflammatory conditions without the 
application of steroids and associated side effects. The scientific rationale for using this 
amnion cell-derived product originated from scarless fetal wound healing partially 


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attributed to cytokines in the amniotic fluid (Larson 2010, Lo 2012). Several in vivo 
animal studies showed faster wound healing with ST266, sometimes with less 
inflammation. In a mouse ear model of inflammation caused by a contact irritant, ST266 
reduced inflammation similar to clobetasol, a class I steroid, by the third day. Nonclinical 
toxicology studies have been performed with topical (dermal, oral cavity, eyes) and 
systemic (IV) formulations of ST266, and no safety issues have been identified. When 
given topically in animal models, there was no evidence of systemic exposure to ST266 
(Bergmann 2009).  
 
ST266 has been shown to be safe in eight separate preclinical GLP safety studies of 
single and multiple repeat-dose administrations for topical applications. A 24-hour ocular 
pharmacokinetic (PK) and tissue distribution study conducted in 36 New Zealand white 
rabbits following topical and IV administration of ST266 (50 µL) found ST266 primarily 
in the lower conjunctiva, with no indication that the protein diffused in the vitreous or 
retina after topical dosing. Peak tissue concentrations were observed at 6 hours after 
dosing. At 24-hrs post-dosing, approximately 70% of the material remained in the 
vitreous, suggesting extended activity. In an acute eye irritation study with three (3) New 
Zealand white rabbits, topical administration of ST266 (0.1 mL) after 72 hours indicated 
that the drug was non-irritating (Investigational Brochure ST266, topical ophthalmic 
administration 2016).  
 
ST266 has been studied in Phase 1 clinical trials involving topical administration to the 
skin or oral cavity. In these studies, ST266 was well tolerated and no safety issues were 
identified. Approximately 100 humans have been exposed to ST266 for up to 42 
consecutive days without drug-related adverse effects in six (6) separate clinical trials. 
One (1) study showed anti-inflammatory efficacy in treating gingivitis. Another Phase 1 
study with topical ST266 treatment in subjects with partial thickness burns indicated no 
evidence of systemic absorption of ST266 components. Noveome is currently conducting 
a Phase 2 randomized, double-blind, placebo-controlled 9-month safety and efficacy 
study of up to 150 subjects with periodontitis. Noveome completed a Phase 1 study (ST-
05-14) to assess the safety of ST266 eye drops in subjects with moderate to severe dry 
eye. Thirty (30) subjects were randomized to receive either study drug or an over-the-
counter artificial tear eye drops four times per day for six (6) weeks. Subjects were 
examined regularly during the six-week dosing period and then followed for an additional 
month for safety. No adverse events were observed related to administration of the study 
drug. No clinically significant changes were observed in best corrected visual acuity 
(BCVA), intraocular pressure (IOP), endothelial cell density (EDC), conjunctival 
staining, tear osmolarity, cup-to-disc ratio, hematology, blood chemistry, urinalysis, or 
vital signs after initiation of the investigational treatment. The results provide preliminary 
evidence of safety and tolerability of ST266 eye drops in human subjects.(Investigational 
Brochure ST266 topical ophthalmic administration 2016).  
The conjunctival allergen challenge (CAC)-induced allergic response mimics the acute 
response that is triggered by intermittent exposure to allergen. The Ora-CAC® model has 
been used to evaluate anti-allergic agents and to identify the cellular and mediator 
responses seen in allergic conjunctivitis (Abelson et al 1990). The Ora-CAC® model has 






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7 STUDY POPULATION 
 NUMBER OF SUBJECTS (APPROXIMATE) 
7.1
Up to 175 subjects will be screened in order to enroll approximately 70 subjects at two 
(2) centers.  
 STUDY POPULATION CHARACTERISTICS 
7.2
Subjects at least 18 years of age, of either gender or any race, who have a positive history 
of allergic conjunctivitis, and who meet all of the inclusion criteria and none of the 
exclusion criteria. 
 INCLUSION CRITERIA 
7.3
Each subject must: 
1) be at least 18 years of age of either gender and any race; 
2) provide written informed consent and sign the HIPAA form; 
3) be willing and able to follow all instructions and attend all study visits; 
4) have a positive history of ocular allergies and a positive skin test reaction to a 
seasonal (individual grass allergen, individual tree allergen, and/or ragweed) 
AND perennial allergen (cat dander, dog dander, dust mites, cockroach) as 
confirmed by an allergic skin test; 
5) be able and willing to avoid all disallowed medication for the appropriate washout 
period and during the study (see exclusion 6); 
6) be able and willing to discontinue wearing contact lenses for at least 72 hours 
prior to and during the study trial period;  


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7) (for females capable of becoming pregnant) agree to have urine pregnancy testing 
performed at Visit 1 (must be negative) and at the exit visit5; must not be 
lactating; and must agree to use a medically acceptable form of birth control6 
throughout the study duration and for at least 14 days prior to instillation of 
investigational product (Visit 3)7. Women considered capable of becoming 
pregnant include all females who have experienced menarche and have not 
experienced menopause (as defined by amenorrhea for greater than 12 
consecutive months) or have not undergone successful surgical sterilization 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy); 
8) have a calculated visual acuity of 
 
   
9) have a positive bilateral post-CAC reaction 
 
 
  
10) have a positive bilateral post-CAC reaction 
 
 
 
 
11) be able to self-administer eye drops satisfactorily or have a caregiver at home8 
routinely available for this purpose. 
 EXCLUSION CRITERIA 
7.4
Each subject must not: 
1) have known contraindications or sensitivities to the use of the investigational 
product or any of its components;  
2) have any ocular condition that, in the opinion of the investigator, could affect 
the subject’s safety or trial parameters (including but not limited to narrow 
angle glaucoma, clinically significant blepharitis, follicular conjunctivitis, iritis, 
or pterygium);  
3) have had ocular surgical intervention within 3 months prior to Visit 1 or during 
the study and/or a history of refractive surgery within the past 6 months; 
                                                 
5 The subject must choose an acceptable method of birth control as specified in inclusion criterion 7 in order to 
continue in the study.  
6 Acceptable forms of birth control are spermicide with barrier, oral contraceptive, injectable or implantable method of 
contraception, transdermal contraceptive, intrauterine device, or surgical sterilization of partner.  For non-sexually 
active females, abstinence will be considered an acceptable form of birth control.  
7 14 day birth control duration will be queried and captured at initial medical/medication history 
8 If a caregiver will be used to administer eye drops, then he/she must be present at Visit 3 to administer eye drops in-
office. 


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4) have a known history of retinal detachment, diabetic retinopathy, or active 
retinal disease; 
5) have the presence of an active ocular infection (bacterial, viral or fungal) or 
positive history of an ocular herpetic infection at any visit; 
6) use any of the following disallowed medications* during the period indicated 
prior to Visit 1 and during the study: 
7 Days 
 systemic or ocular H1 antihistamine, H1 antihistamine/mast-cell stabilizer 
drug combinations, H1 antihistamine- vasoconstrictor drug combinations; 
 decongestants; 
 monoamine oxidase inhibitors; 
 all other topical ophthalmic preparations (including artificial tears); 
 lid scrubs; 
 prostaglandins or prostaglandin derivatives; 
 ocular, topical, or systemic nonsteroidal anti-inflammatory drugs (NSAIDs); 
14 Days 
 inhaled, ocular or topical corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
2 months 
 immunotherapeutic agents: if on treatment at time of consent, treatment must 
have been maintained steadily for at least 2 months prior; neither the 
immunotherapeutic agent nor its dosage may change during the clinical trial. 
*Note: Currently marketed over-the-counter anti-allergy eye drops (ie anti-histamine/ 
vasoconstrictor combination products such as Visine®-A®) may be administered to 
subjects at the end of the subject’s last visit, after all evaluations are completed;  
7) have any significant illness (e.g. any autoimmune disease requiring therapy, 
severe cardiovascular disease [including arrhythmias] the investigator feels 
could be expected to interfere with the subject’s health or with the study 
parameters and/or put the subject at any unnecessary risk (includes but is not 
limited to: poorly controlled hypertension or poorly controlled diabetes, a 
history of status asthmaticus, organ transplants, a known history of persistent 
moderate or severe asthma, or a known history of moderate to severe allergic 
asthmatic reactions to any of the study allergens; 
8) manifest signs or symptoms of clinically active allergic conjunctivitis in either 
eye at the start of Visit 1 
 
; 
9) have planned surgery (ocular or systemic) during the trial period or within 30 
days after;  
10) have used an investigational drug or medical device within 30 days of the study 
or be concurrently enrolled in another investigational product trial; 














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Visit 1. However, informed consent must be obtained prior to Visit 1 if any of the 
following criteria are determined during the telephone screening process: 
o Proper washout of certain medications is necessary 
o Sufficient time of discontinuation of contact lens wear is necessary 
o Post-operative period 
 
Medical/medication history, demographics, skin test, and inclusion/exclusion review may 
be performed at the time of informed consent signing prior to Visit 1, but must be 
confirmed at Visit 1 (with the exception of demographics and skin test). 
Prior to the completion of the Screening Visit, if it is determined a subject did not in fact 
meet certain washout criteria, the subject may be brought back at a later date to re-
attempt the screening process. 
 Washout Intervals 
10.1.3
Subjects will adhere to the following medication washout intervals during the period 
indicated prior to Visit 1 and will refrain from using these medications during the 
study:   
72 Hours 
 Contact lenses 
 
7 Days 
 systemic or ocular H1 antihistamine, H1 antihistamine/mast-cell stabilizer drug 
combinations, H1 antihistamine- vasoconstrictor drug combinations; 
 decongestants; 
 monoamine oxidase inhibitors; 
 all other topical ophthalmic preparations (including artificial tears); 
 lid scrubs; 
 prostaglandins or prostaglandin derivatives; 
 ocular, topical, or systemic nonsteroidal anti-inflammatory drugs (NSAIDs); 
14 Days 
 inhaled, ocular or topical corticosteroids or mast cell stabilizers;  
 
45 Days 
 depot-corticosteroids; 
 
2 months 
 immunotherapeutic agents: if on treatment at time of consent, treatment must 
have been maintained steadily for at least 2 months prior; neither the 
immunotherapeutic agent nor its dosage may change during the clinical trial. 
 




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 depot-corticosteroids; 
 immunotherapeutic agents: if on treatment at time of consent, treatment must have 
been maintained steadily for at least 2 months prior; neither the immunotherapeutic 
agent nor its dosage may change during the clinical trial. 
 
 Escape Medications 
10.2.2
Cold compress should first be used in the management of allergic symptoms. Subjects 
may be prescribed an anti-inflammatory or anti-allergy medication at the Investigator’s 
discretion. Subjects, however, will be discontinued if prescribed such anti-inflammatory 
or anti-allergy medication.  
Currently marketed over-the-counter anti-allergy eye drops (i.e., anti-histamine/ 
vasoconstrictor combination products such as Visine®-A®) may be administered to 
subjects at the end of the subject’s last visit, after all evaluations are completed. 
 Special Diet or Activities 
10.2.3
Not Applicable. 
 EXAMINATION PROCEDURES 
10.3
Procedures to be performed at each study visit with regard to study objective(s) 
 Screening Visit (Day -30 to -3): Informed Consent/Skin Test/Washout 
10.3.1
Period 
 
Informed Consent/HIPAA: Prior to any changes in a subject’s medical treatment 
and/or study visit procedures, the study will be discussed with each subject and 
subjects wishing to participate must give written informed consent and sign a 
HIPAA form. 
Informed consent may be obtained prior to Visit 1 if the subject wishes to 
review and discuss the Informed Consent with the Investigator or wishes to get 
a skin test prior to Visit 1. However, informed consent must be obtained prior to 
Visit 1 if any of the following criteria are determined during the telephone 
screening process: 
o Proper washout of certain medications is necessary 
o Sufficient time of discontinuation of contact lens wear is necessary 
o Post-operative period 
 
Medical/medication history, demographics, skin test, and inclusion/exclusion 
review may be performed at the time of informed consent signing prior to Visit 
1, but must be confirmed at Visit 1 (with the exception of demographics and 
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 
Allergic Skin Test: A diagnostic test for allergic disease (skin test) will be 
performed. 
 
Demographic data and medical/medication/ocular and non-ocular history: 
Collect and record all demographic data, medical history, any medications and 
any underlying condition(s). Current underlying conditions, including those that 
began within the last 45 days, which may have been resolved before screening 
must be recorded. Record any medications the subject is taking, as well as those 
the subject may have taken but discontinued within the 45 days prior to Visit 1. 
 
Review of Inclusion/Exclusion Criteria: Confirm if subject needs to washout 
from any current medications and instruct he/she to follow the appropriate 
washout time periods (refer to Section 10.1.3) 
 
Schedule Visit 1: Qualifying subjects will be scheduled for Visit 1. If a subject 
did not meet a certain washout criteria, the subject may be brought back at a 
later date to re-attempt the screening process. Subjects can be re-screened a 
maximum of three times. 
 
 Visit 1 (Day -2): Screening/Titration CAC 
10.3.2
 
Informed Consent/HIPAA (for subjects who did not come in for a Screening 
Visit): Prior to any changes in a subject’s medical treatment and/or study visit 
procedures, the study will be discussed with each subject and subjects wishing 
to participate must give written informed consent and sign a HIPAA form. 
 
Allergic Skin Test (for subjects who did not come in for a Screening Visit): A 
diagnostic test for allergic disease (skin test) will be performed. 
 
Demographic data and medical/medication/ocular and non-ocular history: 
Collect and record all demographic data, medical history, any medications and 
any underlying condition(s). Current underlying conditions, including those that 
began within the last 45 days, which may have been resolved before screening 
must be recorded. Record any medications the subject is taking, as well as those 
the subject may have taken but discontinued within the 45 days prior to Visit 1. 
If subjects came in for a Screening Visit prior to Visit 1, medical/medication 
history and inclusion/exclusion review must be reviewed and confirmed at Visit 
1.  
 
Urine Pregnancy Test (for females of childbearing potential): Females of 
childbearing potential must have a negative urine pregnancy test to continue in 
the study and must agree to use an adequate method of contraception for the 
duration of the study in order to be enrolled and for at least 14 days prior to the 
instillation of investigational product (Visit 3). 






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 Visit 2b (Day -1; 4 hours from Visit 2a): CAC #2 
10.3.4
 
Update of Medical/Medication History 
 
Visual Acuity Utilizing an ETDRS Chart  
 
Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment  
 
Slit Lamp Biomicroscopy: A slit lamp exam will be performed to exclude 
subjects with disallowed ocular conditions.   
 
Review of Inclusion/Exclusion Criteria 
 
CAC #2: For each qualified subject, one drop of the allergen solution, of the 
same dose that elicited a positive reaction at Visit 1, will be administered 
bilaterally. Challenge will occur 
 following the challenge 
at Visit 2a. 
 
Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: The 
Investigator and the subject will assess ocular and nasal allergic signs and 
symptoms using the Ora-CAC® scales (see Appendix 2) approximately 
 
 following CAC. 
 
Schedule for Visit 3: Subjects will be scheduled for Visit 3 the following day.  
 Visit 3 (Day 1): Baseline CAC/Enrollment/Begin QID Treatment 
10.3.5
 
Update of Medical/Medication History 
 
Visual Acuity Utilizing an ETDRS Chart  
 
Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment  
 
Slit Lamp Biomicroscopy: A slit lamp exam will be performed to exclude 
subjects with disallowed ocular conditions.  
 
Review Inclusion and Exclusion Criteria 
 
Baseline CAC: For each qualified subject, one drop of the allergen solution, of 
the same dose that elicited a positive reaction at Visit 1, will be administered 
bilaterally.  
 
Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: 
Assessments of itching will be made by the subject at 
 
 following allergen challenge. 
Assessments of redness and chemosis will be graded by the Investigator and 
assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms will be 








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(4) doses that day. Subjects will also be dispensed a dosing diary and will be 
instructed to complete daily assessments prior to bedtime and upon awakening 
beginning the evening of Visit 4b. 
 
Subjects will also be instructed to bring both investigational product and diary 
to the next visit (Visit 5a) for a compliance check. Subjects will be instructed to 
dose approximately 
 
 prior to 
their Visit 5a appointment, if time permits. If they are unable to dose prior to 
their appointment, they will receive their first dose in office that day.  
 
Subjects at one center will be instructed to take photographs of both of their 
eyes prior to completing diary assessments.  
 
 
Adverse Event Query 
 
Schedule for Visit 5a: Subjects will be scheduled for Visit 5a the following day. 
 Visit 5a (Day 7): CAC #3 
10.3.8
 
Update of Medical/Medication History 
 
Adverse Event Query 
 
Investigational Product and Dosing and Assessments Diary Review and 
Collection: Investigational product and dosing and assessments diary will be 
collected and reviewed for compliance from Visit 4b to Visit 5a and to address 
any queries. 
 
Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease 
 from Visit 
1 will be considered an adverse event. 
 
Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment  
 
Slit Lamp Biomicroscopy  
 
Investigational Product Instillation:  A trained study technician will instill 
investigational product approximately 
 prior to CAC #3 
according to the directions for use. The investigational product kit number and 
the time of instillation will be recorded. 
 
CAC #3: For each qualified subject, one drop of the allergen solution, of the 
same dose that elicited a positive reaction at Visit 1, will be administered 
bilaterally 
 post instillation of investigational product.  


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 
Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: The 
Investigator and the subject will assess ocular and nasal allergic signs and 
symptoms using the Ora-CAC® scales (see Appendix 2) approximately 
 
 following CAC. 
 
Adverse Event Query 
 
Schedule for Visit 5b: Subjects will be asked to return to the office 3 ½ hours 
after investigational product instillation. Subjects will be allowed to leave the 
clinic and will be instructed to avoid allergens, which may trigger an ocular 
allergic response. 
 Visit 5b (Day 7; 4 hours from Visit 5a): Duration of Action Efficacy 
10.3.9
CAC (4 Hours Post-Dose) 
 
Update of Medical/Medication History 
 
Adverse Event Query 
 
Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease 
 from Visit 
1 will be considered an adverse event. 
 
Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment  
 
Slit Lamp Biomicroscopy  
 
Duration of Action Conjunctival Allergen Challenge 
: For 
each qualified subject, one drop of the allergen solution, of the same dose that 
elicited a positive reaction at Visit 1, will be administered bilaterally. Challenge 
will occur approximately 
 from the time of 
investigational product instillation at Visit 5a. 
 
Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: 
Assessment of itching will be made by the subject at 
 
 following allergen challenge. 
Assessments of redness and chemosis will be graded by the Investigator and 
assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms will be 
made by the subject at 
 (Appendix 2). 
 
Digital Photographs (for subjects at one center): Digital photographs may be 
taken of each eye at 
 post-challenge.  
 
Investigational Product Instillation:  A trained study technician will instill 
investigational product 
 after the Duration of Action CAC 




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 
Investigational Product Instillation:  A trained study technician will instill 
investigational product approximately 
 prior to the Onset of 
Action CAC according to the directions for use. The investigational product kit 
number and the time of instillation will be recorded. 
 
Onset of Action Conjunctival Allergen Challenge 
 For 
each qualified subject, one drop of the allergen solution, of the same dose that 
elicited a positive reaction at Visit 1, will be administered bilaterally. Challenge 
will occur 
 from the time of investigational product instillation.  
 
Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: 
Assessment of itching will be made by the subject at 
 
following allergen challenge. 
Assessments of redness and chemosis will be graded by the investigator and 
assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms will be 
made by the subject at 
 (Appendix 2). 
 
Slit Lamp Biomicroscopy: A slit lamp exam will be performed following the 
completion of all post-CAC assessments. 
 
Digital Photographs (for subjects at one center): Digital photographs may be 
taken of each eye at 
 post-challenge.   
 
Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease 
 from the 
Screening Visit will be considered an adverse event. 
 
Confocal Microscopy (subset of 10 subjects at one center): Subjects’ 
Conjunctival Inflammation Score (CIS) will be evaluated by a masked clinician 
approximately 
post-CAC (after all signs and 
symptoms have been assessed), as outlined in Appendix 2.  
 
Tear Collection (for subjects at one center): Up to 
 of tears / eye may 
be collected from the inferior temporal tear meniscus of each participant. 
 
IOP Measurement: Intraocular Pressure (IOP) will be measured in each eye by 
contact tonometry.
 
 
 will be considered an Adverse Event. 
 
Dilated Fundus Examination 
 
Relief Drop Instillation: Subjects may receive a dose of a currently marketed, 
topical ophthalmic anti-allergic agent (i.e., anti-histamine/vasoconstrictor 
combination products like Visine®-A®) as they leave the office to relieve any 
immediate discomfort caused by the allergic reaction. 






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Regulatory authorities of domestic and foreign agencies, Ora quality assurance and/or its 
designees may carry out on-site inspections and/or audits which may include source data 
checks.  Therefore, direct access to the original source data will be required for 
inspections and/or audits.  All inspections and audits will be carried out giving 
consideration to data protection as well as subject confidentiality to the extent that local, 
state, and federal laws apply. 
11 ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence associated with the use of an 
investigational product (IP) in humans, whether or not considered IP-related. An AE can 
be any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an IP, without any judgment about 
causality. An AE can arise from any use of the IP (eg, off-label use, use in combination 
with another drug or medical device) and from any route of administration, formulation, 
or dose, including an overdose.  
All AEs spontaneously reported by the subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded in the source document and on the appropriate 
pages of the eCRF. Any clinically relevant deterioration in clinical finding is considered 
an AE and must be recorded. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one (1) comprehensive event. Any pre-existing 
medical condition that worsens after administration of study medication will also be 
considered an adverse event. Study medication includes the drug under evaluation or any 
other medications required by the protocol given during any stage of the study. 
Ocular complaints should not be addressed as AEs unless the complaint is outside the 
normal limits for allergic conjunctivitis symptoms after allergen exposure or is associated 
with clinical sequelae (i.e., adverse slit lamp examination finding). 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to IP, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the physician or reported by the subject upon indirect questioning. 
 Severity 
11.1.1
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an 
AE as determined by the Investigator or reported to him/her by the subject.  The 
assessment of severity is made irrespective of relationship to IP or seriousness of the 
event and should be evaluated according to the following scale: 
 Mild:  Event is noticeable to the subject, but is easily tolerated and does not interfere 
with the subject’s daily activities. 


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 Moderate:  Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 
 Severe:  Event is intolerable, necessitates additional therapy or alteration of therapy, 
and interferes with the subject’s daily activities. 
 Relationship to Investigational Product 
11.1.2
The relationship of each AE to the IP should be determined by the Investigator using 
these explanations: 
 Suspected:  A reasonable possibility exists that the IP caused the AE. A suspected AE 
can be further defined as:  
 
 Definite:  Relationship exists when the AE follows a reasonable sequence from 
the time of IP administration, follows a known response pattern of the drug 
class, is confirmed by improvement on stopping the IP and no other reasonable 
cause exists. 
 
 Probable:  Relationship exists when the AE follows a reasonable sequence from 
the time of IP administration, follows a known response pattern of the drug 
class, is confirmed by improvement on stopping the IP and the suspect IP is the 
most likely of all causes. 
 
 Possible:  Relationship exists when the AE follows a reasonable sequence from 
the time of administration, but could also have been produced by the subject’s 
clinical state or by other drugs administered to the subject. 
 
 Not Suspected:  A reasonable possibility does not exist that the IP caused the AE. A 
not suspected AE can further be defined as: 
 
 Not Related:  Concurrent illness, concurrent medication, or other known cause 
is clearly responsible for the AE, the administration of the IP and the occurrence 
of the AE are not reasonably related in time, OR exposure to IP has not 
occurred. 
Types of evidence that would suggest a causal relationship between the IP and the AE 
include:  a single occurrence of an event that is uncommon and known to be strongly 
associated with IP exposure (eg, angioedema, hepatic injury, Stevens-Johnson 
Syndrome); one or more occurrences of an event that is not commonly associated with IP 
exposure, but is otherwise uncommon in the population exposed to the IP (eg, tendon 
rupture); an aggregate analysis of specific events observed in a clinical trial (such as 
known consequences of the underlying disease or condition under investigation or other 
events that commonly occur in the study population independent of drug therapy) that 
indicates those events occur more frequently in the IP-treatment group than in a 
concurrent or historical control group. 


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 Expectedness 
11.1.3
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 
 Unexpected:  an AE that is not listed in the Investigator’s Brochure (IB) or Report of 
Prior Investigations (ROPI) or is not listed at the specificity or severity that has been 
observed. 
 Expected:  an AE that is listed in the IB or ROPI at the specificity and severity that 
has been observed. 
 Not applicable: an AE unrelated to the IP. 
The Investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 
 SERIOUS ADVERSE EVENTS 
11.2
An AE is considered serious if, in the view of either the Investigator or sponsor, it results 
in any of the following outcomes: 
 Death; 
 A life-threatening AE; 
An AE is considered “life-threatening” if, in the view of either the Investigator or 
sponsor, its occurrence places the subject at immediate risk of death.  It does not 
include an AE that, had it occurred in a more severe form, might have caused 
death. 
 Inpatient hospitalization or prolongation of existing hospitalization; 
The term “inpatient hospitalization” refers to any inpatient admission (even if less 
than 24 hours).  For chronic or long-term inpatients, inpatient admission includes 
transfer within the hospital to an acute/intensive care inpatient unit.  Inpatient 
hospitalization does not include:  emergency room visits; outpatient/same-
day/ambulatory procedures; observation/short stay units; rehabilitation facilities; 
hospice facilities; nursing homes; or clinical research/phase 1 units. 
Note:  The term “prolongation of existing hospitalization” refers to any extension 
of an inpatient hospitalization beyond the stay anticipated or required for the 
reason for the initial admission as determined by the Investigator or treating 
physician. 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions; 


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Note:  A serious adverse event (SAE) specifically related to visual threat would 
be interpreted as any potential impairment or damage to the subject’s eyes (eg, 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic 
nerve). 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 PROCEDURES FOR REPORTING ADVERSE EVENTS 
11.3
All AEs and their outcomes must be reported to Ora, the study Sponsor, and the IRB/IEC 
as required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities and recorded on the appropriate eCRF.  
 
Reporting a Suspected Unexpected Adverse Reaction 
11.3.1
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the study 
Sponsor and the IRB/IEC as required by the IRB/IEC, federal, state, or local 
regulations and governing health authorities. 
 
Reporting a Serious Adverse Event 
11.3.2
To ensure subject safety, all SAEs, regardless of relationship to the IP, must be 
immediately reported.  All information relevant to the SAE must be recorded on the 
appropriate eCRF.  The Investigator is obligated to pursue and obtain information 
requested by Ora and/or the sponsor in addition to that information reported on the 
eCRF.  All subjects experiencing a SAE must be followed up and the outcome 
reported. Additionally, in this study there are no expected SAEs and all SAEs will be 
considered suspected unexpected serious adverse reactions (SUSARs). 
In the event of a SAE, the Investigator must notify Ora and the Sponsor Medical 
Monitor immediately; obtain and maintain in his/her files all pertinent medical 
records, information, and medical judgments from colleagues who assisted in the 
treatment and follow-up of the subject; provide Ora and the Sponsor’s Medical 
Monitor with a complete case history, which includes a statement as to the 
relationship to the IP; and inform the IRB of the SAE within their guidelines for 
reporting SAEs. 
Contact information for reporting SAEs: 


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 PROCEDURES FOR UNMASKING (IF APPLICABLE) 
11.4
When medically necessary, the Investigator may need to determine what treatment has 
been assigned to a subject.  When possible (ie, in non-emergent situations), Ora and/or 
the study sponsor should be notified before unmasking IP. 
 TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECTS 
11.5
AFTER ADVERSE EVENTS 
The Investigator will follow unresolved adverse events to resolution until the patient is 
lost to follow-up or until the adverse event is otherwise explained. Resolution means 
the patient has returned to baseline state of health or the Investigator does not expect 
any further improvement or worsening of the adverse event. If the patient is lost to 
follow-up, the Investigator should make 3 reasonable attempts to contact the patient via 
telephone, post, or certified mail. All follow-up will be documented in the subject’s 
source document. Non-serious adverse events identified on the last scheduled contact 
must be recorded on the AE eCRF with the status noted.  
If the Investigator becomes aware of any new information regarding a Serious Adverse 
Event (i.e., resolution, change in condition, or new treatment), a new Serious Adverse 
Event/Unanticipated Report Form must be completed and faxed to Ora Inc. within 24 
hours. The original SAE form is not to be altered. The report should describe whether 
the event has resolved or continues and how the event was treated. 
12 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
  STATISTICAL ANALYSIS PLAN 
12.1
The material described in this section is the basis for the Statistical Analysis Plan (SAP) 
for this study. The SAP will detail all analyses that will be performed and may include 
additional exploratory analyses not explicitly mentioned in the following sections. The 
SAP may be revised during the study to accommodate Clinical Trial Protocol 






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13 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonization (ICH) 
Guidelines, and in general, consistent with the Declaration of Helsinki.  In addition, all 
applicable local, state, and federal requirements relevant to the use of investigational 
products in the countries involved will be adhered to. 
 PROTECTION OF HUMAN SUBJECTS 
13.1
 Subject Informed Consent 
13.1.1
Informed consent must take place before any study specific procedures are initiated.  
Signed and dated written informed consent must be obtained from each subject prior to 
enrollment into the study.   
All informed consent forms must be approved for use by the sponsor and receive 
approval/favorable opinion from an IRB/IEC prior to their use.  If the consent form 
requires revision (eg, due to a protocol amendment or significant new safety 
information), it is the Investigator’s responsibility to ensure that the amended informed 
consent is reviewed and approved by Ora prior to submission to the governing IRB/IEC 
and that it is read, signed and dated by all subjects subsequently enrolled in the study as 
well as those currently enrolled in the study. 
Informed consent may be obtained prior to Visit 1 if the subject wishes to review and 
discuss the Informed Consent with the Investigator or wishes to get a skin test prior to 
Visit 1. However, informed consent must be obtained prior to Visit 1 if any of the 
following criteria are determined during the telephone screening process: 
 Proper washout of certain medications is necessary 
 Sufficient time of discontinuation of contact lens wear is necessary 
 Post-operative period 
Medical/medication history, demographics, skin test and inclusion/exclusion review may 
be performed at the time of informed consent signing prior to Visit 1 (Screening Visit), 
but must be confirmed at Visit 1 (with the exception of demographics and skin test).   
If informed consent is taken under special circumstances (oral informed consent), then 
the procedures to be followed must be determined by Ora and/or study sponsor and 
provided in writing by Ora and/or study sponsor prior to the consent process. 
Prior to the completion of the Screening Visit, if it is determined a subject did not in fact 
meet certain washout criteria, the subject may be brought back at a later date to re-
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Subjects can be re-screened a maximum of three times. 
 Institutional Review Board (IRB) Approval 
13.1.2
This study is to be conducted in accordance with Institutional Review Board regulations 
(U.S. 21 CFR Part 56.103).  The Investigator must obtain appropriate IRB approval 
before initiating the study and re-approval at least annually. 
Only an IRB/ERC approved version of the ICF will be used. 
 ETHICAL CONDUCT OF THE STUDY 
13.2
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 SUBJECT CONFIDENTIALITY 
13.3
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the Investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data in accordance with local, state, and federal laws 
and regulations. 
Monitors, auditors and other authorized representatives of Ora, the sponsor, the IRB/IEC 
approving this study, the Food and Drug Administration, the Department of Health and 
Human Services, other domestic government agencies, and other foreign regulatory 
agencies will be granted direct access to the study subject’s original medical and study 
records for verification of the data and/or clinical trial procedures.  Access to this 
information will be permitted to the aforementioned individuals to the extent permitted 
by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the investigational product may ultimately be 
marketed, but the subject’s identity will not be disclosed in these documents. 
 DOCUMENTATION 
13.4
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the Investigator’s study subject files, as well as the results of diagnostic tests such as X-
rays, laboratory tests, and electrocardiograms.  The Investigator’s copy of the eCRFs 
serves as the Investigator’s record of a subject’s study-related data. 
 Retention of Documentation 
13.4.1
All study related correspondence, subject records, ICFs, record of the distribution and use 
of all IPs and copies of eCRFs should be maintained on file for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region; or until at least 2 years have 


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elapsed since the formal discontinuation of clinical development of the IP. These 
documents will be retained for a longer period if required by the applicable regulatory 
requirements or by an agreement with the sponsor.  It is the responsibility of the sponsor 
to inform the Investigator/institution as to when these documents no longer need to be 
retained. 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will 
accept the responsibility.  The sponsor must be notified in writing of the name and 
address of the new custodian. 
 LABELING, PACKAGING, STORAGE, ACCOUNTABILITY, 
13.5
AND RETURN OR DISPOSAL OF INVESTIGATIONAL 
PRODUCT 
 Labeling/Packaging 
13.5.1
ST266 and placebo will be provided to the clinical site(s) in 
 
 One ready-to-use ampoule is 
intended per treatment per subject. Once an ampoule is opened, it is not to be re-used. 
 Storage of Investigational Product 
13.5.2
The IP must be stored in a secure area accessible only to the Investigator and his/her 
designees.  The IP is to be stored refrigerated 
. The IP will be 
administered only to subjects entered into the clinical study, in accordance with the 
conditions specified in this protocol. 
 Accountability of Investigational Product 
13.5.3
The IP is to only be prescribed by the principal investigator or his/her named sub 
investigator(s), and is to only be used in accordance with this protocol.  The IP must only 
be distributed to subjects properly qualified under this protocol to receive IP. 
The Investigator must keep an accurate accounting of the IP received from the supplier. 
This includes the amount of IP dispensed to subjects, amount of IP returned to the 
Investigator by the subjects, and the amount returned or disposed upon the completion of 
the study.  A detailed inventory must be completed for the IP. 
 Return or Disposal of Investigational Product 
13.5.4
All IP will be returned to the sponsor or their designee or destroyed at the study site.  The 
return or disposal of IP will be specified in writing. 


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 RECORDING OF DATA ON SOURCE DOCUMENTS AND 
13.6
CASE REPORTS FORMS (CRFS) 
The Investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s eCRF, source document, and all study-related material.  All 
study data should also be attributable, legible, contemporaneous, and original.  Recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or render 
illegible the previous entry (eg, by drawing a single line through the incorrect entry and 
writing the revision next to the corrected data).  An individual who has corrected a data 
entry should make clear who made the correction and when, by adding to the correction 
his/her initials as well as the date of the correction. 
 HANDLING OF BIOLOGICAL SPECIMENS 
13.7
Not Applicable. 
 PUBLICATIONS 
13.8
Publication will be in accordance with the terms of Section 6 – Publicity and Publication 
set forth in the Master Service Agreement, (the “AGREEMENT) dated October 07, 2016. 


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14 REFERENCES 
Abelson MB. Loeffler O. Conjuctival allergen challenge: Models in the investigation 
of ocular allergy. Curr Allergy Asthma Reports 2003;3:363-368. 
  
Abelson M B, Chambers WA, Smith LM. Conjunctival allergen challenge. a clinical 
approach to studying allergic conjunctivitis. Arch Ophthalmol 1990;108(1):84-88. 
 
Bacon AS, Ahluwalia P, Irani AM, Schwartz LB, Holgate ST, Church MK, McGill JI. 
Tear and conjunctival changes during the allergen-induced early- and late-phase 
responses. J Allergy Clin Immunol  2000;106(5):948-954. 
Bergmann J, Hackl F, Koyama T, Aflaki P, Smith C, Robson M, Eriksson E. The effect 
of amnion-derived cellular cytokine solution on the epithelialization of partial-thickness 
donor site wounds in normal and streptozotocin-induced diabetic swine. EPlasty 2009;9, 
online Oct 20, 2009. 
 
Bielory L. Allergic and immunologic disorders of the eye. part II: ocular allergy. J 
Allergy Clin Immunol 2000;106:1019-1032. 
C. S. Foster, R. Davanzo, T. E. Flynn, K. McLeod, R. Vogel, and R. S. Crockett, 
“Durezol (Difluprednate Ophthalmic Emulsion 0.05%) compared with Pred Forte 1% 
ophthalmic suspension in the treatment of endogenous anterior uveitis.,” J Ocul 
Pharmacol Ther, vol. 26, no. 5, pp. 475–483, Oct. 2010. 
Ciprandi GS, Buscaglia G, Pesce P, Bagnasco M, Canonica GW. Ocular challenge and 
hyperresponsiveness to histamine in patients with allergic conjunctivitis. J Allergy Clin 
Immunol 1993;91(6): 1227-1230. 
Investigational Brochure ST266. Oct 26, 2016, edition 8. 
Larson BJ, Longaker MT, Lorenz HP. Scarless fetal wound healing: A basic science review. 
Plast Reconstr Surg 2010;126(4): 1172-1180. 
Lo DD, Zimmermann AS, Nauta A, Longaker MT, Lorenz HP. Scarless fetal skin wound 
healing update. Birth Defects Research (Part C) 2012;96(3): 237-247. 
Steed DL, Trumpower C, Duffy D, Smith C, Marshall V, Rupp R, Robson M. Amnion-
derived cellular cytokine solution: a physiological combination of cytokines for wound 
healing. Eplasty 2008;8:157-165. 
 
 
 




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APPENDIX 5   
PROTOCOL AMENDMENT SUMMARY 


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APPENDIX 8   
INVESTIGATOR’S SIGNATURE 
Protocol Title: 
A Multi-Center, Double-Masked, Randomized, Phase 2 
Evaluation of the Effectiveness of ST266 Ophthalmic Drops 
Compared to Placebo of ST266 for the Treatment of Allergic 
Conjunctivitis Using a Modified Conjunctival Allergen 
Challenge Model (Ora-CAC®)  
Protocol Number: 
ST266-AC-201/16-100-0005 
Final Date: 
13 January 2017 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations.  I agree to 
maintain all information supplied by Ora and the sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Ethical Review 
Committee (ERC) or another group, it will be submitted with a designation that the 
material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
 
 
Date:  
 
<enter name and credentials> 
<enter title> 
<enter affiliation> 
<enter address> 
<enter phone number> 

SAP_003.pdf: 
CLINICAL TRIAL PROTOCOL: ST266-AC-201/16-100-0005 
 
A Multi-Center, Double-Masked, Randomized, Phase 2 Evaluation of the Effectiveness of 
ST266 Ophthalmic Drops Compared to Placebo for the Treatment of Allergic Conjunctivitis 
Using a Modified Conjunctival Allergen Challenge Model (Ora-CAC®) 
 
NCT02978183 
 
SAP Date: 05 January 2017 
 
Noveome Biotherapeutics, Inc. 
100 Technology Drive, Suite 200 
Pittsburgh, PA 15219 


FORM.152.03 Updated 30-Aug-2016 
STATISTICAL ANALYSIS PLAN 
A Multi-Center, Double-Masked, Randomized, Phase 2 Evaluation of the 
Effectiveness of ST266 Ophthalmic Drops Compared to Placebo for the 
Treatment of Allergic Conjunctivitis Using a Modified Conjunctival Allergen 
Challenge Model (Ora-CAC®) 
Sponsor:  
Noveome Biotherapeutics, Inc. 
Protocol Number: 
ST266-AC-201 
Author:  
 
 
 
Date: 
05 January 2017 
Version: 
Final 1.0 


Page 2 of 23 
Protocol Title 
A Multi-Center, Double-Masked, Randomized, Phase 2 Evaluation of the Effectiveness of ST266 
Ophthalmic Drops Compared to Placebo for the Treatment of Allergic Conjunctivitis Using a 
Modified Conjunctival Allergen Challenge Model (Ora-CAC®) 
Protocol Number: 
ST266-AC-201 
Version:  
Final 1.0  
Date:    
05 January 2017 
Statistical Analysis Plan Approval 
Prepared by: 
 
 
 
 
Reviewed by: 
___________ 
 
 
 
 
Approved by: 
 
 
 
 
Approved by: 
 
 
    
  
 




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Table of Contents 
1. 
Introduction .............................................................................................................................. 6 
2. 
Study Objectives ...................................................................................................................... 6 
3. 
Study Variables ........................................................................................................................ 6 
3.1 Primary Variables ..................................................................................................................... 6 
3.2 Secondary Variables ................................................................................................................ 6 
3.3 Exploratory Variables ............................................................................................................... 7 
3.4 Safety Variables ....................................................................................................................... 7 
3.5 Statistical Hypotheses .............................................................................................................. 7 
4. 
Study Design and Procedures ................................................................................................. 7 
4.1 General Study Design .............................................................................................................. 7 
4.2 Schedule of Visits and Assessments ....................................................................................... 8 
5. 
Study Treatments ................................................................................................................... 10 
5.1 Method of Assigning Subjects to Treatment Groups ............................................................. 10 
5.2 Masking and Unmasking ........................................................................................................ 10 
6. 
Sample Size and Power Considerations ............................................................................... 11 
7. 
Data Preparation .................................................................................................................... 11 
8. 
Analysis Populations .............................................................................................................. 12 
8.1 Intent-to-Treat ........................................................................................................................ 12 
8.2 Per Protocol ........................................................................................................................... 12 
8.3 Safety ..................................................................................................................................... 12 
9. 
General Statistical Considerations ......................................................................................... 12 
9.1 Unit of Analysis ...................................................................................................................... 12 
9.2 Missing or Inconclusive Data Handling .................................................................................. 12 
9.3 Definition of Baseline ............................................................................................................. 13 
9.4 Data Analysis Conventions .................................................................................................... 13 
9.5 Adjustments for Multiplicity .................................................................................................... 14 
10. 
Disposition of Subjects ........................................................................................................... 14 
11. 
Demographic and Baseline Variables .................................................................................... 14 
11.1 Demographic Variables .......................................................................................................... 14 
11.2 Baseline Variables ................................................................................................................. 15 
12. 
Medical History and Concomitant Medications ...................................................................... 15 
12.1 Medical History ...................................................................................................................... 15 
12.2 Prior and Concomitant Medications ....................................................................................... 15 


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13. 
Dosing Compliance and Treatment Exposure ....................................................................... 16 
13.1 Dosing Compliance ................................................................................................................ 16 
13.2 Treatment Exposure .............................................................................................................. 16 
14. 
Efficacy Analyses ................................................................................................................... 16 
14.1 Primary Analysis .................................................................................................................... 16 
14.2 Secondary Analyses .............................................................................................................. 18 
14.3 Exploratory Analyses ............................................................................................................. 19 
15. 
Safety Analyses ..................................................................................................................... 19 
15.1 Adverse Events ...................................................................................................................... 20 
15.2 Visual Acuity (ETDRS) ........................................................................................................... 21 
15.3 Slit-Lamp Biomicroscopy Examination .................................................................................. 21 
15.4 Dilated Fundus Examination .................................................................................................. 21 
15.5 Intraocular Pressure (IOP) ..................................................................................................... 21 
16. 
Interim Analyses .................................................................................................................... 21 
17. 
Changes from Protocol-Stated Analyses ............................................................................... 21 
18. 
References ............................................................................................................................. 21 
19. 
Revision History ..................................................................................................................... 21 
20. 
Tables .................................................................................................................................... 22 
21. 
Listings ................................................................................................................................... 23 
 
 
 


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List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical Classification 
CAC 
Conjunctival Allergen Challenge 
CI 
Confidence Interval 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
DVM 
Data Validation Manual 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
GCP 
Good Clinical Practice 
HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LS Means 
Least Squares Means 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not clinically significant 
PDF 
Portable Document Format 
PP 
Per Protocol 
PT 
Preferred Term 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics and Data Corporation, Incorporated 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
VA 
Visual Acuity 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol ST266-AC-201, version 2.0 dated 31OCT2016. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports (CSR). 
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 CSR. 
2. Study Objectives 
The primary objective of this study is to evaluate the efficacy of ST266 ophthalmic drops compared to 
placebo for the treatment of the signs and symptoms of allergic conjunctivitis. 
3. Study Variables 
3.1 
Primary Variables 
The primary efficacy variables are the following: 
 
Ocular itching evaluated by the subject at all time points 
) 
at Visits 5b and 6. 
 
Conjunctival redness evaluated by the investigator at all time points 
 
 at Visits 5b and 6. 
3.2 
Secondary Variables 
The following secondary efficacy assessments will occur pre-CAC and at 
 
 post-CAC 
 at Visits 5b and 6:  
 
Ciliary redness evaluated by the investigator  
 
Episcleral redness evaluated by the investigator  
 
Chemosis evaluated by the investigator  
 
Eyelid swelling evaluated by the subject  
 
Tearing evaluated by the subject   
 
Rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal congestion evaluated by the subject   
 
A composite score of presence or absence of at least one nasal symptom evaluated by the 
subject 
All assessments will be evaluated at pre-CAC and 
minutes post-CAC at Visits 4a, 4b, and 5a. 


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3.3 
Exploratory Variables 
The exploratory efficacy variables include the following: 
 
Conjunctival Inflammation Score (CIS) evaluated by a masked clinician using confocal 
microscopy post-CAC 
 Visit 6 (subset of 
 subjects 
at one center). 
 
Diary assessments for all subjects. Assessments of ocular itching, ocular redness, and eyelid 
swelling will occur prior to bedtime and upon awakening from Visit 4b to Visit 6 (
 
   
3.4 
Safety Variables 
The safety variables include the following: 
 
Adverse Events  
 
Visual Acuity at Distance Utilizing an ETDRS chart  
 
Slit-lamp Biomicroscopy  
 
Intraocular Pressure  
 
Dilated Fundoscopy 
3.5 
Statistical Hypotheses 
The null and alternative hypotheses, based on the primary variables, are as follows: 
 
 
 
 
 
 
 
 
All hypothesis testing will be two-sided with a type I error rate (α) of 
.  The above hypothesis tests 
will be applied to Visit 5b and Visit 6 separately.  No multiplicity corrections will be employed in this 
Phase 2 exploratory efficacy study.  Specifics of the statistical tests are provided in Section 14.  
4. Study Design and Procedures 
4.1 
General Study Design 
Study visits will be referred to in all tables and listings as the expected study day corresponding to the 
visit to enable reviewers to understand the assessment timing without referring to the protocol visit 


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schedule.  The following table shows the scheduled study visits, their planned study day, and the 
acceptable visit window for each study visit: 
4.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided below. 
 
 


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5. Study Treatments 
The investigational treatment for this study is ST266 ophthalmic drops.  The control is placebo (0.9% 
Sodium Chloride) ophthalmic drops. 
5.1 
Method of Assigning Subjects to Treatment Groups 
On Day -2 (Visit 1), subjects who provide verbal and written informed consent will be assigned a unique 
4-digit subject ID, which consists of the 1-digit site number plus a unique 3-digit screening number 
(beginning with 001 within each site).  The 3-digit screening numbers must be assigned in ascending 
consecutive order.   
Once a subject meets all qualification criteria, they will be randomly assigned to masked treatment using 
a 
assignment ratio. 
Subjects will be randomized on Visit 3 (Day 1) by assignment of the next 4-digit randomization number 
available at each investigative site. The randomization number will be stratified by the average post-
CAC itching scores 
at baseline 
 
 
to ensure balance within treatment groups for the primary endpoint of ocular itching.  No randomization 
numbers will be skipped or omitted. 
A computer-generated randomization schedule will be produced prior to study enrollment by an 
unmasked statistician who is not otherwise involved in the study. Each randomization number will 
correspond to a treatment group assignment and subject supplies will be labeled according to the 
randomization list and dispensed at each site. 
The 4-digit subject ID will be used to identify subjects in all datasets and listings for this study.  
5.2 
Masking and Unmasking 
An independent biostatistician who is not otherwise involved in the trial will generate the complete 
randomized study drug kit list.  Subjects, Investigators and Ora/SDC staff will be masked during the 
randomization process and throughout the study. 
With each shipment of study drug, sites will receive one emergency unmasking envelope for every study 
drug kit received. The envelopes and kits will both be labeled with the same 4-digit study drug kit number.  
The envelopes are sealed and contain the unmasked treatment information for the corresponding study 
drug kit.  Envelopes should be stored in a secured location. 
Under normal circumstances, the mask should not be broken. When medically necessary, an 
investigator may need to determine what treatment has been assigned to a subject. The investigator will 
contact Noveome Biotherapeutics, Inc. with the details of the emergency unmasking request. Noveome 
Biotherapeutics, Inc. will make the final determination if the unmasking request will be granted. If 


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granted, the investigator will be permitted to use the code-break instructions available on site.  If the 
investigator determines that emergency unmasking is necessary, the investigator should identify and 
retrieve the emergency unmasking envelope for the given subject.  The emergency unmasking envelope 
should be opened by the designated site personnel.  The investigator must also indicate in source 
documents and in the eCRF that the mask was broken and provide the date, time, and reason for 
breaking the mask.  Subjects should have their study drug discontinued immediately if treatment 
assignment is unmasked. 
The overall randomization code will be broken only for reporting purposes.  This will occur once all final 
clinical data have been entered into the database, data queries have been resolved, and assignment of 
subjects to the analysis populations has been completed. The database will be kept masked until after 
the database lock has occurred. 
6. Sample Size and Power Considerations 
This Phase 2 study, designed to evaluate the safety and effectiveness of ST266 for the treatment 
of allergic conjunctivitis, is exploratory in nature.  Given there are no data available on which to base a 
formal power calculation, a sample size of 
subjects per group has been selected based on the 
Investigators’ judgment and experience conducting similar Phase 2 studies of this nature in individuals 
diagnosed with allergic conjunctivitis. 
7. Data Preparation 
Data management procedures, including database design, selection of the data dictionary, and coding 
of all adverse events and medications, will be performed by Statistics & Data Corporation (SDC). All 
reported study data will be recorded on the electronic Case Report Forms (eCRFs) supplied by SDC 
using iMedNet™ v1.163.3 or higher.  Clinical personnel at the study center and Ora, Inc. are responsible 
for ensuring that the protocol is followed and that the eCRFs are properly completed.  
After data are entered into the clinical study database, electronic edit checks will be performed, including 
checks for missing data, out of range values, discrepancies within and across visits, and cross checks 
between different data tables. All data validation specifications and procedures are detailed in the Data 
Validation Manual (DVM). When the database has been declared to be complete and accurate, the 
database will be locked and treatment codes unmasked. Any changes to the database after that time 
can only be made with the approval of the Sponsor in consultation with Ora, Inc. and SDC.  
All analyses outlined in this document will be performed after: 
 
All data management requirements are met according to SDC’s Standard Operating Procedures 
(SOPs), including performance of edit and validation checks, documentation and resolution of 


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data queries, and database lock with written authorization provided by appropriate SDC and 
Ora/Sponsor personnel; 
 
All protocol deviations have been classified as major or minor and the Per Protocol population 
has been determined; and 
 
The treatment codes have been unmasked. 
8. Analysis Populations 
8.1 
Intent-to-Treat 
The Intent-to-Treat (ITT) population consists of 
  All data will be included 
and no subjects will be excluded because of protocol violations.  The ITT population will be analyzed as 
 
8.2 
Per Protocol 
The Per Protocol (PP) population is a 
 
. This population will be 
analyzed as 
. 
8.3 
Safety 
The safety population includes 
. The safety 
population will be analyzed as 
. No data will be excluded 
for any reason. 
9. General Statistical Considerations 
9.1 
Unit of Analysis 
The subject will be considered the unit of analysis for all efficacy variables.  
 
 
 
 
 
9.2 
Missing or Inconclusive Data Handling 
Multiple imputation Markov Chain Monte Carlo (MCMC) methods will be employed to impute missing 
primary efficacy data.  A separate model will be fit for each endpoint, visit and time point.  The model 
will include variables for treatment, baseline measure and response measure.   
Sensitivity analyses will be performed as described in the following text:   


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 
ITT Population: 
 
 
 
 
 
 
 
 
 
ITT population:  
. 
 
PP population:  
 
9.3 
Definition of Baseline 
For each parameter, the last valid assessment before randomization will be used as the baseline for all 
analyses of that parameter.  For each efficacy variable, the last valid assessment before randomization 
will generally be at Visit 3. 
9.4 
Data Analysis Conventions 
All data analysis will be performed by SDC 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.   
Quantitative variables will be summarized using descriptive statistics including the number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum values.  For the 
ocular primary and secondary endpoints (itching, eyelid swelling, tearing, regional redness, and 
chemosis) the unit of analysis is the average of the subject’s eyes. Therefore, for each of these variables, 
the minimum and maximum values will be reported to one decimal, irrespective of the number of 
decimals in the raw collected data.  Similarly, means, medians, and confidence intervals will be reported 
to two decimal places and standard deviations to three.  Summaries for discrete variables will include 
frequency counts and percentages.  All percentages will be rounded to one decimal place (i.e., XX.X%).  
Differences between the active treatment group and placebo will be calculated as Active minus Placebo 
and change from baseline will be calculated as follow-up visit - baseline. 
All statistical tests will be two-sided with a significance level of 
 unless otherwise specified.  
Confidence intervals (CI) for differences between treatment groups will be 
  
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”. 


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Unless otherwise specified, summaries will be presented by treatment group and, where appropriate, 
visit and time point. 
9.5 
Adjustments for Multiplicity 
Adjustments for multiplicity will not be employed in this exploratory Phase 2 study. 
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 are not discontinued 
from the study will be considered study completers.  Disposition will be summarized by treatment group 
and for all subjects. 
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: adverse events, protocol violations, lost to 
follow up, consent withdrawn, sponsor termination of study, investigator decision, screen failure, and 
other.  A subject listing will be provided that includes the date of and reason for premature study 
discontinuation. 
The number and percentage of subjects with protocol deviations will be summarized by treatment group 
for all randomized subjects.  A subject listing will be provided that includes the date of the deviation, 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 the PP population. 
11. Demographic and Baseline Variables 
11.1 
Demographic Variables 
The demographic variables collected in this study include age, 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 and Safety populations, separately. 
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics.  Age 
will also be categorized as follows:  <65 years and ≥65 years.  Age will be reported in years and 
calculated using the following formula: 
 
 
The number and percentage of subjects will be presented, overall and by treatment, for age category, 
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treatment group except for iris color, which will be based on the total number of eyes in each treatment 
group.  A subject listing that includes all demographic variables will be provided. 
11.2 
Baseline Variables 
The number and percentage of subjects with Visit 3 post-CAC® (baseline) itching scores 
 
will be summarized.  A subject listing that includes baseline itching will be provided. 
12. Medical History and Concomitant Medications 
12.1 
Medical History 
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).  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, then that SOC will only be 
reported once.  Separate tables will be created for ocular and non-ocular medical history.  Medical 
history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 19.1.  The 
summaries will be based on the ITT population. 
Listings of medical history will be generated separately for ocular and non-ocular data. 
12.2 
Prior and Concomitant Medications 
At the first screening visit, subjects will be asked what medications they are taking, as well as those the 
subject may have taken but discontinued within the 45 days prior to Visit 1.  At each study visit, subjects 
will be asked what concomitant medications they are currently taking or if there have been any changes 
to their medication since their first visit. 
All prior and concomitant ocular and non-ocular medications will be listed using the ITT population 
including generic name, route of administration, start date, stop date, dosage, and indication.  Prior and 
concomitant medications will be coded using World Health Organization Drug Dictionary Enhanced 
(WHODD) enhanced version B2, September 2016, to the appropriate Anatomical Therapeutic Chemical 
(ATC) classification and WHO generic term. 
Counts and percentages of ocular and non-ocular concomitant medications will be summarized 
separately using WHODrug ATC classification and preferred name.  Summaries will be displayed by 
treatment group and for all subjects.  Subjects with multiple medications in the same ATC class or 
preferred name will be counted only once for that respective ATC class or preferred name.   


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13. Dosing Compliance and Treatment Exposure 
13.1 
Dosing Compliance 
Dosing compliance (% compliance) will be assessed by calculating the number of actual doses received 
and comparing that to the number of expected doses as follows: 
The number of actual doses received will be calculated and summarized using the number of dispensed 
versus returned, used study drug vials.  The number of expected doses that will be used for calculating 
compliance will be calculated as 
 for all subjects, regardless of 
study completion status.  A categorical compliance variable will also be derived as compliant 
 
and non-compliant 
. 
Treatment compliance (%) will be summarized for the Safety population using continuous descriptive 
statistics.  The compliance categories defined above will be summarized with counts and percentages.  
A subject listing of compliance will also be produced. 
13.2 
Treatment Exposure 
Extent of exposure will be calculated in days using the following: 
  
 
Extent of treatment exposure (days) for each subject exposed to study drug will be summarized with 
continuous descriptive statistics for each treatment group, using the Safety population.  A subject listing 
of treatment exposure will also be produced. 
14. Efficacy Analyses 
14.1 
Primary Analysis 
The primary efficacy endpoints are ocular itching assessed at  all time points 
 
and conjunctival redness assessed at all time points 
 
 at Visit 5b and Visit 6. 
 
. Ocular itching and conjunctival 
redness will each be analyzed using an 
 
 
Least squares means (LS Means) for each treatment, LS Means treatment 
differences, and 95% confidence intervals (CIs) for the LS Means treatment differences will be provided.   


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Multiple imputation employing the MCMC method will be performed for the primary analysis of the 
primary endpoints using the SAS procedure PROC MI by applying the following SAS code:  
 
 
   
 
   
 
 
 
where 
 
 
 
 
 
 
 
 
 
 
 
 
After obtaining twenty complete data sets, the following SAS code will be employed to run the model on 
each data set: 
 
 
 
 
 
   
 
   
 
 
 
   
 
 
   
 
 
 
where 
- 
 
 
  
 
 
 
 
Then, the following SAS code will be used to analyze the combined data: 
 
   
 
 
 
       
 
 
 
       
 
 
       
 
 
 
       
 
 
   
 
 
   
 
 
 
       
 
          
 
 
       
 


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The primary efficacy analyses will be conducted on the ITT population using MCMC multiple imputation 
methodology for missing data, as described in Section 9.2 and above. Adjustments for multiplicity will 
not be employed in this exploratory Phase 2 study. 
Sensitivity or supportive analyses will be performed on the ITT population, using LOCF and observed 
data only, as well as on the PP population with observed data only. 
Two-sample t-tests will be used as additional sensitivity analyses at each post-CAC® time point, as well 
as non-parametric Wilcoxon rank sum tests for comparing ST266 ophthalmic drops and placebo. Mean 
treatment differences, 95% CIs for each of the means, and 95% CIs for the mean differences will be 
presented.  
In addition, ANCOVA models will be run separately at Visit 5b and Visit 6 as secondary analyses, with 
treatment, time point, and time appropriate baseline as covariates for adjustment (accounting for 
repeated measurements). LS Means for each treatment, the LS Means treatment difference between 
ST266 ophthalmic drops and placebo, and the corresponding 95% CIs will be calculated from these 
ANCOVA models. SAS pseudo-code for the ANCOVA model accounting for repeated measures at each 
Visit follows: 
 
   
 
 
       
 
 
       
 
 
       
 
          
 
 
   
 
 
An unstructured variance-covariance matrix will be used for the above repeated measures model.  If the 
model does not converge using the unstructured matrix, the first order autoregressive structure and the 
compound symmetry structure will be employed, in that order. 
14.2 
Secondary Analyses 
The secondary endpoints will be measured at Visits 5b and 6.  All secondary endpoints will be assessed 
pre-CAC and at 
 post-CAC® 
 
 at Visits 5b and 6.   
Ocular allergic symptoms will be evaluated by the subject and include eyelid swelling 
 
 and tearing/watery eyes 
  
Nasal allergic symptoms are also evaluated by the subject and include rhinorrhea, nasal pruritis, ear or 
palate pruritis, and nasal congestion.  Nasal allergic symptoms are collected on a 
, NOT 
allowing half unit increments.  


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A binary nasal composite score of nasal allergic symptoms will be derived for each visit and time point 
at which nasal allergic symptoms are collected.  The nasal composite score will be “Present” if 
 
 
, and “Absent” 
if 
 It will be considered missing if 
 
 
Ocular allergic signs will be evaluated by the Investigator and include ciliary redness, episcleral redness, 
and chemosis.  Ocular allergic signs are collected on a 
 scale, 
  
Analyses will be performed on quantitative secondary endpoints in a manner similar to the primary 
endpoints for each visit.  
 
 
  
 
 
 
 
 The ST266 ophthalmic drops will be compared to placebo 
at each time point within each visit. The secondary endpoints will be analyzed for the ITT population 
with observed data only and for the PP population with observed data only. 
14.3 
Exploratory Analyses 
Conjunctival inflammation scores, evaluated by a masked clinician using confocal microscopy post-
CAC® 
 will be measured at Visit 6 in a subset of 
 subjects at 
one site.  Descriptive statistics will be produced for this exploratory endpoint. 
Diary assessments of ocular itching, ocular redness and eyelid swelling will occur for all subjects prior 
to bedtime and upon awakening from Visit 4b to Visit 6 
 
 for all subjects.  Two-sample t-tests will be used at each diary time point, as well as non-parametric 
Wilcoxon rank sum tests, for comparing ST266 ophthalmic drops and placebo.  In addition to descriptive 
summary statistics, mean treatment differences, 95% CIs for each of the means, and 95% CIs for the 
mean differences will be presented.    
15. Safety Analyses 
The primary safety variable is the incidence of subjects with any adverse event (AE) during the entire 
study.  The secondary safety variables are slit lamp biomicroscopy, dilated fundus examination, VA, and 
IOP.  Safety variables will be summarized as appropriate.  All safety analyses will be performed on the 
Safety population.  No statistical inferential testing will be performed for safety variables. 


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15.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of an investigational 
product (IP) in humans, whether or not considered IP-related. Treatment-emergent AEs are defined as 
AEs that occur after the first use of IP.  Per the protocol, only AEs that begin or worsen after receipt of 
the first dose of IP will be captured in the database for this study; therefore, treatment-emergent AEs 
and AEs are equivalent in this study and will be denoted as AEs.  All AEs will be assigned a severity 
grade of mild, moderate, or severe. Their relationship to IP will be classified as suspected (definite, 
probable or possible) or not suspected (not related).  The expectedness of an AE will be classified as 
unexpected, expected or not applicable.  Documentation of AEs will include onset date, severity, 
action(s) taken, IP relationship, expectedness, outcome, resolution date, and seriousness.  All AEs will 
be coded using MedDRA classifications with reference to SOCs and PTs (MedDRA version 19.1). 
An adverse event is considered serious if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes: 
 
Death; 
 
A life-threatening adverse event; 
 
Inpatient hospitalization or prolongation of existing hospitalization; 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions; 
 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes listed above. 
An overall tabular summary of AEs will be presented that includes the number of events and the number 
and percentage of subjects who experienced at least one event, by treatment group and overall.  This 
summary will also include breakdowns of AEs further categorized as ocular or non-ocular, SAEs, AEs 
by maximal severity, AEs leading to subject withdrawal and AEs resulting in death.  Additional 
summaries of AEs will be provided showing the number and percentage of subjects who experienced 
at least one AE, separately for ocular and non-ocular AEs.  Ocular and non-ocular AEs will be 
summarized separately using discrete summary statistics and presented by treatment group at the 
subject and event level by SOC and PT using the Safety population.  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.  The 
occurrence of AEs suspected to be related to IP will also be tabulated by SOC and PT, separately for 
ocular and non-ocular events.  SAEs will also be summarized separately for ocular and non-ocular 
events.  All AEs will be presented in a listing. 


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15.2 
Visual Acuity (ETDRS) 
Visual acuity (VA) will be measured at every study visit prior to the CAC®.  For Visit 6, it will be measured 
again post-CAC®.  VA (logMAR) will be summarized at each visit using quantitative summary statistics 
for both eyes combined by treatment.  
 
  VA results will be presented in a data listing.   
15.3 
Slit-Lamp Biomicroscopy Examination 
Slit lamp biomicroscopy examinations will be performed at every study visit prior to the CAC. For Visit 
6, slit lamp biomicroscopy will be repeated post-CAC®.  Qualitative summaries of biomicroscopy results 
will also be presented for both eyes combined by region (eyelid, conjunctiva, cornea, lens, and anterior 
chamber), treatment group and study visit in tabular form.  Slit lamp biomicroscopy examination results 
will also be listed for both eyes at each visit.   
15.4 
Dilated Fundus Examination 
Dilated fundus examinations will be performed at Visits 1 (post-CAC®) and 6 (post-CAC®).  Counts and 
percentages of normal and abnormal results will be presented for both eyes combined by visit and 
treatment group for the following regions: vitreous, retina, macula, choroid, and optic nerve.  A change 
from baseline will also be summarized as follows: 
 
 
Results will be listed for both eyes at each visit. 
15.5 
Intraocular Pressure (IOP) 
IOP will be measured at Visits 1 (post-CAC®) and 6 (post-CAC®).  IOP will be summarized for both eyes 
combined by visit and treatment group using quantitative summary statistics.  At Visit 6, an IOP of 
 
 AND 
 will be considered an Adverse Event, and presented in 
the tabular summary.  IOP will be listed for both eyes at each visit. 
16. Interim Analyses 
No interim analyses are planned for this study. 
17. Changes from Protocol-Stated Analyses 
There are no changes from the protocol-stated analyses. 
18. References 
Not applicable 
19. Revision History 
Documentation of revision to the SAP will commence after approval of the Final version 1.0. 


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20. Tables 
Tables that will be included in the topline delivery are shown in boldface font.  


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21. Listings