Clinical trial NCT03489941
Conditions: Allergic Conjunctivitis
Sponsor: Bausch & Lomb Incorporated
Start date: 2018-04-07; Completion date: 2018-04-29
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Single-Center study to demonstrate the non-inferiority of EM-100 to Zaditor® in the treatment of ocular itching.

Detailed description:

Arms: arm 1: One drop of EM-100 in either the right or left eye once on Day 1. arm 2: One drop of Zaditor® in either the right or left eye once on Day 1. arm 3: One drop of Vehicle in either the right or left eye once on Day 1.
Interventions: intervention 1: EM-100 intervention 2: Zaditor® intervention 3: Vehicle
Intervention descriptions: intervention 1: Subjects will receive one drop in one eye only based on the randomization list, one time over the course of the trial. intervention 2: Subjects will receive one drop in one eye only based on the randomization list, one time over the course of the trial. intervention 3: Subjects will receive one drop in one eye only based on the randomization list, one time over the course of the trial.

Protocol documents:
Prot_SAP_001.pdf: 
16.1 
Study Information 
16.1.1 Protocol and Protocol Amendments 
Original Protocol Study 17-100-0011 (15 December 2017) 
Protocol Amendment Version 1.0 Study 17-100-0011 (28 February 2018) 
Protocol Amendment Version 2.0 Study 17-100-0011 (04 April 2018) 
EM-100 Topical Ophthalmic Solution 
Clinical Study Report
EyeMax, LLC 
Study # 17-100-0011
Confidential
Page 1 of 197
            NCT03489941


EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
Final 1.0/15Dec2017 
 
Clinical Trial Protocol: 17-100-0011 
Protocol Title: 
A Single-Center Evaluation of the Relative Efficacy 
of EM-100 Compared to Zaditor® (Ketotifen 
Fumarate Ophthalmic Solution 0.035%) and Vehicle 
in the Treatment of Ocular Itching Associated with 
Allergic Conjunctivitis as Induced by the 
Conjunctival Allergen Challenge Model (Ora-
CAC®)  
 
 
Study Phase: 
3  
Investigational Product Name: EM-100 topical ophthalmic solution 
IND Number: 
Not Applicable 
Indication: 
Allergic Conjunctivitis 
Investigators: 
Single-center 
Sponsor: 
EyeMax, LLC 
74 Chestnut St. 
Weston, MA 02493 
 
Contract Research 
Organization: 
Ora, Inc. 
300 Brickstone Square, Third Floor 
Andover, MA 01810 
 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico, Suite C, #497 
San Clemente, CA 92673 
 
 
Date 
Original Protocol: 
15 December 2017 
Amendment 1: 
Not Applicable 
 
Confidentiality Statement 
This protocol contains confidential, proprietary information of Ora, Inc. and/or EyeMax, 
LLC.  Further dissemination, distribution or copying of this protocol or its contents is 
strictly prohibited. 
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Clinical Study Report
EyeMax, LLC 
Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
Final 1.0/15Dec2017 
 
Confidential 
Page 2 
 
 
 
SPONSOR PERSONNEL 
President: 
 
 
Scientific Founder: 
 
ORA PERSONNEL 
Medical Monitor: 
 
 
 
Chief Medical Officer: 
 
 
 
Department Vice President: 
 
 
Project Lead: 
 
 
 
 
 
 
EM-100 Topical Ophthalmic Solution 
Clinical Study Report
EyeMax, LLC 
Study # 17-100-0011
Confidential
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
Final 1.0/15Dec2017 
 
Confidential 
Page 3 
 
 
SYNOPSIS 
Protocol Title: 
A Single-Center Evaluation of the Relative Efficacy of 
EM-100 Compared to Zaditor® (Ketotifen Fumarate 
Ophthalmic Solution 0.035%) and Vehicle in the 
Treatment of Ocular Itching Associated with Allergic 
Conjunctivitis as Induced by the Conjunctival Allergen 
Challenge Model (Ora-CAC®) 
Protocol Number: 
17-100-0011 
Investigational Product: 
EM-100 topical ophthalmic solution 
Study Phase: 
3 
Primary Objective(s): 
To demonstrate the non-inferiority of EM-100 to Zaditor® 
in the treatment of ocular itching associated with allergic 
conjunctivitis. 
Secondary Objective(s): 
 To demonstrate that EM-100 is superior to vehicle in 
the treatment of ocular itching associated with allergic 
conjunctivitis. 
 To demonstrate that Zaditor® is superior to vehicle in 
the treatment of ocular itching associated with allergic 
conjunctivitis. 
 To demonstrate that EM-100 is non-inferior to 
Zaditor® in the treatment of conjunctival redness 
associated with allergic conjunctivitis.    
Overall Study Design: 
Structure: 
Screening Period: At the Screening Visit, subjects will 
sign the informed consent form and an allergic skin test 
will be performed, if required. At Visit 1, each qualifying 
subject will undergo a bilateral conjunctival allergen 
challenge (CAC) titration using an allergen they had a 
positive reaction to on their skin test. Subjects who elicit a 
positive reaction post-CAC will undergo the confirmation 
CAC at Visit 2 using the same allergen they qualified with 
at Visit 1.  
Treatment Period: At Visit 3, qualifying subjects will be 
enrolled and randomized to receive EM-100, Zaditor®, or 
vehicle of EM-100 in the right eye and one of the other 
EM-100 Topical Ophthalmic Solution 
Clinical Study Report
EyeMax, LLC 
Study # 17-100-0011
Confidential
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
Final 1.0/15Dec2017 
 
Confidential 
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two treatments in the left eye. A trained study technician 
will instill one (1) drop of the assigned treatment in the 
right eye and one (1) drop of the assigned treatment in the 
left eye (based on randomization). Subjects will undergo 
CAC approximately 15 minutes post-instillation of the 
investigational product.  
Duration: 
This study consists of four (4) office visits (Screening 
Visit, Visit 1, Visit 2, and Visit 3) over a period of 
approximately three to five (3-5) weeks. 
Controls: 
 Vehicle of EM-100 topical ophthalmic solution 
 Zaditor® (ketotifen fumarate ophthalmic solution 
0.035%, EQ 0.025% Base), ANDA 077200 held by 
Alcon Pharmaceuticals. 
Dosage/ Instillation: 
At Visit 3, qualifying subjects will be enrolled and 
randomized to receive EM-100, Zaditor®, or Vehicle in 
each eye. The treatment arms are listed below: 
 
 
EM-100 in right eye and Zaditor® in left eye 
 
 
Zaditor® in right eye and EM-100 in left eye
 
 
EM-100 in right eye and Vehicle in left eye 
 
 
Vehicle in right eye and EM-100 in left eye 
   
 
Zaditor® in right eye and Vehicle in left eye 
 
 
Vehicle in right eye and Zaditor® in left eye 
 
 
A trained study technician will instill one (1) drop of the 
assigned treatment in the right eye and one (1) drop of the 
assigned treatment in the left eye approximately 15(+1) 
minutes prior to CAC.  
 
The pre-specified technicians responsible for instilling the 
investigational product will not be involved with any other 
study procedures at the site.  
Summary of Visit Schedule: 
Screening Visit  (Day -50 to -22): Screening/ Informed 
Consent/ Skin Test 
 
Visit 1 (Day -21 ± 3): Titration CAC  
 
Visit 2 (Day -14 ± 3): Confirmation CAC 
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Clinical Study Report
EyeMax, LLC 
Study # 17-100-0011
Confidential
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
Final 1.0/15Dec2017 
 
Confidential 
Page 5 
 
 
 
Visit 3 (Day 1):  Enrollment/ Randomization/ In-Office 
Instillation/ Efficacy CAC/ Study Exit 
Measures Taken to Reduce 
Bias: 
Randomization will be used to avoid bias in the 
assignment of subjects to investigational product, to 
increase the likelihood that known and unknown subject 
attributes (e.g. demographics and baseline characteristics) 
are evenly balanced across treatment groups, and to 
enhance the validity of statistical comparisons across 
treatment groups. Finally, masked treatment will be used 
to reduce potential of bias during data collection and 
evaluation of clinical endpoints.   
Study Population Characteristics:  
Number of Subjects: 
Approximately 120 subjects will be screened in order to 
enroll approximately 60 subjects at a single-center.  
Condition/Disease: 
Allergic Conjunctivitis 
Inclusion Criteria: 
Each subject must: 
1) be at least 18 years of age at the Screening Visit, 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 allergic conjunctivitis for at 
least 3 months and a positive skin test reaction to a 
seasonal (grass, ragweed, and/or tree pollen) or 
perennial allergen (cat dander, dog dander, dust mites, 
cockroach) as confirmed by an allergic skin test 
conducted at the Screening Visit or within the past 24 
months; 
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 Visit 1 and during 
the study trial period; 
7) (for females capable of becoming pregnant) agree to 
have urine pregnancy testing performed at Visit 1 
(must be negative) and exit visit; must not be 
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Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
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Clinical Trial Protocol: 17-100-0011 
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lactating; and must agree to use a medically 
acceptable form of birth control1 throughout the 
study duration. 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
 or 
better in each eye as measured using an ETDRS 
chart;   
9) have a positive bilateral post-CAC reaction 
 
 
 of instillation of the 
last titration of allergen at Visit 1; 
10) have a positive bilateral post-CAC reaction 
 
  
   
 for at least two out of the first 
three time points2 following the challenge at Visit 2. 
 
Exclusion Criteria: 
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, pterygium or a diagnosis of dry 
eye);  
3) have had ocular surgical intervention within three (3) 
months prior to Visit 1 or during the study and/or a 
history of refractive surgery within the past six (6) 
months; 
4) have a known history of retinal detachment, diabetic 
retinopathy, or active retinal disease; 
                                                 
1Acceptable 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. 
2 not necessarily at the same time point 
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Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
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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); 
*Baby aspirin (81 mg) is allowed as long as a stable 
dose has been maintained for at least 30 days prior 
to Visit 1 and will continue to be maintained for the 
duration of the study. 
14 Days 
 inhaled, ocular, topical, or systemic 
corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
2 Months 
 immunosuppressive or cancer chemotherapeutic 
agents; 
Note: 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 by trained study personnel at 
the end of Visits 1, 2, and 3, 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 
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Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
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could be expected to interfere with the subject’s 
health or with 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) have a scor
 
 prior to challenge (at Visits 1, 2, 
or 3) in either eye; 
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; 
11) be a female who is currently pregnant, planning a 
pregnancy, or lactating. 
Study Formulations and 
Formulation Numbers: 
 EM-100 topical ophthalmic solution 
 Vehicle of EM-100 topical ophthalmic solution 
 Zaditor® (ketotifen fumarate ophthalmic solution 
0.035%) 
Evaluation Criteria: 
 
Efficacy Measures and 
Endpoints: 
Primary:   
 Ocular itching evaluated by the subject at 3(±1), 
5(±1), and 7(±1) minutes post-CAC (0-4 scale, 
allowing half unit increments) at Visit 3. 
 
Secondary: 
 Conjunctival redness evaluated by the investigator 
at 7(±1), 15(±1), and 20(±1) minutes post-CAC (0 
to 4 scale, allowing half unit increments) at Visit 3.  
Safety Measures: 
 Adverse Events (reported, elicited, and observed)  
 Best Corrected Visual Acuity (BCVA) at Distance  
 Slit Lamp Biomicroscopy  
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Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
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Confidential 
Page 9 
 
 
General Statistical Methods and Types of Analyses 
The following analysis populations will be defined: 
 
 
 
  
 
 
 
 
 
 
 
 
Sample Size: 
The following treatment combinations will be randomized.  The eye receiving each test 
article will also be randomized: 
 
 with EM-100 in right eye and Zaditor® in left eye 
 
 with Zaditor® in right eye and EM-100 in left eye 
 
 with EM-100 in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and EM-100 in left eye 
 
 with Zaditor® in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and Zaditor® in left eye  
 
This sample size requires a total of 60 randomized subjects, while providing 48 eyes treated 
with each of EM-100 and Zaditor® and 24 eyes treated with vehicle, for a 
 ratio of 
treatments across all treated eyes.   
This sample size will provide 
 
 
 
 
 
   
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EyeMax, LLC 
Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
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Clinical Trial Protocol: 17-100-0011 
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The test of non-inferiority between EM-100 and Zaditor® must meet statistical significance 
as the primary analysis.  Upon showing non-inferiority for the primary analysis, the test of 
superiority between EM-100 and vehicle will be performed.  
 
  
Additionally, this sample size yields
 
 
 
 
 
 
Primary Efficacy Analyses: 
The primary efficacy endpoint is ocular itching 
 
 
 
 
 
 
 
 
.   
 
Secondary Efficacy Analyses: 
Analyses will be performed on the secondary endpoint of conjunctival redness in a manner 
similar to the non-inferiority tests of the primary endpoint.
 
 
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EyeMax, LLC 
Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
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Clinical Trial Protocol: 17-100-0011 
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Safety Analyses: 
Safety will be assessed by evaluating the incidence of subjects with any adverse events 
during the entire study.  The percentage of subjects with any AEs will be summarized, as 
well as the percentage of subjects with any treatment-emergent adverse events (TEAEs), 
summarized for each treatment combination.  Ocular TEAEs will similarly be summarized by 
eye for each treatment group.  Incidence will be tabulated by MedDRA System Organ Class 
and preferred term within each system organ class.  Adverse events will also be summarized 
for treatment-related TEAEs, SAEs, by maximal severity, and by day of onset relative to the 
start of treatment. 
The additional safety variables of slit lamp biomicroscopy and visual acuity will be 
summarized descriptively using quantitative and qualitative summary statistics as 
appropriate.  In all cases, outcomes will be summarized by eye for each treatment group. 
Changes and shifts from baseline will also be summarized where applicable. 
Summary of Known and Potential Risks and Benefits to Human Subjects 
Known and potential risks of ketotifen fumarate ophthalmic solution (0.035%) include ocular 
burning/stinging/irritation, headache, rhinorrhea, and photophobia. Benefits include relief and 
prevention of ocular itching associated with allergic conjunctivitis. 
Refer to the Zaditor® Package Insert regarding risks and benefits to human subjects. 
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EyeMax, LLC 
Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
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Clinical Trial Protocol: 17-100-0011 
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TABLE OF CONTENTS 
SYNOPSIS..................................................................................................................3 
TABLE OF CONTENTS..........................................................................................12 
LIST OF ABBREVIATIONS ............................................................................................15 
1 
INTRODUCTION ....................................................................................................16 
2 
STUDY OBJECTIVES .............................................................................................17 
3 
CLINICAL HYPOTHESES .....................................................................................17 
4 
OVERALL STUDY DESIGN ..................................................................................17 
5 
STUDY POPULATION ...........................................................................................18 
 
Number of Subjects (approximate) ................................................................18 
5.1
 
Study Population Characteristics ....................................................................18 
5.2
 
Inclusion Criteria ............................................................................................18 
5.3
 
Exclusion Criteria ...........................................................................................19 
5.4
 
Withdrawal Criteria (if applicable) ................................................................21 
5.5
6 
STUDY PARAMETERS ..........................................................................................21 
 
Efficacy Measures and Endpoints ..................................................................21 
6.1
6.1.1 
Primary Efficacy Endpoint(s) ...........................................................21 
6.1.2 
Secondary Efficacy Endpoints(s) ......................................................21 
6.1.3 
Criteria for Effectiveness ..................................................................21 
 
Safety Measures .............................................................................................22 
6.2
7 
STUDY MATERIALS .............................................................................................22 
 
Study Treatment(s) .........................................................................................22 
7.1
7.1.1 
Study Treatment(s)/ Formulation(s) .................................................22 
7.1.2 
Instructions for Use and Administration ...........................................22 
 
Other Study Supplies ......................................................................................24 
7.2
8 
STUDY METHODS AND PROCEDURES ............................................................24 
 
Subject Entry Procedures ...............................................................................24 
8.1
8.1.1 
Overview ...........................................................................................24 
8.1.2 
Informed Consent..............................................................................24 
8.1.3 
Washout Intervals .............................................................................24 
8.1.4 
Procedures for Final Study Entry ......................................................25 
8.1.5 
Methods for Assignment to Treatment Groups: ...............................25 
 
Concurrent Therapies .....................................................................................25 
8.2
8.2.1 
Prohibited Medications/Treatments ..................................................26 
8.2.2 
Escape Medications ..........................................................................26 
8.2.3 
Special Diet or Activities ..................................................................26 
 
Examination Procedures .................................................................................27 
8.3
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ............................................................................27 
8.3.1.1 
SCREENING VISIT (Day -50 to -22): Screening/ Informed Consent/ 
Skin Test 
27 
8.3.1.2 
VISIT 1 (Day -21 ± 3): Titration CAC ........................................... 27 
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EM-100 Topical Ophthalmic Solution  
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Clinical Trial Protocol: 17-100-0011 
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8.3.1.3 
VISIT 2 (Day -14 ± 3): Confirmation CAC ...................................... 29 
8.3.1.4 
VISIT 3 (Day 1): Enrollment/Randomization/ In-Office Instillation/ 
Efficacy CAC/ Study Exit ...................................................................................... 30 
 
Schedule of Visits, Measurements and Dosing ..............................................32 
8.4
8.4.1 
Scheduled Visits................................................................................32 
8.4.2 
Unscheduled Visits ...........................................................................32 
 
Compliance with Protocol ..............................................................................32 
8.5
 
Subject Disposition .........................................................................................33 
8.6
8.6.1 
Completed Subjects ..........................................................................33 
8.6.2 
Discontinued Subjects .......................................................................33 
 
Study Termination ..........................................................................................33 
8.7
 
Study Duration ...............................................................................................33 
8.8
 
Monitoring and Quality Assurance ................................................................33 
8.9
9 
ADVERSE EVENTS ................................................................................................34 
 
Adverse Event ................................................................................................34 
9.1
9.1.1 
Severity .............................................................................................34 
9.1.2 
Relationship to Investigational Product ............................................35 
9.1.3 
Expectedness .....................................................................................36 
 
Serious Adverse Events ..................................................................................36 
9.2
 
Procedures for Reporting Adverse Events .....................................................37 
9.3
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................37 
9.3.2 
Reporting a Serious Adverse Event ..................................................37 
 
Procedures for Unmasking (if applicable) ......................................................38 
9.4
 
Type and Duration of the Follow-up of Subjects after Adverse Events ........38 
9.5
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .....................39 
 Study Populations ...........................................................................................39 
10.1
10.1.1 Intent-to-Treat Population .................................................................39 
10.1.2 Per-Protocol Population ....................................................................39 
10.1.3 Safety Population ..............................................................................39 
 General Imputation Methods ..........................................................................39 
10.2
 Statistical Hypotheses .....................................................................................39 
10.3
 Sample Size ....................................................................................................41 
10.4
 Primary Efficacy Analyses .............................................................................42 
10.5
 Secondary Efficacy Analyses .........................................................................42 
10.6
 Adjustment for Multiplicity............................................................................43 
10.7
 Demographic and Baseline Medical History ..................................................43 
10.8
 Safety Analysis ...............................................................................................43 
10.9
 Interim Analysis .............................................................................................44 
10.10
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ....................................44 
 Protection of Human Subjects ........................................................................44 
11.1
11.1.1 Subject Informed Consent.................................................................44 
11.1.2 Institutional Review Board (IRB) Approval .....................................44 
 Ethical Conduct of the Study ..........................................................................45 
11.2
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EM-100 Topical Ophthalmic Solution  
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Clinical Trial Protocol: 17-100-0011 
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 Subject Confidentiality ...................................................................................45 
11.3
 Documentation ...............................................................................................45 
11.4
11.4.1 Retention of Documentation .............................................................45 
 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
11.5
Investigational Product ...................................................................................46 
11.5.1 Labeling/Packaging...........................................................................46 
11.5.2 Storage of Investigational Product ....................................................46 
11.5.3 Accountability of Investigational Product ........................................46 
11.5.4 Return or Disposal of Investigational Product ..................................47 
 Recording of Data on Source Documents and Case Reports Forms (CRFs) .47 
11.6
 Handling of Biological Specimens .................................................................47 
11.7
 Publications ....................................................................................................47 
11.8
12 
REFERENCES .........................................................................................................48 
13 
APPENDICES ..........................................................................................................50 
Appendix 1: Schedule of Visits and Measurements ..........................................................50 
Appendix 2: Examination Procedures, Tests, ....................................................................51 
Appendix 3: Package Insert ...............................................................................................55 
Drug Facts.....................................................................................................55 
Active ingredients ............................................................................................... 55 
Purpose ................................................................................................................ 55 
Uses ..................................................................................................................... 55 
Warnings .............................................................................................................. 55 
Directions ............................................................................................................. 55 
Other information ................................................................................................ 56 
Inactive ingredients ............................................................................................ 56 
Appendix 4: Handling of Biological Specimens ...............................................................57 
Appendix 5: Protocol Amendment Summary ....................................................................58 
Appendix 6: Ora Approvals ...............................................................................................59 
Appendix 7: SPONSOR Approvals ...................................................................................60 
Appendix 8: Investigator’s Signature ................................................................................61 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
BCVA 
best-corrected visual acuity 
CAC 
conjunctival allergen challenge 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRF 
case report form 
DHHS 
Department of Health and Human Services 
eCRF 
electronic case report form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent to treat 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
ND  
not done  
NSAID  
nonsteroidal anti-inflammatory drug 
OD 
right eye 
OS 
left eye 
OU 
both eyes 
OTC 
over the counter 
PE 
polyethylene 
PP 
per protocol 
SAE 
serious adverse event 
SD 
standard deviation 
SDC 
Statistics and Data Corporation 
SOP 
standard operating procedure 
VA 
visual acuity 
EM-100 Topical Ophthalmic Solution 
Clinical Study Report
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Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
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1 INTRODUCTION 
Allergies affect approximately 15% of the global population and up to 30% of the U.S. 
population (1). 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 (2). Histamine is the primary 
mediator responsible for the 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 (3, 4). 
Ketotifen is a widely effective therapy for the management of ocular allergies. It has 
demonstrated rapid onset (≤ 15 minutes) and long duration of action (≥ 8 hours) after 
conjunctival allergen challenge (CAC)(5, 6). Ketotifen fumarate ophthalmic solution 
0.035% was found to be safe, well tolerated, and effective for the prevention of the signs 
and symptoms associated with allergic conjunctivitis in multiple CAC studies(7-12). In an 
environmental setting, ketotifen fumarate ophthalmic solution 0.035% was found to 
safely and effectively reduce seasonal allergic conjunctivitis signs and symptoms and 
prevent recurrence(13). 
Ketotifen fumarate ophthalmic solution 0.035% (Zaditor®/Zaditen®; Novartis 
Ophthalmics) is approved in the United States and Canada for the temporary prevention 
of ocular itching due to allergic conjunctivitis at a dose of one drop in the affected eye 
twice daily (every 8-12 hours)(14). In 2006, ketotifen fumarate ophthalmic drops 0.035% 
(ketotifen 0.025%; Alaway®; Bausch and Lomb, Inc., and Zaditor®; Novartis 
Ophthalmics) were approved by the United States Food and Drug Administration (FDA) 
for over-the-counter use, with the indication of temporary relief of itchy eyes due to 
pollen, ragweed, grass, animal hair, and dander, at an approved dose of one drop in the 
affected eye twice daily (every 8-12 hours)(15). 
EM-100 contains ketotifen ophthalmic solution (0.025%) as a non-preserved formulation 
in single-dose vials. This is a single-center, randomized, double-masked study to 
establish the therapeutic equivalence of EM-100 to Zaditor® (ketotifen fumarate 
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
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ophthalmic drops 0.035%).  EM-100 will need to show non-inferiority to Zaditor® in the 
treatment of ocular itching following CAC (15 minutes following study medication 
instillation).  The vehicle is included for assay validation.   
2 STUDY OBJECTIVES 
Primary: 
 To demonstrate the non-inferiority of EM-100 to Zaditor® in the treatment of 
ocular itching associated with allergic conjunctivitis.  
Secondary: 
 To demonstrate that EM-100 is superior to vehicle in the treatment of ocular 
itching associated with allergic conjunctivitis. 
 To demonstrate that Zaditor® is superior to vehicle in the treatment of ocular 
itching associated with allergic conjunctivitis 
 To demonstrate that EM-100 is non-inferior to Zaditor® in the treatment of 
conjunctival redness associated with allergic conjunctivitis.  
3 CLINICAL HYPOTHESES 
The clinical hypotheses are:  
 EM-100 is more effective than vehicle in the treatment of ocular itching 
associated with allergic conjunctivitis induced by CAC 15 minutes following 
product instillation.  
 EM-100 is non-inferior to Zaditor® in the treatment of ocular itching associated 
with allergic conjunctivitis induced by CAC at 15 minutes following product 
instillation. 
 Zaditor® is more effective than vehicle in the treatment of ocular itching 
associated with allergic conjunctivitis induced by CAC at 15 minutes following 
product instillation. 
4 OVERALL STUDY DESIGN 
This is a single-center, randomized, double-masked, contralateral eye study comparing 
topical EM-100 with Zaditor® and the vehicle of EM-100 in subjects with allergic 
conjunctivitis. At the Screening Visit, subjects will sign the informed consent form and 
an allergic skin test will be performed, if required. At Visit 1, each qualifying subject will 
undergo a bilateral conjunctival allergen challenge (CAC) titration using an allergen they 
had a positive reaction to on their skin test. Subjects who elicit a positive reaction post-
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CAC will undergo the confirmation CAC at Visit 2 using the same allergen they qualified 
with at Visit 1.  
At Visit 3, qualifying subjects will be enrolled and randomized to receive EM-100, 
Zaditor®, or Vehicle in each eye. The treatment arms are listed below: 
 
 EM-100 in right eye and Zaditor® in left eye 
 
 Zaditor® in right eye and EM-100 in left eye 
EM-100 in right eye and 
Vehicle in left eye 
 
 Vehicle in right eye and EM-100 in left eye 
 
 Zaditor® in right eye and Vehicle in left eye 
 
 Vehicle in right eye and Zaditor® in left eye 
 
 
 A trained study technician will instill one (1) drop of the assigned treatment in the right 
eye and one (1) drop of the assigned treatment in the left eye (based on randomization). 
Subjects will undergo CAC approximately 15 minutes post-instillation of the 
investigational product. The pre-specified technicians responsible for instilling the 
investigational product will not be involved with any other study procedures at the site. 
5 STUDY POPULATION 
 Number of Subjects (approximate) 
5.1
Approximately 120 subjects will be screened in order to enroll approximately 60 subjects 
at a single-center.  
 Study Population Characteristics 
5.2
 Inclusion Criteria 
5.3
Each subject must: 
 
1) be at least 18 years of age at the Screening Visit, 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 allergic conjunctivitis for at least 3 months and a positive 
skin test reaction to a seasonal (grass, ragweed, and/or tree pollen) or perennial 
allergen (cat dander, dog dander, dust mites, cockroach) as confirmed by an allergic 
skin test conducted at the Screening Visit or within the past 24 months; 
5) be able and willing to avoid all disallowed medication for the appropriate washout 
period and during the study (see exclusion 6); 
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6) be able and willing to discontinue wearing contact lenses for at least 72 hours prior 
to Visit 1 and during the study trial period; 
7) (for females capable of becoming pregnant) agree to have urine pregnancy testing 
performed at Visit 1 (must be negative) and exit visit; must not be lactating; and 
must agree to use a medically acceptable form of birth control1 throughout the 
study duration. 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
 or better in each eye as measured 
using an ETDRS chart;   
9) have a positive bilateral post-CAC reaction 
 
 within 10 (±2) minutes of instillation of the last 
titration of allergen at Visit 1; 
10) have a positive bilateral post-CAC reaction 
  
 
  
 for at least two out of the first three time points2 
following the challenge at Visit 2. 
 
 Exclusion Criteria 
5.4
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, 
pterygium or a diagnosis of dry eye);  
3) have had ocular surgical intervention within three (3) months prior to Visit 1 or 
during the study and/or a history of refractive surgery within the past six (6) 
months; 
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; 
                                                 
1Acceptable 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. 
2 not necessarily at the same time point 
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EM-100 Topical Ophthalmic Solution  
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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); 
*Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained 
for at least 30 days prior to Visit 1 and will continue to be maintained for the 
duration of the study. 
14 Days 
 inhaled, ocular, topical, or systemic corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
2 Months 
 immunosuppressive or cancer chemotherapeutic agents; 
Note: 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 by trained study personnel at the end of Visits 1, 2, and 3, 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 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) have a score 
 prior to challenge 
(at Visits 1, 2, or 3) in either eye;  
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; 
11) be a female who is currently pregnant, planning a pregnancy, or lactating. 
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 Withdrawal Criteria (if applicable) 
5.5
If at any time during the study the Investigator determines that a subject’s safety has been 
compromised, the subject may be withdrawn from the study. 
Subjects may withdraw consent from the study at any time. 
Any female will be removed from the study should she become pregnant during the 
course of the study, and she will undergo a pregnancy test at her exit visit for 
confirmation. The pregnancy test must be confirmed by two (2) additional tests and 
confirmed by the principal investigator (or sub-investigator if the principal investigator is 
not present). If the test result is positive a second and third time, the principal investigator 
(or sub-investigator if the principal investigator is not present) will inform the subject. 
The Investigator will follow-up and document the outcome of the pregnancy and provide 
a copy of the documentation to the sponsor. The Ora Pregnancy Report Form will be used 
to report a pregnancy and follow-up. 
Reason for withdrawal will be included in the eCRF, and all efforts should be made to 
schedule the subject for an Exit Visit to complete exit procedures.  Any subject who is 
withdrawn for the study because of an AE will be followed until AE is resolved or as 
clinically required, and the investigator will prepare a written summary of the event and 
document the available follow-up information on the eCRF.   
Sponsor and/or Investigator may discontinue any subject for non-compliance or any valid 
medical reason (see Section 8.5). 
6 STUDY PARAMETERS 
 Efficacy Measures and Endpoints 
6.1
6.1.1 Primary Efficacy Endpoint(s) 
 
 
 
6.1.2 Secondary Efficacy Endpoints(s) 
 
 
  
 
6.1.3 Criteria for Effectiveness 
This therapeutic equivalence study is designed to evaluate the relative efficacy of EM-
100 topical ophthalmic solution compared to vehicle and Zaditor® in the treatment of 
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ocular itching at each designated time point post-CAC at Visit 3 (Day 1, 15-minute 
onset).  
Although this study is being referred to as a “bioequivalence” or “therapeutic 
equivalence” study, it is in fact a non-inferiority study and all statistical testing will 
determine whether EM-100 is non-inferior to the reference drug, Zaditor®. Vehicle is 
included in this study in order to validate the assay.  
To demonstrate non-inferiority for ocular itching compared to Zaditor®, EM-100 topical 
ophthalmic solution needs to show itching scores no worse than 
 
To demonstrate superiority for ocular itching compared to vehicle, EM-100 topical 
ophthalmic solution needs to show clinical superiority over vehicle by at least 0.5 units of 
a 5 point scale for all 3 post-CAC time points, 3(±1), 5(±1), and 7(±1) minutes post-
CAC, and at least 1 unit for the majority (2:3) of the post-CAC time points.  Statistically 
significant differences at two-sided alpha levels of 0.05 are also required for each post-
CAC time point.  This statistical significance is expected given the clinical superiority 
requirements above.Primary and secondary analyses will be tested using a fixed 
sequence, as described in Section 10.7. 
 Safety Measures 
6.2
 Adverse Events (reported, elicited, and observed)  
 Best Corrected Visual Acuity (BCVA) at Distance  
 Slit Lamp Biomicroscopy  
7 STUDY MATERIALS 
 Study Treatment(s) 
7.1
7.1.1 Study Treatment(s)/ Formulation(s) 
 EM-100 topical ophthalmic solution  
 Vehicle of EM-100 topical ophthalmic solution 
 Zaditor® (ketotifen fumarate ophthalmic solution 0.035%)  
 
7.1.2 Instructions for Use and Administration 
 This trial requires additional attention in order to preserve masking of study 
treatment. There will be a total of 485 identical appearing kits containing all three 
treatments labeled A, B, and C.  Once the kits arrive at the site, a designated staff 
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member will randomly select 65 kits to be used for the trial.  The remaining 420 
kits will be identified and stored as retains.  Both EM-100 and the vehicle of EM-
100 will be identical in appearance as single use vials, while the reference product, 
Zaditor®, will be in its original bottle. All individual kits will be sealed with 
tamper evident tape and the sites will be instructed to not open the kits upon 
receipt of shipment.  At no point during the trial (until database lock) will site staff 
or monitors be allowed to open the kits unless it is the designated “unmasked” 
technicians. These technicians will ensure that opening of the kits is done in a 
manner to prevent the other staff and subjects from seeing the investigational 
product. For each subject treatment will be administered by eye according to a 
randomization list which will be sent to the site in a sealed envelope and opened at 
Visit 3 by the unmasked technicians.  Following Visit 3 dosing, the technicians 
will reseal the kits and randomization list envelope using tamper evident tape and 
return the kits to storage. The sealed randomization list envelope will be filed in 
the investigator’s study file.      
 
 At Visit 3, qualifying subjects will be enrolled and randomized to receive EM-
100, Zaditor®, or vehicle of EM-100. A randomization list will inform the 
technicians which corresponding letter treatment should be instilled in the right 
eye and which one should be instilled in the left eye.  
 
 A trained study technician will instill one (1) drop of the assigned treatment in the 
right eye and one (1) drop of the assigned treatment in the left eye approximately 
15(+1) minutes prior to CAC.  
 
 The 
pre-specified 
unmasked 
technicians 
responsible 
for 
instilling 
the 
investigational product will not be involved with any other study procedures at the 
site.  Care will be taken to hide the container (vial or bottle) from the subject.   
Dosing will occur in a room where no other subjects, staff, or investigators will 
observe the instillation.   
 
 Investigational product must be stored in a secure area of the clinical site, 
accessible only to the Investigator(s) or designees at room temperature between 
20-25°C (68-77°F).  All investigational product will be returned to inventory after 
use.  
 
 In accordance with 21CFR §320.38 and §320.63, samples of both the test article 
(EM-100) and reference listed drug (Zaditor®) will be retained and stored under 
conditions consistent with product labeling and in an area segregated from the 
area where testing is conducted and with access limited to authorized personnel. 
 
 
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 Other Study Supplies 
7.2
The following supplies will be supplied and/or reconstituted by Ora, Inc.: 
 
Pregnancy tests (Clarity HCG, RAC Medical Boca Raton, FL).  
 
The allergens used for skin testing and the conjunctival allergen challenge (cat 
dander, dog dander, dust mite, cockroach, meadow fescue, rye grass, Bermuda 
grass, Kentucky bluegrass, Timothy grass, ragweed, white birch, oak, and maple).   
 
Relief drops (OTC antihistamine/vasoconstrictor combination products). 
8 STUDY METHODS AND PROCEDURES 
 Subject Entry Procedures 
8.1
8.1.1 Overview 
Subjects as defined by the criteria in sections 5.2, 5.3, and 5.4 will be considered for 
entry into this study. 
8.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., changes in a subject’s medical treatment 
and/or study related procedures), the study will be discussed with each subject, and 
subjects wishing to participate must give written informed consent using an informed 
consent form (ICF).  The ICF must be the most recent version that has received 
approval/favorable review by a properly constituted Institutional Review Board. Failure 
to obtain a signed ICF renders the subject ineligible for the study. Subjects must be 
willing to return to the clinic for study Visits 1, 2, and 3. 
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. Subjects can be re-screened a maximum of two times. 
8.1.3 Washout Intervals 
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 stabilizers, H1 
antihistamine- vasoconstrictor drug combinations; 
 decongestants; 
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 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, topical, or systemic corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
 2 Months 
 immunosuppressive or cancer chemotherapeutic agents. 
Note: Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained for 
at least 30 days prior to Visit 1 and will continue to be maintained for the duration of the 
study. 
8.1.4 Procedures for Final Study Entry 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria prior to 
Visit 3 to be enrolled in this study.  
8.1.5 Methods for Assignment to Treatment Groups: 
All subjects screened for the study who sign an ICF will be assigned a screening number 
that will be entered in the Screening and Enrollment Log. The screening number will 
consist of three (3) digits, starting with 001. Randomization will be used to avoid bias in 
the assignment of subjects to treatment, to increase the likelihood that known and 
unknown subject attributes (e.g., demographics and baseline characteristics) are evenly 
balanced across treatment groups, and to enhance the validity of statistical comparisons.   
Once a subject meets qualification criteria at Visit 3 (Day 1), he/she will be enrolled and 
randomized to receive EM-100, Zaditor®, or the vehicle of EM-100. A separate 
treatment will be assigned to each eye. Subjects will be assigned the lowest four (4) digit 
randomization number available.  
 Concurrent Therapies 
8.2
The use of any concurrent medication, prescription or over-the-counter, is to be recorded 
on the subject’s source document and corresponding electronic case report form (eCRF) 
along with the reason the medication was taken. 
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Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
8.2.1 Prohibited Medications/Treatments 
 contact lenses 
 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) 
 inhaled, ocular, topical, or systemic corticosteroids or mast cell stabilizers 
 depot-corticosteroids 
 immunosuppressive or cancer chemotherapeutic agents 
Note: Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained for 
at least 30 days prior to Visit 1 and will continue to be maintained for the duration of the 
study. 
 
8.2.2 Escape Medications 
Subjects may receive either anti-itch cream or Calamine lotion (depending on the 
washout) after the skin test has been completed at the Screening Visit.  
 
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 by trained personnel at the end of Visits 1, 2, and 3 after all evaluations are 
completed. 
 
8.2.3 Special Diet or Activities 
Not Applicable. 
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 Examination Procedures 
8.3
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) 
8.3.1.1 SCREENING VISIT (Day -50 to -22): Screening/ Informed Consent/ Skin 
Test 
 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.  
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. Subjects can be re-screened a maximum of two 
times.  
 Allergic Skin Test (if applicable): A diagnostic test for allergic disease (skin test) will 
be performed according to Ora SOPs if there is no documented skin test within the 
past 24 months. Subjects may receive either anti-itch cream or Calamine lotion 
(depending on the washout) after the skin test has been completed. 
 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 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 8.1.3) 
 Adverse Event Query 
 Schedule Visit 1: Qualifying subjects will be scheduled for Visit 1. 
8.3.1.2 VISIT 1 (Day -21 ± 3): Titration CAC 
 Update of Medical/Medication History 
 Adverse Event Query 
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 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.  
 Initial Visual Acuity Utilizing an ETDRS Chart:  Subjects must have a score of 
 
 or better in each eye in order to qualify.  
 Initial Ocular Itching and Conjunctival Redness Assessments: The investigator and 
the subject will assess initial ocular itching and conjunctival redness using the Ora-
CAC® scales (see Appendix 2). Subjects exhibiting a sign and/or symptom of allergic 
conjunctivitis 
 
 will be excluded. 
 Initial Slit Lamp Biomicroscopy: A slit lamp examination will be performed in both 
eyes to exclude subjects with disallowed ocular conditions (see Appendix 2). 
Findings of abnormality which are not exclusionary should be recorded as Medical 
History.  
 Review of Inclusion/Exclusion Criteria: A review of protocol inclusion and exclusion 
criteria will be confirmed for each subject. 
 Titration Conjunctival Allergen Challenge (CAC): A conjunctival allergen challenge 
(CAC) will be performed bilaterally with a perennial or seasonal allergen serially 
diluted in buffered saline and administered via a micropipette according to Ora SOPs. 
One drop of a solubilized allergen to which the subject is sensitized, at the weakest 
dilution, will be instilled bilaterally into the conjunctival cul-de-sac.  
If the subject fails to react within 10 (±2) minutes, increasingly concentrated doses 
may be instilled bilaterally at approximately ten-minute intervals until a positive 
reaction is elicited. If increasing doses are required (i.e., for insufficient bilateral 
itching and/or redness as evaluated by a trained technician or the Investigator), doses 
may be skipped. If a positive CAC reaction is not elicited with the first allergen 
 
), other allergens to which the subject is 
sensitized may be used starting at the lowest dose.  
 Post-CAC Ocular Itching and Conjunctival Redness Assessments: Upon completion 
of the initial titration CAC, subjects will receive an ocular examination by the 
Investigator to evaluate conjunctival redness and confirm the subject’s qualification. 
Subjects will be asked to assess their ocular itching. 
A positive CAC at Visit 1 is defined as a
 
 
ny subject who fails to test positively will be 
excluded from the study. 
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 Note: The type and concentration of allergen used to elicit a positive reaction will be 
recorded for each qualifying subject.  At all subsequent visits, subjects will receive 
the same type of allergen (same lot number) and same concentration identified at this 
visit.  
 Review of Inclusion/Exclusion Criteria 
 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®) by trained study personnel as they leave the office to 
relieve any immediate discomfort caused by the allergic reaction.  
 Adverse Event Query 
 Schedule Visit 2: Qualifying subjects will be scheduled to return to the office in one 
(1) week for Visit 2. 
8.3.1.3 VISIT 2 (Day -14 ± 3): Confirmation CAC  
 Update of Medical/Medication History 
 Adverse Event Query 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease from Visit 1 may be documented as an AE per the investigator’s discretion. 
An increase of 
or more should be brought to the attention of the investigator. 
Visual Acuity may be repeated in instances of significant decreases. 
 Pre-CAC Ocular Itching and Conjunctival Redness Assessments: The investigator 
and the subject will assess pre-CAC ocular itching and conjunctival redness using the 
Ora-CAC® scales. Subjects exhibiting a sign and/or symptom of allergic 
conjunctivitis 
 
) will be excluded. 
 Slit Lamp Biomicroscopy 
 Review of Inclusion/Exclusion Criteria  
 Confirmation CAC: For each qualified subject, one drop of the allergen solution, of 
the same, final dose that elicited a positive reaction at Visit 1, will be administered 
bilaterally. 
 Post-CAC Ocular Itching and Conjunctival Redness Assessments: Assessments of 
itching will be made by the subject at 3(±1), 5(±1), and 7 (±1) minutes following 
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allergen challenge. Assessments of conjunctival redness will be graded by the 
Investigator at 7(±1), 15(±1), and 20(±1) minutes post-challenge (Appendix 2). If the 
subject fails to react positively 
 
 in both eyes in at least two (2) out of the first three (3) time 
points , he/she will be excluded from the study. 
 Review of Inclusion/Exclusion Criteria 
 
 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. 
  
 Adverse Event Query  
 
 Schedule Visit 3: Subjects will be asked to return to the office two (2) weeks later for 
Visit 3.  
8.3.1.4 VISIT 3 (Day 1): Enrollment/Randomization/ In-Office Instillation/ Efficacy 
CAC/ Study Exit 
 Update of Medical/Medication History 
 Adverse Event Query   
 Urine Pregnancy Test (for females of childbearing potential) 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease from Visit 1 may be documented as an AE per the investigator’s discretion. 
An increase of 
or more should be brought to the attention of the investigator. 
Visual Acuity may be repeated in instances of significant decreases. 
 Pre-CAC Ocular Itching and Conjunctival Redness Assessments: The investigator 
and the subject will assess pre-CAC ocular itching and conjunctival redness using the 
Ora-CAC® scales. Subjects exhibiting a sign and/or symptom of allergic 
conjunctivitis 
 
 will be excluded.      
 Slit Lamp Biomicroscopy 
 Review of Inclusion/Exclusion Criteria  
                                                 
1 not necessarily at the same time point 
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 Randomization: Subjects who meet all of the inclusion criteria and none of the 
exclusion criteria and qualify to continue in the study will be enrolled and 
randomized to receive EM-100, Zaditor®, or the vehicle of EM-100. A separate 
treatment will be assigned to each eye.  Subjects will be assigned the lowest four (4) 
digit randomization number available.  
 Investigational Product Instillation: A trained study technician will instill one drop of 
the assigned treatment in the right eye and one drop of the assigned treatment in the 
left eye, according to the directions for use. The investigational product kit number 
and the time of instillation will be recorded. The pre-specified technicians responsible 
for instilling the investigational product will not be involved with any other study 
procedures at the site.  
 Efficacy CAC: Each subject will receive one drop of the allergen solution of the same, 
final dose that elicited a positive reaction at Visit 1 bilaterally, 15(+1) minutes post-
instillation of investigational product.  
 Post-CAC Ocular Itching and Conjunctival Redness Assessments: Assessments of 
itching will be made by the subject at 3(±1), 5(±1), and 7 (±1) minutes following 
allergen challenge. Assessments of conjunctival redness will be graded by the 
Investigator at 7(±1), 15(±1), and 20(±1) minutes post-challenge (Appendix 2).  
 Exit Slit Lamp Biomicroscopy  
 Exit Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease from Visit 1 may be documented as an AE per the investigator’s discretion. 
An increase of
or more should be brought to the attention of the investigator. 
Visual Acuity may be repeated in instances of significant decreases. 
 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. 
 Adverse Event Query 
 Study Exit: Subjects will be exited from the study. 
Adverse Events (AEs) (both elicited and observed) will be monitored throughout the 
study. All AEs (both elicited and observed) will be promptly reviewed by the investigator 
for accuracy and completeness. All AEs will be documented on the appropriate eCRF. 
If a female has a positive pregnancy test during the study, then the investigator will notify 
Ora immediately. The investigator shall request from the subject and/or the subject’s 
physician copies of all related medical reports during the pregnancy and shall document 
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the outcome of the pregnancy. The investigator will retain these reports together with the 
subject’s source documents and will provide a copy of all documentation to Ora. 
 Schedule of Visits, Measurements and Dosing 
8.4
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
If a subject is discontinued at a scheduled study visit (i.e. Visit 3), the remaining 
assessments should be captured on the Unscheduled Visit/ Early Exit Visit pages of the 
source document and corresponding eCRF. Subjects who screen fail (Screening  
Visits or Visits 1, 2, or 3) may be scheduled for the Unscheduled Visit at the 
Investigator’s discretion due to follow-up of an ongoing AE.  
8.4.2 Unscheduled Visits 
For unscheduled visits, the reason for the visit should be clearly documented on the 
appropriate eCRF, including findings from all evaluations that are completed.  
These visits may be performed in order to ensure subject safety. All information gathered 
at unscheduled visits should be recorded on the Unscheduled Visit/Early Exit Visit pages 
of the source document and corresponding eCRF. 
Evaluations that may be conducted at an Unscheduled Visit (as appropriate, depending on 
the reason for the visit), include:  
 
Assessment of Adverse Events 
 
Assessment of Concomitant Medications 
 
Visual Acuity Utilizing an ETDRS chart 
 
Urine Pregnancy Test (for females of childbearing potential) 
 
Slit lamp Biomicroscopy  
If a randomized subject does not attend their scheduled visit, eCRF pages for missed 
visits will be skipped. All efforts should be made to schedule the subject for an Exit Visit 
to complete exit procedures.  
 Compliance with Protocol 
8.5
Subjects who are inappropriately enrolled or no longer fulfill the study eligibility criteria 
may be discontinued from the study. The reason for such discontinuation will be recorded 
as “protocol violation” in the source document and on the appropriate page in the eCRF.  
Site staff will review concomitant medication by asking subjects if they changed their 
dosing regimen since their previous visit. The response will be recorded in the source 
document and on the eCRF at Visits 1, 2, and 3.  
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All protocol violations, regardless of causation, will be recorded in the subject’s source 
document as well as eCRF. Major protocol violations will be recorded in the subject’s 
source document, entered in the eCRF, and reported to the IRB, as per the applicable 
regulations.   
 Subject Disposition 
8.6
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
8.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
 
subject request/withdrawal 
 
AEs 
 
protocol violations 
 
administrative reasons (e.g., inability to continue, lost to follow up) 
 
sponsor termination of study 
 
other 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to Ora and/or sponsor and will be clearly documented on the eCRF. Subjects who are 
discontinued from the study will not be replaced. 
 Study Termination 
8.7
The study may be stopped at any time by the investigator, the sponsor, and/or Ora with 
appropriate notification. 
 Study Duration 
8.8
This study consists of four (4) office visits (Screening Visit, Visit 1, Visit 2, and Visit 3) 
over a period of approximately three to five (3-5) weeks. 
 Monitoring and Quality Assurance 
8.9
During the course of the study, an Ora monitor, or designee, will make routine site visits 
to review protocol compliance, assess IP accountability, and ensure the study is being 
conducted according to the pertinent regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject 
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confidentiality. Further details of the study monitoring will be outlined in a monitoring 
plan. 
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. 
9 ADVERSE EVENTS 
 Adverse Event 
9.1
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered IP-related. An AE can be any unfavorable and 
unintended sign (e.g., 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 (e.g., off-label use, use in combination with another drug or 
medical device) and from any route of administration, formulation, or dose, including an 
overdose. An AE can arise from any delivery, implantation, or use of a medical device, 
including medical device failure, subject characteristics that may impact medical device 
performance (e.g., anatomical limitations), and therapeutic parameters (e.g., energy 
applied, sizing, dose release, and anatomic fit) associated with medical device use. 
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 comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, and 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.  
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). 
9.1.1 Severity 
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: 
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 
Mild: Event is noticeable to the subject, but is easily tolerated and does not 
interfere with the subject’s daily activities. 
 
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. 
9.1.2 Relationship to Investigational Product 
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 IP 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. 
 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. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the IP caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the IP and the AE. Types of evidence that would suggest a 
causal relationship between the IP and the AE event include: a single occurrence of an 
event that is uncommon and known to be strongly associated with IP exposure (e.g., 
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 (e.g., 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 
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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. 
9.1.3 Expectedness 
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 is not 
listed at the specificity or severity that has been observed. 
 Expected:  An AE that is listed in the IB at the specificity and severity that has been 
observed. 
 Not applicable: An AE unrelated to the IP. 
Adverse events that are mentioned in the IB as occurring with a class of products or as 
anticipated from the pharmacological/mechanical (or other) properties of the product, but 
are not specifically mentioned as occurring with the particular product under 
investigation are to be considered unexpected. 
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 
9.2
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; 
Note: 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; 
Note: 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. 
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 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
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 (e.g., 
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 
9.3
All AEs and their outcomes must be reported to Ora, the 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.  
Collection of AEs/SAEs will begin at the time of informed consent.  
9.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the sponsor and 
the IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities. 
9.3.2 Reporting a Serious Adverse Event 
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 eCRFs. 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. 
In the event of a SAE, the investigator must notify Ora and the sponsor 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 with a complete case history, which includes a 
statement as to whether the event was or was not suspected to be related to the use of the 
IP; and inform the IRB of the SAE within their guidelines for reporting SAEs. All SAEs, 
regardless of expectedness or relationship to the IP, will be reported to the FDA as soon 
as possible but no later than 15 calendar days after becoming aware of the event. 
Contact information for reporting SAEs: 
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 Procedures for Unmasking (if applicable) 
9.4
When medically necessary, the investigator may need to determine what treatment has 
been assigned to a subject. When possible (i.e., in non-emergent situations), Ora and/or 
the sponsor should be notified before unmasking IP. 
 Type and Duration of the Follow-up of Subjects after Adverse 
9.5
Events 
AEs will be followed until: 
 Resolution (return to baseline status or to “normal”) 
 Stabilization of the event has occurred (no improvement or worsening expected 
by the investigator) 
 Event is otherwise explained, regardless of whether the subject is still 
participating in the study 
 Principal investigator determines, for events that do not end (i.e., metastasis), the 
condition to be chronic. The event can be determined to be resolved or resolved 
with sequelae.  
The Investigator will follow unresolved adverse events to resolution until the subject is 
lost to follow-up or until the adverse event is otherwise explained. If the subject is lost to 
follow-up, the Investigator should make three (3) reasonable attempts to contact the 
subject 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 and be followed as 
aforementioned.  
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 
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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. 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
 Study Populations 
10.1
10.1.1 Intent-to-Treat Population 
 
  
  
10.1.2 Per-Protocol Population 
 
 
 
 
10.1.3 Safety Population 
The safety population includes all subjects who received the test article. The safety 
population will be analyzed as treated and will be used for the safety analyses. No 
data will be excluded for any reason. 
 General Imputation Methods 
10.2
Missing data is not expected in this single, post-randomization visit study.  
 
 
 
 
 
 
 Statistical Hypotheses 
10.3
The statistical hypotheses for the non-inferiority test between EM-100 ophthalmic 
solution and Zaditor® are as follows: 
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PRIMARY: 
 
 
 
 
 
SECONDARY: 
Conditional upon H01 being rejected, the statistical hypothesis for the superiority test 
between EM-100 ophthalmic solution and vehicle solution will be tested as follows: 
 
 
 
 
 
Conditional upon H01 and H02 being rejected, the statistical hypothesis for the 
superiority test between Zaditor® and vehicle solution will be tested as follows: 
 
 
 
 
Conditional upon H01, H02, and H03 being rejected, the statistical hypothesis for the 
non-inferiority test between EM-100 ophthalmic solution and Zaditor® will be tested as 
follows: 
 
 
 
 
 
  
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 Sample Size 
10.4
The following treatment combinations will be randomized.  The eye receiving each test 
article will also be randomized: 
 
 with EM-100 in right eye and Zaditor® in left eye 
 
 with Zaditor® in right eye and EM-100 in left eye 
 
 with EM-100 in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and EM-100 in left eye 
 
 with Zaditor® in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and Zaditor® in left eye 
This sample size requires a total of 60 randomized subjects
 
 
   
 
 
 
 
.   
 
 
 
 
   
 
 
 
 
  
 
 
 
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 Primary Efficacy Analyses  
10.5
The primary efficacy endpoint is ocular itching 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 Secondary Efficacy Analyses 
10.6
Analyses will be performed on the secondary endpoint of conjunctival redness in a 
manner similar to the non-inferiority tests of the primary endpoint.
 
 
 
 
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 Adjustment for Multiplicity 
10.7
The primary and secondary analyses will be tested in a fixed sequence to maintain the 
study-wide Type I error for these analyses. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Demographic and Baseline Medical History  
10.8
The demographic and baseline medical history data will be summarized descriptively 
overall subjects and for each treatment combination. For quantitative variables, the 
summaries will include the number of observations, mean, standard deviation, median, 
minimum, and maximum. Qualitative variables will be summarized using counts and 
percentages.  
 Safety Analysis 
10.9
Safety will be assessed by evaluating the incidence of subjects with any adverse events 
during the entire study.  The percentage of subjects with any AEs will be summarized, 
as well as the percentage of subjects with any treatment-emergent adverse events 
(TEAEs), summarized for each treatment combination.  Ocular TEAEs will similarly be 
summarized by eye for each treatment group.  Incidence will be tabulated by MedDRA 
System Organ Class and preferred term within each system organ class.  Adverse events 
will also be summarized for treatment-related TEAEs, SAEs, by maximal severity, and 
by day of onset relative to the start of treatment. 
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The additional safety variables of slit lamp biomicroscopy and visual acuity will be 
summarized descriptively using quantitative and qualitative summary statistics as 
appropriate.  In all cases, outcomes will be summarized by eye for each treatment 
group. Changes and shifts from baseline will also be summarized where applicable. 
 Interim Analysis 
10.10
No interim analyses are planned. 
11 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 IP in the countries 
involved will be adhered to. 
 Protection of Human Subjects 
11.1
11.1.1 Subject Informed Consent 
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 (e.g., 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 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. 
 
11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB 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 approved version of the informed consent form will be used. 
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 Ethical Conduct of the Study 
11.2
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 Subject Confidentiality 
11.3
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 is in accordance with local, state, and federal 
laws and regulations. 
Monitors, auditors and other authorized representatives of Ora, the sponsor, the IRB 
approving this study, the FDA, the DHHS, other domestic government agencies, and 
other foreign regulatory agencies will be granted direct access to the 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 IP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
 Documentation 
11.4
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 EKGs. The investigator’s copy of the eCRFs serves as the 
investigator’s record of a subject’s study-related data. 
11.4.1 Retention of Documentation 
All study related correspondence, subject records, consent forms, record of the 
distribution and use of all IP, and copies of eCRFs should be maintained on file for at 
least two 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 two years have 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. 
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 Labeling, Packaging, Storage, Accountability, and Return or 
11.5
Disposal of Investigational Product 
11.5.1 Labeling/Packaging 
Each kit will contain the 3 treatments labeled A, B, and C.  The EM-100 and vehicle will 
consist of five single use 0.4mL vials packaged in an aluminum pouch.  Zaditor® will be 
in its original bottle with the label removed.  A label containing the letter A, B, or C will 
be on the bottles of Zaditor® and the pouches of both EM-100 and vehicle of EM-100. 
There will be 485 kits created.  Kits will be labeled on the outside with a kit number 
ranging from 001-485.  Each kit will be sealed with tamper evident tape.    
11.5.2 Storage of Investigational Product 
The IP must be stored in a secure area accessible only to the investigator and his/her 
designees. Kits will be left unopened until the authorized unmasked technicians open the 
assigned kit for administration to each randomized subject.  Following administration to 
the subject, the technicians will return the product to the kit and seal the kit with tamper 
evident tape.   
Investigational product must be stored at room temperature between 20-25°C (68-77°F). 
All investigational product will be returned to inventory after use. 
Upon receiving the shipment of IP, the investigator or his/her designee will select at 
random the appropriate number of units to be designated as the retain samples. A label 
will be affixed to the designated units to identify these as “retain samples.” These retain 
samples will not be assigned to study subjects for clinical use. All of the retain samples 
will be stored in a secure area accessible only to the investigator and his/her designees. 
The retain samples will be segregated from the investigational product to be assigned to 
study subjects for clinical use, but will be stored in the same area and under the same 
conditions for the duration of the study.   
 
11.5.3 Accountability of Investigational Product 
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 administered 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 returned or disposed upon the completion of the study. A 
detailed inventory must be completed for the IP.  Note only the kit number and number of 
kits will be tallied.  The kits will remain sealed prior to and following Visit 3. There will 
be no counting of individual IP inside the kit.   
 
The investigator must also keep an accurate accounting of the retain samples and must 
properly document the inventory.  
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11.5.4 Return or Disposal of Investigational Product 
All IP used in the clinical trial 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. All of 
the retain samples will be shipped to a third party vendor for long-term storage.   
 Recording of Data on Source Documents and Case Reports Forms 
11.6
(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 (e.g., 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 
11.7
Not Applicable. 
 Publications 
11.8
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript. Ora 
and the sponsor will have the final decision regarding the manuscript and publication. 
 
 
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12 REFERENCES 
1. 
Bielory L. Allergic and immunologic disorders of the eye. Part II: ocular allergy. 
The Journal of allergy and clinical immunology. 2000;106(6):1019-32. 
2. 
Abelson MB, Loeffler O. Conjunctival allergen challenge: models in the 
investigation of ocular allergy. Current allergy and asthma reports. 2003;3(4):363-8. 
3. 
Ciprandi G, Buscaglia S, Pesce GP, Bagnasco M, Canonica GW. Ocular 
challenge and hyperresponsiveness to histamine in patients with allergic conjunctivitis. 
The Journal of allergy and clinical immunology. 1993;91(6):1227-30. 
4. 
Bacon AS, Ahluwalia P, Irani AM, Schwartz LB, Holgate ST, Church MK, et al. 
Tear and conjunctival changes during the allergen-induced early- and late-phase 
responses. The Journal of allergy and clinical immunology. 2000;106(5):948-54. 
5. 
Greiner JV, Mundorf T, Dubiner H, Lonsdale J, Casey R, Parver L, et al. Efficacy 
and safety of ketotifen fumarate 0.025% in the conjunctival antigen challenge model of 
ocular allergic conjunctivitis. American journal of ophthalmology. 2003;136(6):1097-
105. 
6. 
Abelson MB, Chapin MJ, Kapik BM, Shams NB. Efficacy of ketotifen fumarate 
0.025% ophthalmic solution compared with placebo in the conjunctival allergen 
challenge model. Archives of ophthalmology. 2003;121(5):626-30. 
7. 
Leonardi A, Busca F, Tavolato M, Secchi AG. The anti-allergic effects of a 
cromolyn sodium-chlorpheniramine combination compared to ketotifen in the 
conjunctival allergen challenge model. European journal of ophthalmology. 
2003;13(2):128-33. 
8. 
Crampton HJ. Comparison of ketotifen fumarate ophthalmic solution alone, 
desloratadine alone, and their combination for inhibition of the signs and symptoms of 
seasonal allergic rhinoconjunctivitis in the conjunctival allergen challenge model: a 
double-masked, placebo- and active-controlled trial. Clinical therapeutics. 
2003;25(7):1975-87. 
9. 
Crampton HJ. A comparison of the relative clinical efficacy of a single dose of 
ketotifen fumarate 0.025% ophthalmic solution versus placebo in inhibiting the signs and 
symptoms of allergic rhinoconjunctivitis as induced by the conjunctival allergen 
challenge model. Clinical therapeutics. 2002;24(11):1800-8. 
10. 
Greiner JV, Minno G. A placebo-controlled comparison of ketotifen fumarate and 
nedocromil sodium ophthalmic solutions for the prevention of ocular itching with the 
conjunctival allergen challenge model. Clinical therapeutics. 2003;25(7):1988-2005. 
11. 
D'Arienzo PA, Leonardi A, Bensch G. Randomized, double-masked, placebo-
controlled comparison of the efficacy of emedastine difumarate 0.05% ophthalmic 
solution and ketotifen fumarate 0.025% ophthalmic solution in the human conjunctival 
allergen challenge model. Clinical therapeutics. 2002;24(3):409-16. 
12. 
Greiner JV, Michaelson C, McWhirter CL, Shams NB. Single dose of ketotifen 
fumarate .025% vs 2 weeks of cromolyn sodium 4% for allergic conjunctivitis. Advances 
in therapy. 2002;19(4):185-93. 
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13. 
Kidd M, McKenzie SH, Steven I, Cooper C, Lanz R, Australian Ketotifen Study 
G. Efficacy and safety of ketotifen eye drops in the treatment of seasonal allergic 
conjunctivitis. The British journal of ophthalmology. 2003;87(10):1206-11. 
14. 
ZADITOR. Ketotifen Fumarate Ophthalmic Solution, 0.035% [package insert]. 
In: Ophthalmics N, editor. East Hanover, NJ: CIBA Vision Sterile Mfg; 2006. 
 
 
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13 
APPENDICES 
APPENDIX 1: SCHEDULE OF VISITS AND MEASUREMENTS 
 
 
 
                                                 
1 Informed consent must be signed before any study-related procedure can be performed. 
2 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 surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy).   
3 Instilled 15(+1) minutes prior to CAC 
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APPENDIX 2: EXAMINATION PROCEDURES, TESTS,  
Visual Acuity Procedures (ETDRS Chart) 
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LogMAR Visual Acuity Calculations 
Slit Lamp Biomicroscopy Procedures 
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APPENDIX 3: PACKAGE INSERT 
Drug Facts 
Active ingredients 
Ketotifen (0.025%) 
(equivalent to ketotifen fumarate 0.035%) 
Purpose 
Antihistamine 
  
Uses 
Temporarily relieves itchy eyes due to pollen, ragweed, grass, animal hair, and dander. 
  
Warnings 
For external use only 
 
Do not use 
 
if solution changes color or becomes cloudy 
 
if you are sensitive to any ingredient in this product 
 
to treat contact lens related irritation 
 
When using this product 
 
do not touch tip of container to any surface to avoid contamination 
 
remove contact lenses before use 
 
wait at least 10 minutes before reinserting contact lenses after use 
 
replace cap after each use 
 
Stop use and ask doctor if you experience any of the following: 
 
eye pain 
 
changes in vision 
 
redness of the eyes 
 
itching worsens or lasts for more than 72 hours 
 
Keep out of reach of children. 
If swallowed, get medical help or contact a Poison Control Center right away. 
  
Directions 
 
Adults and children 3 years of age and older: 
Put 1 drop in the affected eye(s) twice daily, every 8–12 hours, no more than twice per day. 
 
Children under 3 years of age: Consult a doctor. 
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Other information 
 
Only for use in the eye. 
 
Store between 4°–25°C (39°–77°F). 
  
Inactive ingredients 
benzalkonium chloride 0.01%, glycerol, purified water, sodium hydroxide, and/or hydrochloric acid 
 
 
 
 
 
 
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APPENDIX 4: HANDLING OF BIOLOGICAL SPECIMENS 
Not Applicable. 
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APPENDIX 5: PROTOCOL AMENDMENT SUMMARY 
Not Applicable. 
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n 
 
 
 
 
 
  
 
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APPENDIX 8: INVESTIGATOR’S SIGNATURE 
 
Protocol Title: 
A Single-Center Evaluation of the Relative Efficacy of EM-100 
Compared to Zaditor® (Ketotifen Fumarate Ophthalmic Solution 
0.035%) and Vehicle in the Treatment of Ocular Itching 
Associated with Allergic Conjunctivitis as Induced by the 
Conjunctival Allergen Challenge Model (Ora-CAC®) 
Protocol Number: 
17-100-0011 
Final Date: 
15 December 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> 
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EM-100 Topical Ophthalmic Solution  
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Clinical Trial Protocol: 17-100-0011 
Amendment 1.0/28Feb2018 
 
Clinical Trial Protocol: 17-100-0011 
Protocol Title: 
A Single-Center Evaluation of the Relative Efficacy 
of EM-100 Compared to Zaditor® (Ketotifen 
Fumarate Ophthalmic Solution 0.035%) and Vehicle 
in the Treatment of Ocular Itching Associated with 
Allergic Conjunctivitis as Induced by the 
Conjunctival Allergen Challenge Model (Ora-
CAC®)  
 
 
Study Phase: 
3  
Investigational Product Name: EM-100 topical ophthalmic solution 
IND Number: 
Not Applicable 
Indication: 
Allergic Conjunctivitis 
Investigators: 
Single-center 
Sponsor: 
EyeMax, LLC 
74 Chestnut St. 
Weston, MA 02493 
 
Contract Research 
Organization: 
Ora, Inc. 
300 Brickstone Square, Third Floor 
Andover, MA 01810 
 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico, Suite C, #497 
San Clemente, CA 92673 
 
 
Date 
Original Protocol: 
15 December 2017 
Amendment 1: 
28 February 2018 
 
Confidentiality Statement 
This protocol contains confidential, proprietary information of Ora, Inc. and/or EyeMax, 
LLC.  Further dissemination, distribution or copying of this protocol or its contents is 
strictly prohibited. 
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SPONSOR PERSONNEL 
President: 
 
 
ORA PERSONNEL 
Medical Monitor: 
 
 
 
Chief Medical Officer: 
 
 
 
Department Vice President: 
 
 
Project Lead: 
 
 
 
 
 
 
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SYNOPSIS 
Protocol Title: 
A Single-Center Evaluation of the Relative Efficacy of 
EM-100 Compared to Zaditor® (Ketotifen Fumarate 
Ophthalmic Solution 0.035%) and Vehicle in the 
Treatment of Ocular Itching Associated with Allergic 
Conjunctivitis as Induced by the Conjunctival Allergen 
Challenge Model (Ora-CAC®) 
Protocol Number: 
17-100-0011 
Investigational Product: 
EM-100 topical ophthalmic solution 
Study Phase: 
3 
Primary Objective(s): 
To demonstrate the non-inferiority of EM-100 to Zaditor® 
in the treatment of ocular itching associated with allergic 
conjunctivitis. 
Secondary Objective(s): 
 To demonstrate that EM-100 is superior to vehicle in 
the treatment of ocular itching associated with allergic 
conjunctivitis. 
 To demonstrate that Zaditor® is superior to vehicle in 
the treatment of ocular itching associated with allergic 
conjunctivitis. 
 To demonstrate that EM-100 is non-inferior to 
Zaditor® in the treatment of conjunctival redness 
associated with allergic conjunctivitis.    
Overall Study Design: 
Structure: 
Screening Period: At the Screening Visit, subjects will 
sign the informed consent form and an allergic skin test 
will be performed, if required. At Visit 1, each qualifying 
subject will undergo a bilateral conjunctival allergen 
challenge (CAC) titration using an allergen they had a 
positive reaction to on their skin test. Subjects who elicit a 
positive reaction post-CAC will undergo the confirmation 
CAC at Visit 2 using the same allergen they qualified with 
at Visit 1.  
Treatment Period: At Visit 3, qualifying subjects will be 
enrolled and randomized to receive EM-100, Zaditor®, or 
vehicle of EM-100 in the right eye and one of the other 
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two treatments in the left eye. A trained study technician 
will instill one (1) drop of the assigned treatment in the 
right eye and one (1) drop of the assigned treatment in the 
left eye (based on randomization). Subjects will undergo 
CAC approximately 15 minutes post-instillation of the 
investigational product.  
Duration: 
This study consists of four (4) office visits (Screening 
Visit, Visit 1, Visit 2, and Visit 3) over a period of 
approximately three to five (3-5) weeks. 
Controls: 
 Vehicle of EM-100 topical ophthalmic solution 
 Zaditor® (ketotifen fumarate ophthalmic solution 
0.035%, EQ 0.025% Base), ANDA 077200 held by 
Alcon Pharmaceuticals. 
Dosage/ Instillation: 
At Visit 3, qualifying subjects will be enrolled and 
randomized to receive EM-100, Zaditor®, or Vehicle in 
each eye. The treatment arms are listed below: 
 
 
EM-100 in right eye and Zaditor® in left eye 
 
 
Zaditor® in right eye and EM-100 in left eye 
 
 
EM-100 in right eye and Vehicle in left eye
 
 
Vehicle in right eye and EM-100 in left eye 
   
 
Zaditor® in right eye and Vehicle in left eye 
 
 
Vehicle in right eye and Zaditor® in left eye 
 
 
A trained study technician will instill one (1) drop of the 
assigned treatment in the right eye and one (1) drop of the 
assigned treatment in the left eye approximately 15(+1) 
minutes prior to CAC.  
 
The pre-specified technicians responsible for instilling the 
investigational product will not be involved with any other 
study procedures at the site.  
Summary of Visit Schedule: 
Screening Visit  (Day -50 to -22): Screening/ Informed 
Consent/ Skin Test 
 
Visit 1 (Day -21 ± 3): Titration CAC  
 
Visit 2 (Day -14 ± 3): Confirmation CAC 
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Visit 3 (Day 1):  Enrollment/ Randomization/ In-Office 
Instillation/ Efficacy CAC/ Study Exit 
Measures Taken to Reduce 
Bias: 
Randomization will be used to avoid bias in the 
assignment of subjects to investigational product, to 
increase the likelihood that known and unknown subject 
attributes (e.g. demographics and baseline characteristics) 
are evenly balanced across treatment groups, and to 
enhance the validity of statistical comparisons across 
treatment groups. Finally, masked treatment will be used 
to reduce potential of bias during data collection and 
evaluation of clinical endpoints.   
Study Population Characteristics:  
Number of Subjects: 
Approximately 120 subjects will be screened in order to 
enroll approximately 60 subjects at a single-center.  
Condition/Disease: 
Allergic Conjunctivitis 
Inclusion Criteria: 
Each subject must: 
1) be at least 18 years of age at the Screening Visit, 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 allergic conjunctivitis for at 
least 3 months and a positive skin test reaction to a 
seasonal (grass, ragweed, and/or tree pollen) or 
perennial allergen (cat dander, dog dander, dust mites, 
cockroach) as confirmed by an allergic skin test 
conducted at the Screening Visit or within the past 24 
months; 
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 Visit 1 and during 
the study trial period; 
7) (for females capable of becoming pregnant) agree to 
have urine pregnancy testing performed at Visit 1 
(must be negative) and exit visit; must not be 
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lactating; and must agree to use a medically 
acceptable form of birth control1 throughout the 
study duration. 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 
 or 
better in each eye as measured using an ETDRS 
chart;   
9) have a positive bilateral post-CAC reaction 
 
 
within 10 (±2) minutes of instillation of the 
last titration of allergen at Visit 1; 
10) have a positive bilateral post-CAC reaction
 
  
   
 for at least two out of the first 
three time points2 following the challenge at Visit 2. 
 
Exclusion Criteria: 
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, pterygium or a diagnosis of dry 
eye);  
3) have had ocular surgical intervention within three (3) 
months prior to Visit 1 or during the study and/or a 
history of refractive surgery within the past six (6) 
months; 
4) have a known history of retinal detachment, diabetic 
retinopathy, or active retinal disease; 
                                                 
1Acceptable 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. 
2 not necessarily at the same time point 
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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); 
*Baby aspirin (81 mg) is allowed as long as a stable 
dose has been maintained for at least 30 days prior 
to Visit 1 and will continue to be maintained for the 
duration of the study. 
14 Days 
 inhaled, ocular, topical, or systemic 
corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
2 Months 
 immunosuppressive or cancer chemotherapeutic 
agents; 
Note: 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 by trained study personnel at 
the end of Visits 1, 2, and 3, 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 
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could be expected to interfere with the subject’s 
health or with 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) have a score of
 
 prior to challenge (at Visits 1, 2, 
or 3) in either eye; 
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; 
11) be a female who is currently pregnant, planning a 
pregnancy, or lactating. 
Study Formulations and 
Formulation Numbers: 
 EM-100 topical ophthalmic solution 
 Vehicle of EM-100 topical ophthalmic solution 
 Zaditor® (ketotifen fumarate ophthalmic solution 
0.035%) 
Evaluation Criteria: 
 
Efficacy Measures and 
Endpoints: 
Primary:   
 Ocular itching evaluated by the subject at 3(±1), 
5(±1), and 7(±1) minutes post-CAC 
 
 at Visit 3. 
 
Secondary: 
The following assessments will occur at 7(±1), 15(±1), and 
20(±1) minutes post-CAC at Visit 3: 
 Conjunctival redness evaluated by the investigator 
  
 Ciliary redness evaluated by the investigator 
 
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 Episcleral redness evaluated by the investigator 
 
  
 Chemosis evaluated by the investigator 
 
  
 Eyelid swelling evaluated by the subject
 
 
 Tearing/watery eyes evaluated by the subject 
 
 
 Ocular mucous discharge evaluated by the subject 
CAC (absent/present)  
 Rhinorrhea, nasal pruritus, ear or palate pruritus, 
and nasal congestion evaluated by the subject
 
  
Safety Measures: 
 Adverse Events (reported, elicited, and observed)  
 Best Corrected Visual Acuity (BCVA) at Distance  
 Slit Lamp Biomicroscopy  
General Statistical Methods and Types of Analyses 
The following analysis populations will be defined: 
Intent-to-Treat (ITT) – 
 
  
Per Protocol Set –
 
 
 
Safety Analysis Set – 
 
 
. 
Sample Size: 
 
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 
 with EM-100 in right eye and Zaditor® in left eye 
 
 with Zaditor® in right eye and EM-100 in left eye 
 
 with EM-100 in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and EM-100 in left eye 
 
 with Zaditor® in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and Zaditor® in left eye  
 
This sample size requires a total of 60 randomized subjects,
 
 
  
This sample size will provide
 
 
 
 
 
   
 
 
 
 
   
   
The test of non-inferiority between EM-100 and Zaditor® must meet statistical significance 
as the primary analysis.  
 
 
   
 
 
 
 
 
 
 
 
 
Primary Efficacy Analyses: 
The primary efficacy endpoint is ocular itching assessed at 3(±1), 5(±1), and 7(±1) minutes 
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post-CAC 
 
 
 
 
 
 
 
   
 
Secondary Efficacy Analyses: 
Analyses will be performed on the secondary endpoint of conjunctival redness in a manner 
similar to the non-inferiority tests of the primary endpoint.
 
 
 
Safety Analyses: 
Safety will be assessed by evaluating the incidence of subjects with any adverse events 
during the entire study.  The percentage of subjects with any AEs will be summarized, as 
well as the percentage of subjects with any treatment-emergent adverse events (TEAEs), 
summarized for each treatment combination.  Ocular TEAEs will similarly be summarized by 
eye for each treatment group.  Incidence will be tabulated by MedDRA System Organ Class 
and preferred term within each system organ class.  Adverse events will also be summarized 
for treatment-related TEAEs, SAEs, by maximal severity, and by day of onset relative to the 
start of treatment. 
The additional safety variables of slit lamp biomicroscopy and visual acuity will be 
summarized descriptively using quantitative and qualitative summary statistics as 
appropriate.  In all cases, outcomes will be summarized by eye for each treatment group. 
Changes and shifts from baseline will also be summarized where applicable. 
Summary of Known and Potential Risks and Benefits to Human Subjects 
Known and potential risks of ketotifen fumarate ophthalmic solution (0.035%) include ocular 
burning/stinging/irritation, headache, rhinorrhea, and photophobia. Benefits include relief and 
prevention of ocular itching associated with allergic conjunctivitis. 
Refer to the Zaditor® Package Insert regarding risks and benefits to human subjects. 
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TABLE OF CONTENTS 
SYNOPSIS..................................................................................................................3 
TABLE OF CONTENTS..........................................................................................12 
LIST OF ABBREVIATIONS ............................................................................................15 
1 
INTRODUCTION ....................................................................................................16 
2 
STUDY OBJECTIVES .............................................................................................17 
3 
CLINICAL HYPOTHESES .....................................................................................17 
4 
OVERALL STUDY DESIGN ..................................................................................17 
5 
STUDY POPULATION ...........................................................................................18 
 
Number of Subjects (approximate) ................................................................18 
5.1
 
Study Population Characteristics ....................................................................18 
5.2
 
Inclusion Criteria ............................................................................................18 
5.3
 
Exclusion Criteria ...........................................................................................19 
5.4
 
Withdrawal Criteria (if applicable) ................................................................21 
5.5
6 
STUDY PARAMETERS ..........................................................................................21 
 
Efficacy Measures and Endpoints ..................................................................21 
6.1
6.1.1 
Primary Efficacy Endpoint(s) ...........................................................21 
6.1.2 
Secondary Efficacy Endpoints(s) ......................................................21 
6.1.3 
Criteria for Effectiveness ..................................................................22 
 
Safety Measures .............................................................................................22 
6.2
7 
STUDY MATERIALS .............................................................................................23 
 
Study Treatment(s) .........................................................................................23 
7.1
7.1.1 
Study Treatment(s)/ Formulation(s) .................................................23 
7.1.2 
Instructions for Use and Administration ...........................................23 
 
Other Study Supplies ......................................................................................24 
7.2
8 
STUDY METHODS AND PROCEDURES ............................................................24 
 
Subject Entry Procedures ...............................................................................24 
8.1
8.1.1 
Overview ...........................................................................................24 
8.1.2 
Informed Consent..............................................................................24 
8.1.3 
Washout Intervals .............................................................................25 
8.1.4 
Procedures for Final Study Entry ......................................................25 
8.1.5 
Methods for Assignment to Treatment Groups: ...............................26 
 
Concurrent Therapies .....................................................................................26 
8.2
8.2.1 
Prohibited Medications/Treatments ..................................................26 
8.2.2 
Escape Medications ..........................................................................27 
8.2.3 
Special Diet or Activities ..................................................................27 
 
Examination Procedures .................................................................................27 
8.3
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ............................................................................27 
8.3.1.1 
SCREENING VISIT (Day -50 to -22): Screening/ Informed Consent/ 
Skin Test 
27 
8.3.1.2 
VISIT 1 (Day -21 ± 3): Titration CAC ........................................... 28 
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8.3.1.3 
VISIT 2 (Day -14 ± 3): Confirmation CAC ...................................... 29 
8.3.1.4 
VISIT 3 (Day 1): Enrollment/Randomization/ In-Office Instillation/ 
Efficacy CAC/ Study Exit ...................................................................................... 30 
 
Schedule of Visits, Measurements and Dosing ..............................................32 
8.4
8.4.1 
Scheduled Visits................................................................................32 
8.4.2 
Unscheduled Visits ...........................................................................32 
 
Compliance with Protocol ..............................................................................33 
8.5
 
Subject Disposition .........................................................................................33 
8.6
8.6.1 
Completed Subjects ..........................................................................33 
8.6.2 
Discontinued Subjects .......................................................................33 
 
Study Termination ..........................................................................................34 
8.7
 
Study Duration ...............................................................................................34 
8.8
 
Monitoring and Quality Assurance ................................................................34 
8.9
9 
ADVERSE EVENTS ................................................................................................34 
 
Adverse Event ................................................................................................34 
9.1
9.1.1 
Severity .............................................................................................35 
9.1.2 
Relationship to Investigational Product ............................................35 
9.1.3 
Expectedness .....................................................................................36 
 
Serious Adverse Events ..................................................................................37 
9.2
 
Procedures for Reporting Adverse Events .....................................................37 
9.3
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................38 
9.3.2 
Reporting a Serious Adverse Event ..................................................38 
 
Procedures for Unmasking (if applicable) ......................................................38 
9.4
 
Type and Duration of the Follow-up of Subjects after Adverse Events ........38 
9.5
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .....................39 
 Study Populations ...........................................................................................39 
10.1
10.1.1 Intent-to-Treat Population .................................................................39 
10.1.2 Per-Protocol Population ....................................................................39 
10.1.3 Safety Population ..............................................................................40 
 General Imputation Methods ..........................................................................40 
10.2
 Statistical Hypotheses .....................................................................................40 
10.3
 Sample Size ....................................................................................................41 
10.4
 Primary Efficacy Analyses .............................................................................42 
10.5
 Secondary Efficacy Analyses .........................................................................43 
10.6
 Adjustment for Multiplicity............................................................................43 
10.7
 Demographic and Baseline Medical History ..................................................44 
10.8
 Safety Analysis ...............................................................................................44 
10.9
 Interim Analysis .............................................................................................44 
10.10
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ....................................45 
 Protection of Human Subjects ........................................................................45 
11.1
11.1.1 Subject Informed Consent.................................................................45 
11.1.2 Institutional Review Board (IRB) Approval .....................................45 
 Ethical Conduct of the Study ..........................................................................45 
11.2
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 Subject Confidentiality ...................................................................................45 
11.3
 Documentation ...............................................................................................46 
11.4
11.4.1 Retention of Documentation .............................................................46 
 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
11.5
Investigational Product ...................................................................................46 
11.5.1 Labeling/Packaging...........................................................................46 
11.5.2 Storage of Investigational Product ....................................................47 
11.5.3 Accountability of Investigational Product ........................................47 
11.5.4 Return or Disposal of Investigational Product ..................................47 
 Recording of Data on Source Documents and Case Reports Forms (CRFs) .47 
11.6
 Handling of Biological Specimens .................................................................48 
11.7
 Publications ....................................................................................................48 
11.8
12 
REFERENCES .........................................................................................................49 
13 
APPENDICES ..........................................................................................................51 
Appendix 1: Schedule of Visits and Measurements ..........................................................51 
Appendix 2: Examination Procedures, Tests, ....................................................................52 
Appendix 3: Package Insert ...............................................................................................59 
Drug Facts.....................................................................................................59 
Active ingredients ............................................................................................... 59 
Purpose ................................................................................................................ 59 
Uses ..................................................................................................................... 59 
Warnings .............................................................................................................. 59 
Directions ............................................................................................................. 59 
Other information ................................................................................................ 60 
Inactive ingredients ............................................................................................ 60 
Appendix 4: Handling of Biological Specimens ...............................................................61 
Appendix 5: Protocol Amendment Summary ....................................................................62 
Appendix 6: Ora Approvals ...............................................................................................64 
Appendix 7: SPONSOR Approvals ...................................................................................65 
Appendix 8: Investigator’s Signature ................................................................................66 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
BCVA 
best-corrected visual acuity 
CAC 
conjunctival allergen challenge 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRF 
case report form 
DHHS 
Department of Health and Human Services 
eCRF 
electronic case report form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent to treat 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
ND  
not done  
NSAID  
nonsteroidal anti-inflammatory drug 
OD 
right eye 
OS 
left eye 
OU 
both eyes 
OTC 
over the counter 
PE 
polyethylene 
PP 
per protocol 
SAE 
serious adverse event 
SD 
standard deviation 
SDC 
Statistics and Data Corporation 
SOP 
standard operating procedure 
VA 
visual acuity 
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1 INTRODUCTION 
Allergies affect approximately 15% of the global population and up to 30% of the U.S. 
population (1). 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 (2). Histamine is the primary 
mediator responsible for the 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 (3, 4). 
Ketotifen is a widely effective therapy for the management of ocular allergies. It has 
demonstrated rapid onset (≤ 15 minutes) and long duration of action (≥ 8 hours) after 
conjunctival allergen challenge (CAC)(5, 6). Ketotifen fumarate ophthalmic solution 
0.035% was found to be safe, well tolerated, and effective for the prevention of the signs 
and symptoms associated with allergic conjunctivitis in multiple CAC studies(7-12). In an 
environmental setting, ketotifen fumarate ophthalmic solution 0.035% was found to 
safely and effectively reduce seasonal allergic conjunctivitis signs and symptoms and 
prevent recurrence(13). 
Ketotifen fumarate ophthalmic solution 0.035% (Zaditor®/Zaditen®; Novartis 
Ophthalmics) is approved in the United States and Canada for the temporary prevention 
of ocular itching due to allergic conjunctivitis at a dose of one drop in the affected eye 
twice daily (every 8-12 hours)(14). In 2006, ketotifen fumarate ophthalmic drops 0.035% 
(ketotifen 0.025%; Alaway®; Bausch and Lomb, Inc., and Zaditor®; Novartis 
Ophthalmics) were approved by the United States Food and Drug Administration (FDA) 
for over-the-counter use, with the indication of temporary relief of itchy eyes due to 
pollen, ragweed, grass, animal hair, and dander, at an approved dose of one drop in the 
affected eye twice daily (every 8-12 hours)(15). 
EM-100 contains ketotifen ophthalmic solution (0.025%) as a non-preserved formulation 
in single-dose vials. This is a single-center, randomized, double-masked study to 
establish the therapeutic equivalence of EM-100 to Zaditor® (ketotifen fumarate 
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ophthalmic drops 0.035%).  EM-100 will need to show non-inferiority to Zaditor® in the 
treatment of ocular itching following CAC (15 minutes following study medication 
instillation).  The vehicle is included for assay validation.   
2 STUDY OBJECTIVES 
Primary: 
 To demonstrate the non-inferiority of EM-100 to Zaditor® in the treatment of 
ocular itching associated with allergic conjunctivitis.  
Secondary: 
 To demonstrate that EM-100 is superior to vehicle in the treatment of ocular 
itching associated with allergic conjunctivitis. 
 To demonstrate that Zaditor® is superior to vehicle in the treatment of ocular 
itching associated with allergic conjunctivitis 
 To demonstrate that EM-100 is non-inferior to Zaditor® in the treatment of 
conjunctival redness associated with allergic conjunctivitis.  
3 CLINICAL HYPOTHESES 
The clinical hypotheses are:  
 EM-100 is more effective than vehicle in the treatment of ocular itching 
associated with allergic conjunctivitis induced by CAC 15 minutes following 
product instillation.  
 EM-100 is non-inferior to Zaditor® in the treatment of ocular itching associated 
with allergic conjunctivitis induced by CAC at 15 minutes following product 
instillation. 
 Zaditor® is more effective than vehicle in the treatment of ocular itching 
associated with allergic conjunctivitis induced by CAC at 15 minutes following 
product instillation. 
4 OVERALL STUDY DESIGN 
This is a single-center, randomized, double-masked, contralateral eye study comparing 
topical EM-100 with Zaditor® and the vehicle of EM-100 in subjects with allergic 
conjunctivitis. At the Screening Visit, subjects will sign the informed consent form and 
an allergic skin test will be performed, if required. At Visit 1, each qualifying subject will 
undergo a bilateral conjunctival allergen challenge (CAC) titration using an allergen they 
had a positive reaction to on their skin test. Subjects who elicit a positive reaction post-
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CAC will undergo the confirmation CAC at Visit 2 using the same allergen they qualified 
with at Visit 1.  
At Visit 3, qualifying subjects will be enrolled and randomized to receive EM-100, 
Zaditor®, or Vehicle in each eye. The treatment arms are listed below: 
 
 EM-100 in right eye and Zaditor® in left eye
 
 Zaditor® in right eye and EM-100 in left eye 
EM-100 in right eye and 
Vehicle in left eye 
 
 Vehicle in right eye and EM-100 in left eye
) 
 Zaditor® in right eye and Vehicle in left eye 
 
 Vehicle in right eye and Zaditor® in left eye 
 
 
 A trained study technician will instill one (1) drop of the assigned treatment in the right 
eye and one (1) drop of the assigned treatment in the left eye (based on randomization). 
Subjects will undergo CAC approximately 15 minutes post-instillation of the 
investigational product. The pre-specified technicians responsible for instilling the 
investigational product will not be involved with any other study procedures at the site. 
5 STUDY POPULATION 
 Number of Subjects (approximate) 
5.1
Approximately 120 subjects will be screened in order to enroll approximately 60 subjects 
at a single-center.  
 Study Population Characteristics 
5.2
 Inclusion Criteria 
5.3
Each subject must: 
 
1) be at least 18 years of age at the Screening Visit, 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 allergic conjunctivitis for at least 3 months and a positive 
skin test reaction to a seasonal (grass, ragweed, and/or tree pollen) or perennial 
allergen (cat dander, dog dander, dust mites, cockroach) as confirmed by an allergic 
skin test conducted at the Screening Visit or within the past 24 months; 
5) be able and willing to avoid all disallowed medication for the appropriate washout 
period and during the study (see exclusion 6); 
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6) be able and willing to discontinue wearing contact lenses for at least 72 hours prior 
to Visit 1 and during the study trial period; 
7) (for females capable of becoming pregnant) agree to have urine pregnancy testing 
performed at Visit 1 (must be negative) and exit visit; must not be lactating; and 
must agree to use a medically acceptable form of birth control1 throughout the 
study duration. 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
 or better in each eye as measured 
using an ETDRS chart;   
9) have a positive bilateral post-CAC reaction 
 
 within 10 (±2) minutes of instillation of the last 
titration of allergen at Visit 1; 
10) have a positive bilateral post-CAC reaction 
  
 
  
 for at least two out of the first three time points2 
following the challenge at Visit 2. 
 
 Exclusion Criteria 
5.4
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, 
pterygium or a diagnosis of dry eye);  
3) have had ocular surgical intervention within three (3) months prior to Visit 1 or 
during the study and/or a history of refractive surgery within the past six (6) 
months; 
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; 
                                                 
1Acceptable 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. 
2 not necessarily at the same time point 
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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); 
*Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained 
for at least 30 days prior to Visit 1 and will continue to be maintained for the 
duration of the study. 
14 Days 
 inhaled, ocular, topical, or systemic corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
2 Months 
 immunosuppressive or cancer chemotherapeutic agents; 
Note: 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 by trained study personnel at the end of Visits 1, 2, and 3, 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 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) have a score of 
 prior to challenge 
(at Visits 1, 2, or 3) in either eye;  
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; 
11) be a female who is currently pregnant, planning a pregnancy, or lactating. 
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 Withdrawal Criteria (if applicable) 
5.5
If at any time during the study the Investigator determines that a subject’s safety has been 
compromised, the subject may be withdrawn from the study. 
Subjects may withdraw consent from the study at any time. 
Any female will be removed from the study should she become pregnant during the 
course of the study, and she will undergo a pregnancy test at her exit visit for 
confirmation. The pregnancy test must be confirmed by two (2) additional tests and 
confirmed by the principal investigator (or sub-investigator if the principal investigator is 
not present). If the test result is positive a second and third time, the principal investigator 
(or sub-investigator if the principal investigator is not present) will inform the subject. 
The Investigator will follow-up and document the outcome of the pregnancy and provide 
a copy of the documentation to the sponsor. The Ora Pregnancy Report Form will be used 
to report a pregnancy and follow-up. 
Reason for withdrawal will be included in the eCRF, and all efforts should be made to 
schedule the subject for an Exit Visit to complete exit procedures.  Any subject who is 
withdrawn for the study because of an AE will be followed until AE is resolved or as 
clinically required, and the investigator will prepare a written summary of the event and 
document the available follow-up information on the eCRF.   
Sponsor and/or Investigator may discontinue any subject for non-compliance or any valid 
medical reason (see Section 8.5). 
6 STUDY PARAMETERS 
 Efficacy Measures and Endpoints 
6.1
6.1.1 Primary Efficacy Endpoint(s) 
 Ocular itching evaluated by the subject at 3(±1), 5(±1), and 7(±1) minutes post-
CAC 
 
 
6.1.2 Secondary Efficacy Endpoints(s) 
The following assessments will occur at 7(±1), 15(±1), and 20(±1) minutes post-CAC at 
 
 Conjunctival redness evaluated by the investigator
 
  
 Ciliary redness evaluated by the investigator 
 
  
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 Episcleral redness evaluated by the investigator 
 
  
 Chemosis evaluated by the investigator 
 
  
 Eyelid swelling evaluated by the subject 
 
 
 Tearing/watery eyes evaluated by the subject 
 
 
 Ocular mucous discharge evaluated by the subject CAC (absent/present) 
 Rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal congestion evaluated 
by the subject
 
 
6.1.3 Criteria for Effectiveness 
This therapeutic equivalence study is designed to evaluate the relative efficacy of EM-
100 topical ophthalmic solution compared to vehicle and Zaditor® in the treatment of 
ocular itching at each designated time point post-CAC at Visit 3 (Day 1, 15-minute 
onset).  
Although this study is being referred to as a “bioequivalence” or “therapeutic 
equivalence” study, it is in fact a non-inferiority study and all statistical testing will 
determine whether EM-100 is non-inferior to the reference drug, Zaditor®. Vehicle is 
included in this study in order to validate the assay.  
To demonstrate non-inferiority for ocular itching compared to Zaditor®, EM-100 topical 
ophthalmic solution needs to show itching scores no worse than 
 
 
 
 
 
 
 
 Safety Measures 
6.2
 Adverse Events (reported, elicited, and observed)  
 Best Corrected Visual Acuity (BCVA) at Distance  
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 Slit Lamp Biomicroscopy  
7 STUDY MATERIALS 
 Study Treatment(s) 
7.1
7.1.1 Study Treatment(s)/ Formulation(s) 
 EM-100 topical ophthalmic solution  
 Vehicle of EM-100 topical ophthalmic solution 
 Zaditor® (ketotifen fumarate ophthalmic solution 0.035%)  
 
7.1.2 Instructions for Use and Administration 
 This trial requires additional attention in order to preserve masking of study 
treatment. There will be a total of 485 identical appearing kits containing all three 
treatments labeled A, B, and C.  Once the kits arrive at the site, a designated staff 
member will randomly select 65 kits to be used for the trial.  The remaining 420 
kits will be identified and stored as retains.  Both EM-100 and the vehicle of EM-
100 will be identical in appearance as single use vials, while the reference product, 
Zaditor®, will be in its original bottle. All individual kits will be sealed with 
tamper evident tape and the sites will be instructed to not open the kits upon 
receipt of shipment.  At no point during the trial (until database lock) will site staff 
or monitors be allowed to open the kits unless it is the designated “unmasked” 
technicians. These technicians will ensure that opening of the kits is done in a 
manner to prevent the other staff and subjects from seeing the investigational 
product. For each subject treatment will be administered by eye according to a 
randomization list which will be sent to the site in a sealed envelope and opened at 
Visit 3 by the unmasked technicians.  Following Visit 3 dosing, the technicians 
will reseal the kits and randomization list envelope using tamper evident tape and 
return the kits to storage. The sealed randomization list envelope will be filed in 
the investigator’s study file.      
 
 At Visit 3, qualifying subjects will be enrolled and randomized to receive EM-
100, Zaditor®, or vehicle of EM-100. A randomization list will inform the 
technicians which corresponding letter treatment should be instilled in the right 
eye and which one should be instilled in the left eye.  
 
 A trained study technician will instill one (1) drop of the assigned treatment in the 
right eye and one (1) drop of the assigned treatment in the left eye approximately 
15(+1) minutes prior to CAC.  
 
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 The 
pre-specified 
unmasked 
technicians 
responsible 
for 
instilling 
the 
investigational product will not be involved with any other study procedures at the 
site.  Care will be taken to hide the container (vial or bottle) from the subject.   
Dosing will occur in a room where no other subjects, staff, or investigators will 
observe the instillation.   
 
 Investigational product must be stored in a secure area of the clinical site, 
accessible only to the Investigator(s) or designees at room temperature between 
20-25°C (68-77°F).  All investigational product will be returned to inventory after 
use.  
 
 In accordance with 21CFR §320.38 and §320.63, samples of both the test article 
(EM-100) and reference listed drug (Zaditor®) will be retained and stored under 
conditions consistent with product labeling and in an area segregated from the 
area where testing is conducted and with access limited to authorized personnel. 
 
 
 Other Study Supplies 
7.2
The following supplies will be supplied and/or reconstituted by Ora, Inc.: 
 
Pregnancy tests (Clarity HCG, RAC Medical Boca Raton, FL).  
 
The allergens used for skin testing and the conjunctival allergen challenge (cat 
dander, dog dander, dust mite, cockroach, meadow fescue, rye grass, Bermuda 
grass, Kentucky bluegrass, Timothy grass, ragweed, white birch, oak, and maple).   
 
Relief drops (OTC antihistamine/vasoconstrictor combination products). 
8 STUDY METHODS AND PROCEDURES 
 Subject Entry Procedures 
8.1
8.1.1 Overview 
Subjects as defined by the criteria in sections 5.2, 5.3, and 5.4 will be considered for 
entry into this study. 
8.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., changes in a subject’s medical treatment 
and/or study related procedures), the study will be discussed with each subject, and 
subjects wishing to participate must give written informed consent using an informed 
consent form (ICF).  The ICF must be the most recent version that has received 
approval/favorable review by a properly constituted Institutional Review Board. Failure 
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to obtain a signed ICF renders the subject ineligible for the study. Subjects must be 
willing to return to the clinic for study Visits 1, 2, and 3. 
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. Subjects can be re-screened a maximum of two times. 
8.1.3 Washout Intervals 
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 stabilizers, 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, topical, or systemic corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
 2 Months 
 immunosuppressive or cancer chemotherapeutic agents. 
Note: Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained for 
at least 30 days prior to Visit 1 and will continue to be maintained for the duration of the 
study. 
8.1.4 Procedures for Final Study Entry 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria prior to 
Visit 3 to be enrolled in this study.  
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8.1.5 Methods for Assignment to Treatment Groups: 
All subjects screened for the study who sign an ICF will be assigned a screening number 
that will be entered in the Screening and Enrollment Log. The screening number will 
consist of three (3) digits, starting with 001. Randomization will be used to avoid bias in 
the assignment of subjects to treatment, to increase the likelihood that known and 
unknown subject attributes (e.g., demographics and baseline characteristics) are evenly 
balanced across treatment groups, and to enhance the validity of statistical comparisons.   
Once a subject meets qualification criteria at Visit 3 (Day 1), he/she will be enrolled and 
randomized to receive EM-100, Zaditor®, or the vehicle of EM-100. A separate 
treatment will be assigned to each eye. Subjects will be assigned the lowest four (4) digit 
randomization number available.  
 Concurrent Therapies 
8.2
The use of any concurrent medication, prescription or over-the-counter, is to be recorded 
on the subject’s source document and corresponding electronic case report form (eCRF) 
along with the reason the medication was taken. 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
8.2.1 Prohibited Medications/Treatments 
 contact lenses 
 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) 
 inhaled, ocular, topical, or systemic corticosteroids or mast cell stabilizers 
 depot-corticosteroids 
 immunosuppressive or cancer chemotherapeutic agents 
Note: Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained for 
at least 30 days prior to Visit 1 and will continue to be maintained for the duration of the 
study. 
 
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8.2.2 Escape Medications 
Subjects may receive either anti-itch cream or Calamine lotion (depending on the 
washout) after the skin test has been completed at the Screening Visit.  
 
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 by trained personnel at the end of Visits 1, 2, and 3 after all evaluations are 
completed. 
 
8.2.3 Special Diet or Activities 
Not Applicable. 
 Examination Procedures 
8.3
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) 
8.3.1.1 SCREENING VISIT (Day -50 to -22): Screening/ Informed Consent/ Skin 
Test 
 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.  
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. Subjects can be re-screened a maximum of two 
times.  
 Allergic Skin Test (if applicable): A diagnostic test for allergic disease (skin test) will 
be performed according to Ora SOPs if there is no documented skin test within the 
past 24 months. Subjects may receive either anti-itch cream or Calamine lotion 
(depending on the washout) after the skin test has been completed. 
 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 
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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 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 8.1.3) 
 Adverse Event Query 
 Schedule Visit 1: Qualifying subjects will be scheduled for Visit 1. 
8.3.1.2 VISIT 1 (Day -21 ± 3): Titration CAC 
 Update of Medical/Medication History 
 Adverse Event Query 
 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.  
 Initial Visual Acuity Utilizing an ETDRS Chart:  Subjects must have a score of 
 
or better in each eye in order to qualify.  
 Initial Ocular Itching and Conjunctival Redness Assessments: The investigator and 
the subject will assess initial ocular itching and conjunctival redness using the Ora-
CAC® scales (see Appendix 2). Subjects exhibiting a sign and/or symptom of allergic 
conjunctivitis
 
 will be excluded. 
 Initial Slit Lamp Biomicroscopy: A slit lamp examination will be performed in both 
eyes to exclude subjects with disallowed ocular conditions (see Appendix 2). 
Findings of abnormality which are not exclusionary should be recorded as Medical 
History.  
 Review of Inclusion/Exclusion Criteria: A review of protocol inclusion and exclusion 
criteria will be confirmed for each subject. 
 Titration Conjunctival Allergen Challenge (CAC): A conjunctival allergen challenge 
(CAC) will be performed bilaterally with a perennial or seasonal allergen serially 
diluted in buffered saline and administered via a micropipette according to Ora SOPs. 
One drop of a solubilized allergen to which the subject is sensitized, at the weakest 
dilution, will be instilled bilaterally into the conjunctival cul-de-sac.  
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If the subject fails to react within 10 (±2) minutes, increasingly concentrated doses 
may be instilled bilaterally at approximately ten-minute intervals until a positive 
reaction is elicited. If increasing doses are required (i.e., for insufficient bilateral 
itching and/or redness as evaluated by a trained technician or the Investigator), doses 
may be skipped. If a positive CAC reaction is not elicited with the first allergen 
 
 other allergens to which the subject is 
sensitized may be used starting at the lowest dose.  
 Post-CAC Ocular Itching and Conjunctival Redness Assessments: Upon completion 
of the initial titration CAC, subjects will receive an ocular examination by the 
Investigator to evaluate conjunctival redness and confirm the subject’s qualification. 
Subjects will be asked to assess their ocular itching. 
A positive CAC at Visit 1 is defined as a score of 
 
for itching in each eye within 10 (±2) minutes of 
receiving that dose of allergen. Any subject who fails to test positively will be 
excluded from the study. 
 Note: The type and concentration of allergen used to elicit a positive reaction will be 
recorded for each qualifying subject.  At all subsequent visits, subjects will receive 
the same type of allergen (same lot number) and same concentration identified at this 
visit.  
 Review of Inclusion/Exclusion Criteria 
 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®) by trained study personnel as they leave the office to 
relieve any immediate discomfort caused by the allergic reaction.  
 Adverse Event Query 
 Schedule Visit 2: Qualifying subjects will be scheduled to return to the office in one 
(1) week for Visit 2. 
8.3.1.3 VISIT 2 (Day -14 ± 3): Confirmation CAC  
 Update of Medical/Medication History 
 Adverse Event Query 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease from Visit 1 may be documented as an AE per the investigator’s discretion. 
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An increase of 
 or more should be brought to the attention of the investigator. 
Visual Acuity may be repeated in instances of significant decreases. 
 Pre-CAC Ocular Itching and Conjunctival Redness Assessments: The investigator 
and the subject will assess pre-CAC ocular itching and conjunctival redness using the 
Ora-CAC® scales. Subjects exhibiting a sign and/or symptom of allergic 
conjunctivitis 
 
ill be excluded. 
 Slit Lamp Biomicroscopy 
 Review of Inclusion/Exclusion Criteria  
 Confirmation CAC: For each qualified subject, one drop of the allergen solution, of 
the same, final dose that elicited a positive reaction at Visit 1, will be administered 
bilaterally. 
 Post-CAC Ocular Itching and Conjunctival Redness Assessments: Assessments of 
itching will be made by the subject at 3(±1), 5(±1), and 7 (±1) minutes following 
allergen challenge. Assessments of conjunctival redness will be graded by the 
Investigator at 7(±1), 15(±1), and 20(±1) minutes post-challenge (Appendix 
 
 
 
 Review of Inclusion/Exclusion Criteria 
 
 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. 
  
 Adverse Event Query  
 
 Schedule Visit 3: Subjects will be asked to return to the office two (2) weeks later for 
Visit 3.  
8.3.1.4 VISIT 3 (Day 1): Enrollment/Randomization/ In-Office Instillation/ Efficacy 
CAC/ Study Exit 
 Update of Medical/Medication History 
                                                 
1 not necessarily at the same time point 
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 Adverse Event Query   
 Urine Pregnancy Test (for females of childbearing potential) 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease from Visit 1 may be documented as an AE per the investigator’s discretion. 
An increase of
 or more should be brought to the attention of the investigator. 
Visual Acuity may be repeated in instances of significant decreases. 
 Pre-CAC Ocular Itching and Conjunctival Redness Assessments: The investigator 
and the subject will assess pre-CAC ocular itching and conjunctival redness using the 
Ora-CAC® scales. Subjects exhibiting a sign and/or symptom of allergic 
conjunctivitis 
 
 will be excluded.      
 Slit Lamp Biomicroscopy 
 Review of Inclusion/Exclusion Criteria  
 Randomization: Subjects who meet all of the inclusion criteria and none of the 
exclusion criteria and qualify to continue in the study will be enrolled and 
randomized to receive EM-100, Zaditor®, or the vehicle of EM-100. A separate 
treatment will be assigned to each eye.  Subjects will be assigned the lowest four (4) 
digit randomization number available.  
 Investigational Product Instillation: A trained study technician will instill one drop of 
the assigned treatment in the right eye and one drop of the assigned treatment in the 
left eye, according to the directions for use. The investigational product kit number 
and the time of instillation will be recorded. The pre-specified technicians responsible 
for instilling the investigational product will not be involved with any other study 
procedures at the site.  
 Efficacy CAC: Each subject will receive one drop of the allergen solution of the same, 
final dose that elicited a positive reaction at Visit 1 bilaterally, 15(+1) minutes post-
instillation of investigational product.  
 Post-CAC Ocular Itching and Conjunctival Redness Assessments: Assessments of 
itching will be made by the subject at 3(±1), 5(±1), and 7 (±1) minutes following 
allergen challenge. Assessments of redness and chemosis will be graded by the 
Investigator at 7(±1), 15(±1), and 20(±1) minutes post-challenge and assessments of 
eyelid swelling, tearing/watery eyes, ocular mucous discharge, and nasal symptoms 
will be made by the subject at 7(±1), 15(±1), and 20(±1) minutes post-challenge 
(Appendix 2).  
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 Exit Slit Lamp Biomicroscopy  
 Exit Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease from Visit 1 may be documented as an AE per the investigator’s discretion. 
An increase of 
or more should be brought to the attention of the investigator. 
Visual Acuity may be repeated in instances of significant decreases. 
 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. 
 Adverse Event Query 
 Study Exit: Subjects will be exited from the study. 
Adverse Events (AEs) (both elicited and observed) will be monitored throughout the 
study. All AEs (both elicited and observed) will be promptly reviewed by the investigator 
for accuracy and completeness. All AEs will be documented on the appropriate eCRF. 
If a female has a positive pregnancy test during the study, then the investigator will notify 
Ora immediately. The investigator shall request from the subject and/or the subject’s 
physician copies of all related medical reports during the pregnancy and shall document 
the outcome of the pregnancy. The investigator will retain these reports together with the 
subject’s source documents and will provide a copy of all documentation to Ora. 
 Schedule of Visits, Measurements and Dosing 
8.4
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
If a subject is discontinued at a scheduled study visit (i.e. Visit 3), the remaining 
assessments should be captured on the Unscheduled Visit/ Early Exit Visit pages of the 
source document and corresponding eCRF. Subjects who screen fail (Screening  
Visits or Visits 1, 2, or 3) may be scheduled for the Unscheduled Visit at the 
Investigator’s discretion due to follow-up of an ongoing AE.  
8.4.2 Unscheduled Visits 
For unscheduled visits, the reason for the visit should be clearly documented on the 
appropriate eCRF, including findings from all evaluations that are completed.  
These visits may be performed in order to ensure subject safety. All information gathered 
at unscheduled visits should be recorded on the Unscheduled Visit/Early Exit Visit pages 
of the source document and corresponding eCRF. 
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Evaluations that may be conducted at an Unscheduled Visit (as appropriate, depending on 
the reason for the visit), include:  
 
Assessment of Adverse Events 
 
Assessment of Concomitant Medications 
 
Visual Acuity Utilizing an ETDRS chart 
 
Urine Pregnancy Test (for females of childbearing potential) 
 
Slit lamp Biomicroscopy  
If a randomized subject does not attend their scheduled visit, eCRF pages for missed 
visits will be skipped. All efforts should be made to schedule the subject for an Exit Visit 
to complete exit procedures.  
 Compliance with Protocol 
8.5
Subjects who are inappropriately enrolled or no longer fulfill the study eligibility criteria 
may be discontinued from the study. The reason for such discontinuation will be recorded 
as “protocol violation” in the source document and on the appropriate page in the eCRF.  
Site staff will review concomitant medication by asking subjects if they changed their 
dosing regimen since their previous visit. The response will be recorded in the source 
document and on the eCRF at Visits 1, 2, and 3.  
All protocol violations, regardless of causation, will be recorded in the subject’s source 
document as well as eCRF. Major protocol violations will be recorded in the subject’s 
source document, entered in the eCRF, and reported to the IRB, as per the applicable 
regulations.   
 Subject Disposition 
8.6
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
8.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
 
subject request/withdrawal 
 
AEs 
 
protocol violations 
 
administrative reasons (e.g., inability to continue, lost to follow up) 
 
sponsor termination of study 
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 
other 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to Ora and/or sponsor and will be clearly documented on the eCRF. Subjects who are 
discontinued from the study will not be replaced. 
 Study Termination 
8.7
The study may be stopped at any time by the investigator, the sponsor, and/or Ora with 
appropriate notification. 
 Study Duration 
8.8
This study consists of four (4) office visits (Screening Visit, Visit 1, Visit 2, and Visit 3) 
over a period of approximately three to five (3-5) weeks. 
 Monitoring and Quality Assurance 
8.9
During the course of the study, an Ora monitor, or designee, will make routine site visits 
to review protocol compliance, assess IP accountability, and ensure the study is being 
conducted according to the pertinent regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject 
confidentiality. Further details of the study monitoring will be outlined in a monitoring 
plan. 
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. 
9 ADVERSE EVENTS 
 Adverse Event 
9.1
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered IP-related. An AE can be any unfavorable and 
unintended sign (e.g., 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 (e.g., off-label use, use in combination with another drug or 
medical device) and from any route of administration, formulation, or dose, including an 
overdose. An AE can arise from any delivery, implantation, or use of a medical device, 
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including medical device failure, subject characteristics that may impact medical device 
performance (e.g., anatomical limitations), and therapeutic parameters (e.g., energy 
applied, sizing, dose release, and anatomic fit) associated with medical device use. 
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 comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, and 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.  
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). 
9.1.1 Severity 
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. 
 
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. 
9.1.2 Relationship to Investigational Product 
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 
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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 IP 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. 
 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. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the IP caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the IP and the AE. Types of evidence that would suggest a 
causal relationship between the IP and the AE event include: a single occurrence of an 
event that is uncommon and known to be strongly associated with IP exposure (e.g., 
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 (e.g., 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. 
9.1.3 Expectedness 
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 is not 
listed at the specificity or severity that has been observed. 
 Expected:  An AE that is listed in the IB at the specificity and severity that has been 
observed. 
 Not applicable: An AE unrelated to the IP. 
Adverse events that are mentioned in the IB as occurring with a class of products or as 
anticipated from the pharmacological/mechanical (or other) properties of the product, but 
are not specifically mentioned as occurring with the particular product under 
investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 
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 Serious Adverse Events 
9.2
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; 
Note: 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; 
Note: 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; 
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 (e.g., 
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 
9.3
All AEs and their outcomes must be reported to Ora, the 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.  
Collection of AEs/SAEs will begin at the time of informed consent.  
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9.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the sponsor and 
the IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities. 
9.3.2 Reporting a Serious Adverse Event 
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 eCRFs. 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. 
In the event of a SAE, the investigator must notify Ora and the sponsor 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 with a complete case history, which includes a 
statement as to whether the event was or was not suspected to be related to the use of the 
IP; and inform the IRB of the SAE within their guidelines for reporting SAEs. All SAEs, 
regardless of expectedness or relationship to the IP, will be reported to the FDA as soon 
as possible but no later than 15 calendar days after becoming aware of the event. 
Contact information for reporting SAEs: 
                       
                   
                   
 
 
 
 
 
 
 
        
         
 
 Procedures for Unmasking (if applicable) 
9.4
When medically necessary, the investigator may need to determine what treatment has 
been assigned to a subject. When possible (i.e., in non-emergent situations), Ora and/or 
the sponsor should be notified before unmasking IP. 
 Type and Duration of the Follow-up of Subjects after Adverse 
9.5
Events 
AEs will be followed until: 
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 Resolution (return to baseline status or to “normal”) 
 Stabilization of the event has occurred (no improvement or worsening expected 
by the investigator) 
 Event is otherwise explained, regardless of whether the subject is still 
participating in the study 
 Principal investigator determines, for events that do not end (i.e., metastasis), the 
condition to be chronic. The event can be determined to be resolved or resolved 
with sequelae.  
The Investigator will follow unresolved adverse events to resolution until the subject is 
lost to follow-up or until the adverse event is otherwise explained. If the subject is lost to 
follow-up, the Investigator should make three (3) reasonable attempts to contact the 
subject 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 and be followed as 
aforementioned.  
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. 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
 Study Populations 
10.1
10.1.1 Intent-to-Treat Population 
 
  
.  
10.1.2 Per-Protocol Population 
 
 
 
 
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10.1.3 Safety Population 
The safety population includes all subjects who received the test article. The safety 
population will be analyzed as treated and will be used for the safety analyses. No 
data will be excluded for any reason. 
 General Imputation Methods 
10.2
Missing data is not expected in this single, post-randomization visit study.  
 
 
 
 
 
 
 
 Statistical Hypotheses 
10.3
The statistical hypotheses for the non-inferiority test between EM-100 ophthalmic 
solution and Zaditor® are as follows: 
PRIMARY: 
 
 
 
 
 
SECONDARY: 
Conditional upon H01 being rejected, the statistical hypothesis for the superiority test 
between EM-100 ophthalmic solution and vehicle solution will be tested as follows: 
 
 
 
 
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Conditional upon H01 and H02 being rejected, the statistical hypothesis for the 
superiority test between Zaditor® and vehicle solution will be tested as follows: 
 
 
 
 
Conditional upon H01, H02, and H03 being rejected, the statistical hypothesis for the 
non-inferiority test between EM-100 ophthalmic solution and Zaditor® will be tested as 
follows: 
 
 
 
 
 
  
 Sample Size 
10.4
The following treatment combinations will be randomized.  The eye receiving each test 
article will also be randomized: 
 
 with EM-100 in right eye and Zaditor® in left eye 
 
 with Zaditor® in right eye and EM-100 in left eye 
 
 with EM-100 in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and EM-100 in left eye 
 
 with Zaditor® in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and Zaditor® in left eye 
This sample size requires a total of 60 randomized subjects,
 
 
   
This sample size will provide
 
 
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non-inferiority test at alpha=0.025.  The power becomes >97% when considering that 
 
   
 
 
 
 
   
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 Primary Efficacy Analyses  
10.5
The primary efficacy endpoint is ocular itching assessed at 3(±1), 5(±1), and 7(±1) 
minutes post-CAC 
 
 
 
 
 
 
 
 
 
 
  
 
 
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 Secondary Efficacy Analyses 
10.6
Analyses will be performed on the secondary endpoint of conjunctival redness in a 
manner similar to the non-inferiority test of the primary endpoint. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Adjustment for Multiplicity 
10.7
The primary and secondary analyses will be tested 
 
 
 
 
 
 
 
 
 
 
 
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 Demographic and Baseline Medical History  
10.8
The demographic and baseline medical history data will be summarized descriptively 
overall subjects and for each treatment combination. For quantitative variables, the 
summaries will include the number of observations, mean, standard deviation, median, 
minimum, and maximum. Qualitative variables will be summarized using counts and 
percentages.  
 Safety Analysis 
10.9
Safety will be assessed by evaluating the incidence of subjects with any adverse events 
during the entire study.  The percentage of subjects with any AEs will be summarized, 
as well as the percentage of subjects with any treatment-emergent adverse events 
(TEAEs), summarized for each treatment combination.  Ocular TEAEs will similarly be 
summarized by eye for each treatment group.  Incidence will be tabulated by MedDRA 
System Organ Class and preferred term within each system organ class.  Adverse events 
will also be summarized for treatment-related TEAEs, SAEs, by maximal severity, and 
by day of onset relative to the start of treatment. 
The additional safety variables of slit lamp biomicroscopy and visual acuity will be 
summarized descriptively using quantitative and qualitative summary statistics as 
appropriate.  In all cases, outcomes will be summarized by eye for each treatment 
group. Changes and shifts from baseline will also be summarized where applicable. 
 Interim Analysis 
10.10
No interim analyses are planned. 
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11 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 IP in the countries 
involved will be adhered to. 
 Protection of Human Subjects 
11.1
11.1.1 Subject Informed Consent 
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 (e.g., 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 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. 
 
11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB 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 approved version of the informed consent form will be used. 
 Ethical Conduct of the Study 
11.2
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 Subject Confidentiality 
11.3
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 is in accordance with local, state, and federal 
laws and regulations. 
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Monitors, auditors and other authorized representatives of Ora, the sponsor, the IRB 
approving this study, the FDA, the DHHS, other domestic government agencies, and 
other foreign regulatory agencies will be granted direct access to the 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 IP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
 Documentation 
11.4
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 EKGs. The investigator’s copy of the eCRFs serves as the 
investigator’s record of a subject’s study-related data. 
11.4.1 Retention of Documentation 
All study related correspondence, subject records, consent forms, record of the 
distribution and use of all IP, and copies of eCRFs should be maintained on file for at 
least two 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 two years have 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, and Return or 
11.5
Disposal of Investigational Product 
11.5.1 Labeling/Packaging 
Each kit will contain the 3 treatments labeled A, B, and C.  The EM-100 and vehicle will 
consist of five single use 0.4mL vials packaged in an aluminum pouch.  Zaditor® will be 
in its original bottle with the label removed.  A label containing the letter A, B, or C will 
be on the bottles of Zaditor® and the pouches of both EM-100 and vehicle of EM-100. 
There will be 485 kits created.  Kits will be labeled on the outside with a kit number 
ranging from 001-485.  Each kit will be sealed with tamper evident tape.    
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11.5.2 Storage of Investigational Product 
The IP must be stored in a secure area accessible only to the investigator and his/her 
designees. Kits will be left unopened until the authorized unmasked technicians open the 
assigned kit for administration to each randomized subject.  Following administration to 
the subject, the technicians will return the product to the kit and seal the kit with tamper 
evident tape.   
Investigational product must be stored at room temperature between 20-25°C (68-77°F). 
All investigational product will be returned to inventory after use. 
Upon receiving the shipment of IP, the investigator or his/her designee will select at 
random the appropriate number of units to be designated as the retain samples. A label 
will be affixed to the designated units to identify these as “retain samples.” These retain 
samples will not be assigned to study subjects for clinical use. All of the retain samples 
will be stored in a secure area accessible only to the investigator and his/her designees. 
The retain samples will be segregated from the investigational product to be assigned to 
study subjects for clinical use, but will be stored in the same area and under the same 
conditions for the duration of the study.   
 
11.5.3 Accountability of Investigational Product 
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 administered 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 returned or disposed upon the completion of the study. A 
detailed inventory must be completed for the IP.  Note only the kit number and number of 
kits will be tallied.  The kits will remain sealed prior to and following Visit 3. There will 
be no counting of individual IP inside the kit.   
 
The investigator must also keep an accurate accounting of the retain samples and must 
properly document the inventory.  
 
11.5.4 Return or Disposal of Investigational Product 
All IP used in the clinical trial 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. All of 
the retain samples will be shipped to a third party vendor for long-term storage.   
 Recording of Data on Source Documents and Case Reports Forms 
11.6
(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 
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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 (e.g., 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 
11.7
Not Applicable. 
 Publications 
11.8
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript. Ora 
and the sponsor will have the final decision regarding the manuscript and publication. 
 
 
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12 REFERENCES 
1. 
Bielory L. Allergic and immunologic disorders of the eye. Part II: ocular allergy. 
The Journal of allergy and clinical immunology. 2000;106(6):1019-32. 
2. 
Abelson MB, Loeffler O. Conjunctival allergen challenge: models in the 
investigation of ocular allergy. Current allergy and asthma reports. 2003;3(4):363-8. 
3. 
Ciprandi G, Buscaglia S, Pesce GP, Bagnasco M, Canonica GW. Ocular 
challenge and hyperresponsiveness to histamine in patients with allergic conjunctivitis. 
The Journal of allergy and clinical immunology. 1993;91(6):1227-30. 
4. 
Bacon AS, Ahluwalia P, Irani AM, Schwartz LB, Holgate ST, Church MK, et al. 
Tear and conjunctival changes during the allergen-induced early- and late-phase 
responses. The Journal of allergy and clinical immunology. 2000;106(5):948-54. 
5. 
Greiner JV, Mundorf T, Dubiner H, Lonsdale J, Casey R, Parver L, et al. Efficacy 
and safety of ketotifen fumarate 0.025% in the conjunctival antigen challenge model of 
ocular allergic conjunctivitis. American journal of ophthalmology. 2003;136(6):1097-
105. 
6. 
Abelson MB, Chapin MJ, Kapik BM, Shams NB. Efficacy of ketotifen fumarate 
0.025% ophthalmic solution compared with placebo in the conjunctival allergen 
challenge model. Archives of ophthalmology. 2003;121(5):626-30. 
7. 
Leonardi A, Busca F, Tavolato M, Secchi AG. The anti-allergic effects of a 
cromolyn sodium-chlorpheniramine combination compared to ketotifen in the 
conjunctival allergen challenge model. European journal of ophthalmology. 
2003;13(2):128-33. 
8. 
Crampton HJ. Comparison of ketotifen fumarate ophthalmic solution alone, 
desloratadine alone, and their combination for inhibition of the signs and symptoms of 
seasonal allergic rhinoconjunctivitis in the conjunctival allergen challenge model: a 
double-masked, placebo- and active-controlled trial. Clinical therapeutics. 
2003;25(7):1975-87. 
9. 
Crampton HJ. A comparison of the relative clinical efficacy of a single dose of 
ketotifen fumarate 0.025% ophthalmic solution versus placebo in inhibiting the signs and 
symptoms of allergic rhinoconjunctivitis as induced by the conjunctival allergen 
challenge model. Clinical therapeutics. 2002;24(11):1800-8. 
10. 
Greiner JV, Minno G. A placebo-controlled comparison of ketotifen fumarate and 
nedocromil sodium ophthalmic solutions for the prevention of ocular itching with the 
conjunctival allergen challenge model. Clinical therapeutics. 2003;25(7):1988-2005. 
11. 
D'Arienzo PA, Leonardi A, Bensch G. Randomized, double-masked, placebo-
controlled comparison of the efficacy of emedastine difumarate 0.05% ophthalmic 
solution and ketotifen fumarate 0.025% ophthalmic solution in the human conjunctival 
allergen challenge model. Clinical therapeutics. 2002;24(3):409-16. 
12. 
Greiner JV, Michaelson C, McWhirter CL, Shams NB. Single dose of ketotifen 
fumarate .025% vs 2 weeks of cromolyn sodium 4% for allergic conjunctivitis. Advances 
in therapy. 2002;19(4):185-93. 
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13. 
Kidd M, McKenzie SH, Steven I, Cooper C, Lanz R, Australian Ketotifen Study 
G. Efficacy and safety of ketotifen eye drops in the treatment of seasonal allergic 
conjunctivitis. The British journal of ophthalmology. 2003;87(10):1206-11. 
14. 
ZADITOR. Ketotifen Fumarate Ophthalmic Solution, 0.035% [package insert]. 
In: Ophthalmics N, editor. East Hanover, NJ: CIBA Vision Sterile Mfg; 2006. 
 
 
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13 
APPENDICES 
APPENDIX 1: SCHEDULE OF VISITS AND MEASUREMENTS 
  
 
 
 
                                                 
1 Informed consent must be signed before any study-related procedure can be performed. 
2 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 surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy).   
3 Instilled 15(+1) minutes prior to CAC 
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APPENDIX 2: EXAMINATION PROCEDURES, TESTS,  
Visual Acuity Procedures (ETDRS Chart) 
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Slit Lamp Biomicroscopy  
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Ora proprietary scales – Not for distribution without permission 
 
 
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APPENDIX 3: PACKAGE INSERT 
Drug Facts 
Active ingredients 
Ketotifen (0.025%) 
(equivalent to ketotifen fumarate 0.035%) 
Purpose 
Antihistamine 
  
Uses 
Temporarily relieves itchy eyes due to pollen, ragweed, grass, animal hair, and dander. 
  
Warnings 
For external use only 
 
Do not use 
 
if solution changes color or becomes cloudy 
 
if you are sensitive to any ingredient in this product 
 
to treat contact lens related irritation 
 
When using this product 
 
do not touch tip of container to any surface to avoid contamination 
 
remove contact lenses before use 
 
wait at least 10 minutes before reinserting contact lenses after use 
 
replace cap after each use 
 
Stop use and ask doctor if you experience any of the following: 
 
eye pain 
 
changes in vision 
 
redness of the eyes 
 
itching worsens or lasts for more than 72 hours 
 
Keep out of reach of children. 
If swallowed, get medical help or contact a Poison Control Center right away. 
  
Directions 
 
Adults and children 3 years of age and older: 
Put 1 drop in the affected eye(s) twice daily, every 8–12 hours, no more than twice per day. 
 
Children under 3 years of age: Consult a doctor. 
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Other information 
 
Only for use in the eye. 
 
Store between 4°–25°C (39°–77°F). 
  
Inactive ingredients 
benzalkonium chloride 0.01%, glycerol, purified water, sodium hydroxide, and/or hydrochloric acid 
 
 
 
 
 
 
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APPENDIX 4: HANDLING OF BIOLOGICAL SPECIMENS 
Not Applicable. 
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APPENDIX 5: PROTOCOL AMENDMENT SUMMARY 
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APPENDIX 6: ORA APPROVALS 
Protocol Title: 
A Single-Center Evaluation of the Relative Efficacy of EM-100 
Compared to Zaditor® (Ketotifen Fumarate Ophthalmic Solution 
0.035%) and Vehicle in the Treatment of Ocular Itching 
Associated with Allergic Conjunctivitis as Induced by the 
Conjunctival Allergen Challenge Model (Ora-CAC®) 
Protocol Number: 
17-100-0011 
Final Date: 
28 February 2018 
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APPENDIX 8: INVESTIGATOR’S SIGNATURE 
 
Protocol Title: 
A Single-Center Evaluation of the Relative Efficacy of EM-100 
Compared to Zaditor® (Ketotifen Fumarate Ophthalmic Solution 
0.035%) and Vehicle in the Treatment of Ocular Itching 
Associated with Allergic Conjunctivitis as Induced by the 
Conjunctival Allergen Challenge Model (Ora-CAC®) 
Protocol Number: 
17-100-0011 
Amendment Date: 
28 February 2018 
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> 
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Clinical Trial Protocol: 17-100-0011 
Protocol Title: 
A Single-Center Evaluation of the Relative Efficacy 
of EM-100 Compared to Zaditor® (Ketotifen 
Fumarate Ophthalmic Solution 0.035%) and Vehicle 
in the Treatment of Ocular Itching Associated with 
Allergic Conjunctivitis as Induced by the 
Conjunctival Allergen Challenge Model (Ora-
CAC®)  
 
 
Study Phase: 
3  
Investigational Product Name: EM-100 topical ophthalmic solution 
IND Number: 
Not Applicable 
Indication: 
Allergic Conjunctivitis 
Investigators: 
Single-center 
Sponsor: 
EyeMax, LLC 
74 Chestnut St. 
Weston, MA 02493 
 
Contract Research 
Organization: 
Ora, Inc. 
300 Brickstone Square, Third Floor 
Andover, MA 01810 
 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico, Suite C, #497 
San Clemente, CA 92673 
 
 
Date 
Original Protocol: 
15 December 2017 
Amendment 1: 
28 February 2018 
Amendment 2: 
04 April 2018 
 
Confidentiality Statement 
This protocol contains confidential, proprietary information of Ora, Inc. and/or EyeMax, 
LLC.  Further dissemination, distribution or copying of this protocol or its contents is 
strictly prohibited. 
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SPONSOR PERSONNEL 
President: 
 
 
ORA PERSONNEL 
Medical Monitor: 
 
 
 
Chief Medical Officer: 
 
 
 
Department Vice President: 
 
 
Project Lead: 
 
 
 
 
 
 
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SYNOPSIS 
Protocol Title: 
A Single-Center Evaluation of the Relative Efficacy of 
EM-100 Compared to Zaditor® (Ketotifen Fumarate 
Ophthalmic Solution 0.035%) and Vehicle in the 
Treatment of Ocular Itching Associated with Allergic 
Conjunctivitis as Induced by the Conjunctival Allergen 
Challenge Model (Ora-CAC®) 
Protocol Number: 
17-100-0011 
Investigational Product: 
EM-100 topical ophthalmic solution 
Study Phase: 
3 
Primary Objective(s): 
To demonstrate the non-inferiority of EM-100 to Zaditor® 
in the treatment of ocular itching associated with allergic 
conjunctivitis. 
Secondary Objective(s): 
 To demonstrate that EM-100 is superior to vehicle in 
the treatment of ocular itching associated with allergic 
conjunctivitis. 
 To demonstrate that Zaditor® is superior to vehicle in 
the treatment of ocular itching associated with allergic 
conjunctivitis. 
 To demonstrate that EM-100 is non-inferior to 
Zaditor® in the treatment of conjunctival redness 
associated with allergic conjunctivitis.    
Overall Study Design: 
Structure: 
Screening Period: At the Screening Visit, subjects will 
sign the informed consent form and an allergic skin test 
will be performed, if required. At Visit 1, each qualifying 
subject will undergo a bilateral conjunctival allergen 
challenge (CAC) titration using an allergen they had a 
positive reaction to on their skin test. Subjects who elicit a 
positive reaction post-CAC will undergo the confirmation 
CAC at Visit 2 using the same allergen they qualified with 
at Visit 1.  
Treatment Period: At Visit 3, qualifying subjects will be 
enrolled and randomized to receive EM-100, Zaditor®, or 
vehicle of EM-100 in the right eye and one of the other 
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two treatments in the left eye. A trained study technician 
will instill one (1) drop of the assigned treatment in the 
right eye and one (1) drop of the assigned treatment in the 
left eye (based on randomization). Subjects will undergo 
CAC approximately 15 minutes post-instillation of the 
investigational product.  
Duration: 
This study consists of four (4) office visits (Screening 
Visit, Visit 1, Visit 2, and Visit 3) over a period of 
approximately three to five (3-5) weeks. 
Controls: 
 Vehicle of EM-100 topical ophthalmic solution 
 Zaditor® (ketotifen fumarate ophthalmic solution 
0.035%, EQ 0.025% Base), ANDA 077200 held by 
Alcon Pharmaceuticals. 
Dosage/ Instillation: 
At Visit 3, qualifying subjects will be enrolled and 
randomized to receive EM-100, Zaditor®, or Vehicle in 
each eye. The treatment arms are listed below: 
 
 
EM-100 in right eye and Zaditor® in left eye 
 
 
Zaditor® in right eye and EM-100 in left eye 
 
 
EM-100 in right eye and Vehicle in left eye 
 
 
Vehicle in right eye and EM-100 in left eye 
   
 
Zaditor® in right eye and Vehicle in left eye 
 
 
Vehicle in right eye and Zaditor® in left eye 
 
 
A trained study technician will instill one (1) drop of the 
assigned treatment in the right eye and one (1) drop of the 
assigned treatment in the left eye approximately 15(+1) 
minutes prior to CAC.  
 
The pre-specified technicians responsible for instilling the 
investigational product will not be involved with any other 
study procedures at the site.  
Summary of Visit Schedule: 
Screening Visit  (Day -50 to -22): Screening/ Informed 
Consent/ Skin Test 
 
Visit 1 (Day -21 ± 3): Titration CAC  
 
Visit 2 (Day -14 ± 3): Confirmation CAC 
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Visit 3 (Day 1):  Enrollment/ Randomization/ In-Office 
Instillation/ Efficacy CAC/ Study Exit 
Measures Taken to Reduce 
Bias: 
Randomization will be used to avoid bias in the 
assignment of subjects to investigational product, to 
increase the likelihood that known and unknown subject 
attributes (e.g. demographics and baseline characteristics) 
are evenly balanced across treatment groups, and to 
enhance the validity of statistical comparisons across 
treatment groups. Finally, masked treatment will be used 
to reduce potential of bias during data collection and 
evaluation of clinical endpoints.   
Study Population Characteristics:  
Number of Subjects: 
Approximately 120 subjects will be screened in order to 
enroll approximately 60 subjects at a single-center.  
Condition/Disease: 
Allergic Conjunctivitis 
Inclusion Criteria: 
Each subject must: 
1) be at least 18 years of age at the Screening Visit, 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 allergic conjunctivitis for at 
least 3 months and a positive skin test reaction to a 
seasonal (grass, ragweed, and/or tree pollen) or 
perennial allergen (cat dander, dog dander, dust mites, 
cockroach) as confirmed by an allergic skin test 
conducted at the Screening Visit or within the past 24 
months; 
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 Visit 1 and during 
the study trial period; 
7) (for females capable of becoming pregnant) agree to 
have urine pregnancy testing performed at Visit 1 
(must be negative) and exit visit; must not be 
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lactating; and must agree to use a medically 
acceptable form of birth control1 throughout the 
study duration. 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 
 or 
better in each eye as measured using an ETDRS 
chart;   
9) have a positive bilateral post-CAC reaction 
 
 
 within 10 (±2) minutes of instillation of the 
last titration of allergen at Visit 1; 
10) have a positive bilateral post-CAC reaction 
 
  
   
 for at least two out of the first 
three time points2 following the challenge at Visit 2. 
 
Exclusion Criteria: 
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, pterygium or a diagnosis of dry 
eye);  
3) have had ocular surgical intervention within three (3) 
months prior to Visit 1 or during the study and/or a 
history of refractive surgery within the past six (6) 
months; 
4) have a known history of retinal detachment, diabetic 
retinopathy, or active retinal disease; 
                                                 
1Acceptable 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. 
2 not necessarily at the same time point 
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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); 
*Baby aspirin (81 mg) is allowed as long as a stable 
dose has been maintained for at least 30 days prior 
to Visit 1 and will continue to be maintained for the 
duration of the study. 
14 Days 
 inhaled, ocular, topical, or systemic 
corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
2 Months 
 immunosuppressive or cancer chemotherapeutic 
agents; 
Note: 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 by trained study personnel at 
the end of Visits 1, 2, and 3, 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 
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could be expected to interfere with the subject’s 
health or with 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) have a score of 
 
 prior to challenge (at Visits 1, 2, 
or 3) in either eye; 
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; 
11) be a female who is currently pregnant, planning a 
pregnancy, or lactating. 
Study Formulations and 
Formulation Numbers: 
 EM-100 topical ophthalmic solution 
 Vehicle of EM-100 topical ophthalmic solution 
 Zaditor® (ketotifen fumarate ophthalmic solution 
0.035%) 
Evaluation Criteria: 
 
Efficacy Measures and 
Endpoints: 
Primary:   
 Ocular itching evaluated by the subject at 3(±1), 
5(±1), and 7(±1) minutes post-CAC (0-4 scale, 
allowing half unit increments) at Visit 3. 
 
Secondary: 
The following assessments will occur at 7(±1), 15(±1), and 
20(±1) minutes post-CAC at Visit 3: 
 Conjunctival redness evaluated by the investigator 
  
 Ciliary redness evaluated by the investigator 
 
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)  
 Episcleral redness evaluated by the investigator 
 
  
 Chemosis evaluated by the investigator 
 
  
 Eyelid swelling evaluated by the subject
 
 
 Tearing/watery eyes evaluated by the subject 
 
 
 Ocular mucous discharge evaluated by the subject 
CAC (absent/present)  
 Rhinorrhea, nasal pruritus, ear or palate pruritus, 
and nasal congestion evaluated by the subject 
 
  
Safety Measures: 
 Adverse Events (reported, elicited, and observed)  
 Best Corrected Visual Acuity (BCVA) at Distance  
 Slit Lamp Biomicroscopy  
General Statistical Methods and Types of Analyses 
The following analysis populations will be defined: 
Intent-to-Treat (ITT) – 
 
  
Per Protocol Set –
 
 
 
Safety Analysis Set – 
 
 
 
Sample Size: 
The following treatment combinations will be randomized.  The eye receiving each test 
article will also be randomized: 
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 
 with EM-100 in right eye and Zaditor® in left eye 
 
 with Zaditor® in right eye and EM-100 in left eye 
 
 with EM-100 in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and EM-100 in left eye 
 
 with Zaditor® in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and Zaditor® in left eye  
 
This sample size requires a total of 60 randomized subjects, 
 
 
  
This sample size will provide 
 
 
 
 
 
   
 
 
 
 
   
   
 
 
 
   
 
 
 
 
 
 
 
 
Primary Efficacy Analyses: 
The primary efficacy endpoint is ocular itching assessed at 3(±1), 5(±1), and 7(±1) minutes 
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Secondary Efficacy Analyses: 
Analyses will be performed on the secondary endpoint of conjunctival redness in a manner 
similar to the non-inferiority tests of the primary endpoint. Secondary endpoints (Ciliary 
redness, Episcleral redness, Chemosis, Eyelid Swelling, Tearing, Ocular Mucous Discharge, 
Rhinorrhea, Nasal Pruritus, Ear/Palate Pruritus, Nasal Congestion) will be analyzed as 
supportive analyses. 
Safety Analyses: 
Safety will be assessed by evaluating the incidence of subjects with any adverse events 
during the entire study.  The percentage of subjects with any AEs will be summarized, as 
well as the percentage of subjects with any treatment-emergent adverse events (TEAEs), 
summarized for each treatment combination.  Ocular TEAEs will similarly be summarized by 
eye for each treatment group.  Incidence will be tabulated by MedDRA System Organ Class 
and preferred term within each system organ class.  Adverse events will also be summarized 
for treatment-related TEAEs, SAEs, by maximal severity, and by day of onset relative to the 
start of treatment. 
The additional safety variables of slit lamp biomicroscopy and visual acuity will be 
summarized descriptively using quantitative and qualitative summary statistics as 
appropriate.  In all cases, outcomes will be summarized by eye for each treatment group. 
Changes and shifts from baseline will also be summarized where applicable. 
Summary of Known and Potential Risks and Benefits to Human Subjects 
Known and potential risks of ketotifen fumarate ophthalmic solution (0.035%) include ocular 
burning/stinging/irritation, headache, rhinorrhea, and photophobia. Benefits include relief and 
prevention of ocular itching associated with allergic conjunctivitis. 
Refer to the Zaditor® Package Insert regarding risks and benefits to human subjects. 
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TABLE OF CONTENTS 
SYNOPSIS..................................................................................................................3 
TABLE OF CONTENTS..........................................................................................12 
LIST OF ABBREVIATIONS ............................................................................................15 
1 
INTRODUCTION ....................................................................................................16 
2 
STUDY OBJECTIVES .............................................................................................17 
3 
CLINICAL HYPOTHESES .....................................................................................17 
4 
OVERALL STUDY DESIGN ..................................................................................17 
5 
STUDY POPULATION ...........................................................................................18 
 
Number of Subjects (approximate) ................................................................18 
5.1
 
Study Population Characteristics ....................................................................18 
5.2
 
Inclusion Criteria ............................................................................................18 
5.3
 
Exclusion Criteria ...........................................................................................19 
5.4
 
Withdrawal Criteria (if applicable) ................................................................21 
5.5
6 
STUDY PARAMETERS ..........................................................................................21 
 
Efficacy Measures and Endpoints ..................................................................21 
6.1
6.1.1 
Primary Efficacy Endpoint(s) ...........................................................21 
6.1.2 
Secondary Efficacy Endpoints(s) ......................................................21 
6.1.3 
Criteria for Effectiveness ..................................................................22 
 
Safety Measures .............................................................................................22 
6.2
7 
STUDY MATERIALS .............................................................................................23 
 
Study Treatment(s) .........................................................................................23 
7.1
7.1.1 
Study Treatment(s)/ Formulation(s) .................................................23 
7.1.2 
Instructions for Use and Administration ...........................................23 
 
Other Study Supplies ......................................................................................24 
7.2
8 
STUDY METHODS AND PROCEDURES ............................................................24 
 
Subject Entry Procedures ...............................................................................24 
8.1
8.1.1 
Overview ...........................................................................................24 
8.1.2 
Informed Consent..............................................................................24 
8.1.3 
Washout Intervals .............................................................................25 
8.1.4 
Procedures for Final Study Entry ......................................................25 
8.1.5 
Methods for Assignment to Treatment Groups: ...............................26 
 
Concurrent Therapies .....................................................................................26 
8.2
8.2.1 
Prohibited Medications/Treatments ..................................................26 
8.2.2 
Escape Medications ..........................................................................27 
8.2.3 
Special Diet or Activities ..................................................................27 
 
Examination Procedures .................................................................................27 
8.3
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ............................................................................27 
8.3.1.1 
SCREENING VISIT (Day -50 to -22): Screening/ Informed Consent/ 
Skin Test 
27 
8.3.1.2 
VISIT 1 (Day -21 ± 3): Titration CAC ........................................... 28 
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8.3.1.3 
VISIT 2 (Day -14 ± 3): Confirmation CAC ...................................... 29 
8.3.1.4 
VISIT 3 (Day 1): Enrollment/Randomization/ In-Office Instillation/ 
Efficacy CAC/ Study Exit ...................................................................................... 31 
 
Schedule of Visits, Measurements and Dosing ..............................................32 
8.4
8.4.1 
Scheduled Visits................................................................................32 
8.4.2 
Unscheduled Visits ...........................................................................32 
 
Compliance with Protocol ..............................................................................33 
8.5
 
Subject Disposition .........................................................................................33 
8.6
8.6.1 
Completed Subjects ..........................................................................33 
8.6.2 
Discontinued Subjects .......................................................................33 
 
Study Termination ..........................................................................................34 
8.7
 
Study Duration ...............................................................................................34 
8.8
 
Monitoring and Quality Assurance ................................................................34 
8.9
9 
ADVERSE EVENTS ................................................................................................34 
 
Adverse Event ................................................................................................34 
9.1
9.1.1 
Severity .............................................................................................35 
9.1.2 
Relationship to Investigational Product ............................................35 
9.1.3 
Expectedness .....................................................................................36 
 
Serious Adverse Events ..................................................................................37 
9.2
 
Procedures for Reporting Adverse Events .....................................................37 
9.3
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................38 
9.3.2 
Reporting a Serious Adverse Event ..................................................38 
 
Procedures for Unmasking (if applicable) ......................................................38 
9.4
 
Type and Duration of the Follow-up of Subjects after Adverse Events ........39 
9.5
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .....................39 
 Study Populations ...........................................................................................39 
10.1
10.1.1 Intent-to-Treat Population .................................................................39 
10.1.2 Per-Protocol Population ....................................................................39 
10.1.3 Safety Population ..............................................................................40 
 General Imputation Methods ..........................................................................40 
10.2
 Statistical Hypotheses .....................................................................................40 
10.3
 Sample Size ....................................................................................................41 
10.4
 Primary Efficacy Analyses .............................................................................42 
10.5
 Secondary Efficacy Analyses .........................................................................43 
10.6
 Adjustment for Multiplicity............................................................................43 
10.7
 Demographic and Baseline Medical History ..................................................44 
10.8
 Safety Analysis ...............................................................................................44 
10.9
 Interim Analysis .............................................................................................44 
10.10
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ....................................45 
 Protection of Human Subjects ........................................................................45 
11.1
11.1.1 Subject Informed Consent.................................................................45 
11.1.2 Institutional Review Board (IRB) Approval .....................................45 
 Ethical Conduct of the Study ..........................................................................45 
11.2
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 Subject Confidentiality ...................................................................................45 
11.3
 Documentation ...............................................................................................46 
11.4
11.4.1 Retention of Documentation .............................................................46 
 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
11.5
Investigational Product ...................................................................................46 
11.5.1 Labeling/Packaging...........................................................................46 
11.5.2 Storage of Investigational Product ....................................................47 
11.5.3 Accountability of Investigational Product ........................................47 
11.5.4 Return or Disposal of Investigational Product ..................................47 
 Recording of Data on Source Documents and Case Reports Forms (CRFs) .47 
11.6
 Handling of Biological Specimens .................................................................48 
11.7
 Publications ....................................................................................................48 
11.8
12 
REFERENCES .........................................................................................................49 
13 
APPENDICES ..........................................................................................................51 
Appendix 1: Schedule of Visits and Measurements ..........................................................51 
Appendix 2: Examination Procedures, Tests, ....................................................................52 
Appendix 3: Package Insert ...............................................................................................59 
Drug Facts.....................................................................................................59 
Active ingredients ............................................................................................... 59 
Purpose ................................................................................................................ 59 
Uses ..................................................................................................................... 59 
Warnings .............................................................................................................. 59 
Directions ............................................................................................................. 59 
Other information ................................................................................................ 60 
Inactive ingredients ............................................................................................ 60 
Appendix 4: Handling of Biological Specimens ...............................................................61 
Appendix 5: Protocol Amendment Summary ....................................................................62 
Appendix 6: Ora Approvals ...............................................................................................63 
Appendix 7: SPONSOR Approvals ...................................................................................64 
Appendix 8: Investigator’s Signature ................................................................................65 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
BCVA 
best-corrected visual acuity 
CAC 
conjunctival allergen challenge 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRF 
case report form 
DHHS 
Department of Health and Human Services 
eCRF 
electronic case report form 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent to treat 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
ND  
not done  
NSAID  
nonsteroidal anti-inflammatory drug 
OD 
right eye 
OS 
left eye 
OU 
both eyes 
OTC 
over the counter 
PE 
polyethylene 
PP 
per protocol 
SAE 
serious adverse event 
SD 
standard deviation 
SDC 
Statistics and Data Corporation 
SOP 
standard operating procedure 
VA 
visual acuity 
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1 INTRODUCTION 
Allergies affect approximately 15% of the global population and up to 30% of the U.S. 
population (1). 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 (2). Histamine is the primary 
mediator responsible for the 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 (3, 4). 
Ketotifen is a widely effective therapy for the management of ocular allergies. It has 
demonstrated rapid onset (≤ 15 minutes) and long duration of action (≥ 8 hours) after 
conjunctival allergen challenge (CAC)(5, 6). Ketotifen fumarate ophthalmic solution 
0.035% was found to be safe, well tolerated, and effective for the prevention of the signs 
and symptoms associated with allergic conjunctivitis in multiple CAC studies(7-12). In an 
environmental setting, ketotifen fumarate ophthalmic solution 0.035% was found to 
safely and effectively reduce seasonal allergic conjunctivitis signs and symptoms and 
prevent recurrence(13). 
Ketotifen fumarate ophthalmic solution 0.035% (Zaditor®/Zaditen®; Novartis 
Ophthalmics) is approved in the United States and Canada for the temporary prevention 
of ocular itching due to allergic conjunctivitis at a dose of one drop in the affected eye 
twice daily (every 8-12 hours)(14). In 2006, ketotifen fumarate ophthalmic drops 0.035% 
(ketotifen 0.025%; Alaway®; Bausch and Lomb, Inc., and Zaditor®; Novartis 
Ophthalmics) were approved by the United States Food and Drug Administration (FDA) 
for over-the-counter use, with the indication of temporary relief of itchy eyes due to 
pollen, ragweed, grass, animal hair, and dander, at an approved dose of one drop in the 
affected eye twice daily (every 8-12 hours)(15). 
EM-100 contains ketotifen ophthalmic solution (0.025%) as a non-preserved formulation 
in single-dose vials. This is a single-center, randomized, double-masked study to 
establish the therapeutic equivalence of EM-100 to Zaditor® (ketotifen fumarate 
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ophthalmic drops 0.035%).  EM-100 will need to show non-inferiority to Zaditor® in the 
treatment of ocular itching following CAC (15 minutes following study medication 
instillation).  The vehicle is included for assay validation.   
2 STUDY OBJECTIVES 
Primary: 
 To demonstrate the non-inferiority of EM-100 to Zaditor® in the treatment of 
ocular itching associated with allergic conjunctivitis.  
Secondary: 
 To demonstrate that EM-100 is superior to vehicle in the treatment of ocular 
itching associated with allergic conjunctivitis. 
 To demonstrate that Zaditor® is superior to vehicle in the treatment of ocular 
itching associated with allergic conjunctivitis 
 To demonstrate that EM-100 is non-inferior to Zaditor® in the treatment of 
conjunctival redness associated with allergic conjunctivitis.  
3 CLINICAL HYPOTHESES 
The clinical hypotheses are:  
 EM-100 is more effective than vehicle in the treatment of ocular itching 
associated with allergic conjunctivitis induced by CAC 15 minutes following 
product instillation.  
 EM-100 is non-inferior to Zaditor® in the treatment of ocular itching associated 
with allergic conjunctivitis induced by CAC at 15 minutes following product 
instillation. 
 Zaditor® is more effective than vehicle in the treatment of ocular itching 
associated with allergic conjunctivitis induced by CAC at 15 minutes following 
product instillation. 
4 OVERALL STUDY DESIGN 
This is a single-center, randomized, double-masked, contralateral eye study comparing 
topical EM-100 with Zaditor® and the vehicle of EM-100 in subjects with allergic 
conjunctivitis. At the Screening Visit, subjects will sign the informed consent form and 
an allergic skin test will be performed, if required. At Visit 1, each qualifying subject will 
undergo a bilateral conjunctival allergen challenge (CAC) titration using an allergen they 
had a positive reaction to on their skin test. Subjects who elicit a positive reaction post-
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CAC will undergo the confirmation CAC at Visit 2 using the same allergen they qualified 
with at Visit 1.  
At Visit 3, qualifying subjects will be enrolled and randomized to receive EM-100, 
Zaditor®, or Vehicle in each eye. The treatment arms are listed below: 
 
 EM-100 in right eye and Zaditor® in left eye 
 
 Zaditor® in right eye and EM-100 in left eye
)EM-100 in right eye and 
Vehicle in left eye 
 
 Vehicle in right eye and EM-100 in left eye 
 
 Zaditor® in right eye and Vehicle in left eye 
 
 Vehicle in right eye and Zaditor® in left eye 
 
 
 A trained study technician will instill one (1) drop of the assigned treatment in the right 
eye and one (1) drop of the assigned treatment in the left eye (based on randomization). 
Subjects will undergo CAC approximately 15 minutes post-instillation of the 
investigational product. The pre-specified technicians responsible for instilling the 
investigational product will not be involved with any other study procedures at the site. 
5 STUDY POPULATION 
 Number of Subjects (approximate) 
5.1
Approximately 120 subjects will be screened in order to enroll approximately 60 subjects 
at a single-center.  
 Study Population Characteristics 
5.2
 Inclusion Criteria 
5.3
Each subject must: 
 
1) be at least 18 years of age at the Screening Visit, 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 allergic conjunctivitis for at least 3 months and a positive 
skin test reaction to a seasonal (grass, ragweed, and/or tree pollen) or perennial 
allergen (cat dander, dog dander, dust mites, cockroach) as confirmed by an allergic 
skin test conducted at the Screening Visit or within the past 24 months; 
5) be able and willing to avoid all disallowed medication for the appropriate washout 
period and during the study (see exclusion 6); 
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6) be able and willing to discontinue wearing contact lenses for at least 72 hours prior 
to Visit 1 and during the study trial period; 
7) (for females capable of becoming pregnant) agree to have urine pregnancy testing 
performed at Visit 1 (must be negative) and exit visit; must not be lactating; and 
must agree to use a medically acceptable form of birth control1 throughout the 
study duration. 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 
 or better in each eye as measured 
using an ETDRS chart;   
9) have a positive bilateral post-CAC reaction 
 
 within 10 (±2) minutes of instillation of the last 
titration of allergen at Visit 1; 
10) have a positive bilateral post-CAC reaction (defined as having scores of  
 
  
 for at least two out of the first three time points2 
following the challenge at Visit 2. 
 
 Exclusion Criteria 
5.4
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, 
pterygium or a diagnosis of dry eye);  
3) have had ocular surgical intervention within three (3) months prior to Visit 1 or 
during the study and/or a history of refractive surgery within the past six (6) 
months; 
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; 
                                                 
1Acceptable 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. 
2 not necessarily at the same time point 
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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); 
*Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained 
for at least 30 days prior to Visit 1 and will continue to be maintained for the 
duration of the study. 
14 Days 
 inhaled, ocular, topical, or systemic corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
2 Months 
 immunosuppressive or cancer chemotherapeutic agents; 
Note: 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 by trained study personnel at the end of Visits 1, 2, and 3, 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 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) have a score of 
 prior to challenge 
(at Visits 1, 2, or 3) in either eye;  
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; 
11) be a female who is currently pregnant, planning a pregnancy, or lactating. 
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 Withdrawal Criteria (if applicable) 
5.5
If at any time during the study the Investigator determines that a subject’s safety has been 
compromised, the subject may be withdrawn from the study. 
Subjects may withdraw consent from the study at any time. 
Any female will be removed from the study should she become pregnant during the 
course of the study, and she will undergo a pregnancy test at her exit visit for 
confirmation. The pregnancy test must be confirmed by two (2) additional tests and 
confirmed by the principal investigator (or sub-investigator if the principal investigator is 
not present). If the test result is positive a second and third time, the principal investigator 
(or sub-investigator if the principal investigator is not present) will inform the subject. 
The Investigator will follow-up and document the outcome of the pregnancy and provide 
a copy of the documentation to the sponsor. The Ora Pregnancy Report Form will be used 
to report a pregnancy and follow-up. 
Reason for withdrawal will be included in the eCRF, and all efforts should be made to 
schedule the subject for an Exit Visit to complete exit procedures.  Any subject who is 
withdrawn for the study because of an AE will be followed until AE is resolved or as 
clinically required, and the investigator will prepare a written summary of the event and 
document the available follow-up information on the eCRF.   
Sponsor and/or Investigator may discontinue any subject for non-compliance or any valid 
medical reason (see Section 8.5). 
6 STUDY PARAMETERS 
 Efficacy Measures and Endpoints 
6.1
6.1.1 Primary Efficacy Endpoint(s) 
 Ocular itching evaluated by the subject at 3(±1), 5(±1), and 7(±1) minutes post-
CAC 
 at Visit 3. 
 
6.1.2 Secondary Efficacy Endpoints(s) 
The following assessments will occur at 7(±1), 15(±1), and 20(±1) minutes post-CAC at 
Visit 3: 
 Conjunctival redness evaluated by the investigator 
 
  
 Ciliary redness evaluated by the investigator 
 
  
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 Episcleral redness evaluated by the investigator 
 
  
 Chemosis evaluated by the investigator 
 
  
 Eyelid swelling evaluated by the subject 
 
 
 Tearing/watery eyes evaluated by the subject 
 
 
 Ocular mucous discharge evaluated by the subject CAC (absent/present) 
 Rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal congestion evaluated 
by the subject 
 
 
6.1.3 Criteria for Effectiveness 
This therapeutic equivalence study is designed to evaluate the relative efficacy of EM-
100 topical ophthalmic solution compared to vehicle and Zaditor® in the treatment of 
ocular itching at each designated time point post-CAC at Visit 3 (Day 1, 15-minute 
onset).  
Although this study is being referred to as a “bioequivalence” or “therapeutic 
equivalence” study, it is in fact a non-inferiority study and all statistical testing will 
determine whether EM-100 is non-inferior to the reference drug, Zaditor®. Vehicle is 
included in this study in order to validate the assay.  
 
 
 
 
 
 
 
 
 Safety Measures 
6.2
 Adverse Events (reported, elicited, and observed)  
 Best Corrected Visual Acuity (BCVA) at Distance  
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 Slit Lamp Biomicroscopy  
7 STUDY MATERIALS 
 Study Treatment(s) 
7.1
7.1.1 Study Treatment(s)/ Formulation(s) 
 EM-100 topical ophthalmic solution  
 Vehicle of EM-100 topical ophthalmic solution 
 Zaditor® (ketotifen fumarate ophthalmic solution 0.035%)  
 
7.1.2 Instructions for Use and Administration 
 This trial requires additional attention in order to preserve masking of study 
treatment. There will be a total of 485 identical appearing kits containing all three 
treatments labeled A, B, and C.  Once the kits arrive at the site, a designated staff 
member will randomly select 65 kits to be used for the trial.  The remaining 420 
kits will be identified and stored as retains.  Both EM-100 and the vehicle of EM-
100 will be identical in appearance as single use vials, while the reference product, 
Zaditor®, will be in its original bottle. All individual kits will be sealed with 
tamper evident tape and the sites will be instructed to not open the kits upon 
receipt of shipment.  At no point during the trial (until database lock) will site staff 
or monitors be allowed to open the kits unless it is the designated “unmasked” 
technicians. These technicians will ensure that opening of the kits is done in a 
manner to prevent the other staff and subjects from seeing the investigational 
product. For each subject treatment will be administered by eye according to a 
randomization list which will be sent to the site in a sealed envelope and opened at 
Visit 3 by the unmasked technicians.  Following Visit 3 dosing, the technicians 
will reseal the kits and randomization list envelope using tamper evident tape and 
return the kits to storage. The sealed randomization list envelope will be filed in 
the investigator’s study file.      
 
 At Visit 3, qualifying subjects will be enrolled and randomized to receive EM-
100, Zaditor®, or vehicle of EM-100. A randomization list will inform the 
technicians which corresponding letter treatment should be instilled in the right 
eye and which one should be instilled in the left eye.  
 
 A trained study technician will instill one (1) drop of the assigned treatment in the 
right eye and one (1) drop of the assigned treatment in the left eye approximately 
15(+1) minutes prior to CAC.  
 
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 The 
pre-specified 
unmasked 
technicians 
responsible 
for 
instilling 
the 
investigational product will not be involved with any other study procedures at the 
site.  Care will be taken to hide the container (vial or bottle) from the subject.   
Dosing will occur in a room where no other subjects, staff, or investigators will 
observe the instillation.   
 
 Investigational product must be stored in a secure area of the clinical site, 
accessible only to the Investigator(s) or designees at room temperature between 
20-25°C (68-77°F).  All investigational product will be returned to inventory after 
use.  
 
 In accordance with 21CFR §320.38 and §320.63, samples of both the test article 
(EM-100) and reference listed drug (Zaditor®) will be retained and stored under 
conditions consistent with product labeling and in an area segregated from the 
area where testing is conducted and with access limited to authorized personnel. 
 
 
 Other Study Supplies 
7.2
The following supplies will be supplied and/or reconstituted by Ora, Inc.: 
 
Pregnancy tests (Clarity HCG, RAC Medical Boca Raton, FL).  
 
The allergens used for skin testing and the conjunctival allergen challenge (cat 
dander, dog dander, dust mite, cockroach, meadow fescue, rye grass, Bermuda 
grass, Kentucky bluegrass, Timothy grass, ragweed, white birch, oak, and maple).   
 
Relief drops (OTC antihistamine/vasoconstrictor combination products). 
8 STUDY METHODS AND PROCEDURES 
 Subject Entry Procedures 
8.1
8.1.1 Overview 
Subjects as defined by the criteria in sections 5.2, 5.3, and 5.4 will be considered for 
entry into this study. 
8.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., changes in a subject’s medical treatment 
and/or study related procedures), the study will be discussed with each subject, and 
subjects wishing to participate must give written informed consent using an informed 
consent form (ICF).  The ICF must be the most recent version that has received 
approval/favorable review by a properly constituted Institutional Review Board. Failure 
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to obtain a signed ICF renders the subject ineligible for the study. Subjects must be 
willing to return to the clinic for study Visits 1, 2, and 3. 
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. Subjects can be re-screened a maximum of two times. 
8.1.3 Washout Intervals 
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 stabilizers, 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, topical, or systemic corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
 2 Months 
 immunosuppressive or cancer chemotherapeutic agents. 
Note: Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained for 
at least 30 days prior to Visit 1 and will continue to be maintained for the duration of the 
study. 
8.1.4 Procedures for Final Study Entry 
Subjects must meet all of the inclusion criteria and none of the exclusion criteria prior to 
Visit 3 to be enrolled in this study.  
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8.1.5 Methods for Assignment to Treatment Groups: 
All subjects screened for the study who sign an ICF will be assigned a screening number 
that will be entered in the Screening and Enrollment Log. The screening number will 
consist of three (3) digits, starting with 001. Randomization will be used to avoid bias in 
the assignment of subjects to treatment, to increase the likelihood that known and 
unknown subject attributes (e.g., demographics and baseline characteristics) are evenly 
balanced across treatment groups, and to enhance the validity of statistical comparisons.   
Once a subject meets qualification criteria at Visit 3 (Day 1), he/she will be enrolled and 
randomized to receive EM-100, Zaditor®, or the vehicle of EM-100. A separate 
treatment will be assigned to each eye. Subjects will be assigned the lowest four (4) digit 
randomization number available.  
 Concurrent Therapies 
8.2
The use of any concurrent medication, prescription or over-the-counter, is to be recorded 
on the subject’s source document and corresponding electronic case report form (eCRF) 
along with the reason the medication was taken. 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
8.2.1 Prohibited Medications/Treatments 
 contact lenses 
 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) 
 inhaled, ocular, topical, or systemic corticosteroids or mast cell stabilizers 
 depot-corticosteroids 
 immunosuppressive or cancer chemotherapeutic agents 
Note: Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained for 
at least 30 days prior to Visit 1 and will continue to be maintained for the duration of the 
study. 
 
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8.2.2 Escape Medications 
Subjects may receive either anti-itch cream or Calamine lotion (depending on the 
washout) after the skin test has been completed at the Screening Visit.  
 
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 by trained personnel at the end of Visits 1, 2, and 3 after all evaluations are 
completed. 
 
8.2.3 Special Diet or Activities 
Not Applicable. 
 Examination Procedures 
8.3
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) 
8.3.1.1 SCREENING VISIT (Day -50 to -22): Screening/ Informed Consent/ Skin 
Test 
 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.  
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. Subjects can be re-screened a maximum of two 
times.  
 Allergic Skin Test (if applicable): A diagnostic test for allergic disease (skin test) will 
be performed according to Ora SOPs if there is no documented skin test within the 
past 24 months. Subjects may receive either anti-itch cream or Calamine lotion 
(depending on the washout) after the skin test has been completed. 
 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 
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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 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 8.1.3) 
 Adverse Event Query 
 Schedule Visit 1: Qualifying subjects will be scheduled for Visit 1. 
8.3.1.2 VISIT 1 (Day -21 ± 3): Titration CAC 
 Update of Medical/Medication History 
 Adverse Event Query 
 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.  
 Initial Visual Acuity Utilizing an ETDRS Chart:  Subjects must have a score of
 
or better in each eye in order to qualify.  
 Initial Ocular Itching and Conjunctival Redness Assessments: The investigator and 
the subject will assess initial ocular itching and conjunctival redness using the Ora-
CAC® scales (see Appendix 2). Subjects exhibiting a sign and/or symptom of allergic 
conjunctivitis 
 
 will be excluded. 
 Initial Slit Lamp Biomicroscopy: A slit lamp examination will be performed in both 
eyes to exclude subjects with disallowed ocular conditions (see Appendix 2). 
Findings of abnormality which are not exclusionary should be recorded as Medical 
History.  
 Review of Inclusion/Exclusion Criteria: A review of protocol inclusion and exclusion 
criteria will be confirmed for each subject. 
 Titration Conjunctival Allergen Challenge (CAC): A conjunctival allergen challenge 
(CAC) will be performed bilaterally with a perennial or seasonal allergen serially 
diluted in buffered saline and administered via a micropipette according to Ora SOPs. 
One drop of a solubilized allergen to which the subject is sensitized, at the weakest 
dilution, will be instilled bilaterally into the conjunctival cul-de-sac.  
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If the subject fails to react within 10 (±2) minutes, increasingly concentrated doses 
may be instilled bilaterally at approximately ten-minute intervals until a positive 
reaction is elicited. If increasing doses are required (i.e., for insufficient bilateral 
itching and/or redness as evaluated by a trained technician or the Investigator), doses 
may be skipped. If a positive CAC reaction is not elicited with the first allergen 
 
, other allergens to which the subject is 
sensitized may be used starting at the lowest dose.  
 Post-CAC Ocular Itching and Conjunctival Redness Assessments: Upon completion 
of the initial titration CAC, subjects will receive an ocular examination by the 
Investigator to evaluate conjunctival redness and confirm the subject’s qualification. 
Subjects will be asked to assess their ocular itching. 
A positive CAC at Visit 1 is defined as a score of 
 
 in each eye within 10 (±2) minutes of 
receiving that dose of allergen. Any subject who fails to test positively will be 
excluded from the study. 
 Note: The type and concentration of allergen used to elicit a positive reaction will be 
recorded for each qualifying subject.  At all subsequent visits, subjects will receive 
the same type of allergen (same lot number) and same concentration identified at this 
visit.  
 Review of Inclusion/Exclusion Criteria 
 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®) by trained study personnel as they leave the office to 
relieve any immediate discomfort caused by the allergic reaction.  
 Adverse Event Query 
 Schedule Visit 2: Qualifying subjects will be scheduled to return to the office in one 
(1) week for Visit 2. 
8.3.1.3 VISIT 2 (Day -14 ± 3): Confirmation CAC  
 Update of Medical/Medication History 
 Adverse Event Query 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease from Visit 1 may be documented as an AE per the investigator’s discretion. 
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An increase of
 or more should be brought to the attention of the investigator. 
Visual Acuity may be repeated in instances of significant decreases. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessments: The 
investigator and the subject will assess pre-CAC ocular and nasal allergic signs and 
symptoms using the Ora-CAC® scales. Subjects exhibiting a sign and/or symptom of 
allergic conjunctivitis
 
 will be excluded. 
 Slit Lamp Biomicroscopy 
 Review of Inclusion/Exclusion Criteria  
 Confirmation CAC: For each qualified subject, one drop of the allergen solution, of 
the same, final dose that elicited a positive reaction at Visit 1, will be administered 
bilaterally. 
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessments: Assessments 
of itching will be made by the subject at 3(±1), 5(±1), and 7 (±1) minutes following 
allergen challenge. Assessments of conjunctival redness and chemosis will be graded 
by the Investigator at 7(±1), 15(±1), and 20(±1) minutes post-challenge and 
assessments of eyelid swelling, tearing/watery eyes, ocular mucous discharge, and 
nasal symptoms will be made by the subject at 7(±1), 15(±1), and 20(±1) minutes 
post-challenge (Appendix 2). If the subject fails to react positively 
 
 
 
, he/she will be excluded from the study. 
 Review of Inclusion/Exclusion Criteria 
 
 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. 
  
 Adverse Event Query  
 
 Schedule Visit 3: Subjects will be asked to return to the office two (2) weeks later for 
Visit 3.  
                                                 
1 not necessarily at the same time point 
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8.3.1.4 VISIT 3 (Day 1): Enrollment/Randomization/ In-Office Instillation/ Efficacy 
CAC/ Study Exit 
 Update of Medical/Medication History 
 Adverse Event Query   
 Urine Pregnancy Test (for females of childbearing potential) 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease from Visit 1 may be documented as an AE per the investigator’s discretion. 
An increase of 
or more should be brought to the attention of the investigator. 
Visual Acuity may be repeated in instances of significant decreases. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessments: The 
investigator and the subject will assess pre-CAC ocular  and nasal allergic signs and 
symptoms using the Ora-CAC® scales. Subjects exhibiting a sign and/or symptom of 
allergic conjunctivitis 
 
will be excluded.      
 Slit Lamp Biomicroscopy 
 Review of Inclusion/Exclusion Criteria  
 Randomization: Subjects who meet all of the inclusion criteria and none of the 
exclusion criteria and qualify to continue in the study will be enrolled and 
randomized to receive EM-100, Zaditor®, or the vehicle of EM-100. A separate 
treatment will be assigned to each eye.  Subjects will be assigned the lowest four (4) 
digit randomization number available.  
 Investigational Product Instillation: A trained study technician will instill one drop of 
the assigned treatment in the right eye and one drop of the assigned treatment in the 
left eye, according to the directions for use. The investigational product kit number 
and the time of instillation will be recorded. The pre-specified technicians responsible 
for instilling the investigational product will not be involved with any other study 
procedures at the site.  
 Efficacy CAC: Each subject will receive one drop of the allergen solution of the same, 
final dose that elicited a positive reaction at Visit 1 bilaterally, 15(+1) minutes post-
instillation of investigational product.  
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessments: Assessments 
of itching will be made by the subject at 3(±1), 5(±1), and 7 (±1) minutes following 
allergen challenge. Assessments of redness and chemosis will be graded by the 
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Investigator at 7(±1), 15(±1), and 20(±1) minutes post-challenge and assessments of 
eyelid swelling, tearing/watery eyes, ocular mucous discharge, and nasal symptoms 
will be made by the subject at 7(±1), 15(±1), and 20(±1) minutes post-challenge 
(Appendix 2).  
 Exit Slit Lamp Biomicroscopy  
 Exit Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease from Visit 1 may be documented as an AE per the investigator’s discretion. 
An increase of 
 or more should be brought to the attention of the investigator. 
Visual Acuity may be repeated in instances of significant decreases. 
 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. 
 Adverse Event Query 
 Study Exit: Subjects will be exited from the study. 
Adverse Events (AEs) (both elicited and observed) will be monitored throughout the 
study. All AEs (both elicited and observed) will be promptly reviewed by the investigator 
for accuracy and completeness. All AEs will be documented on the appropriate eCRF. 
If a female has a positive pregnancy test during the study, then the investigator will notify 
Ora immediately. The investigator shall request from the subject and/or the subject’s 
physician copies of all related medical reports during the pregnancy and shall document 
the outcome of the pregnancy. The investigator will retain these reports together with the 
subject’s source documents and will provide a copy of all documentation to Ora. 
 Schedule of Visits, Measurements and Dosing 
8.4
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
If a subject is discontinued at a scheduled study visit (i.e. Visit 3), the remaining 
assessments should be captured on the Unscheduled Visit/ Early Exit Visit pages of the 
source document and corresponding eCRF. Subjects who screen fail (Screening  
Visits or Visits 1, 2, or 3) may be scheduled for the Unscheduled Visit at the 
Investigator’s discretion due to follow-up of an ongoing AE.  
8.4.2 Unscheduled Visits 
For unscheduled visits, the reason for the visit should be clearly documented on the 
appropriate eCRF, including findings from all evaluations that are completed.  
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These visits may be performed in order to ensure subject safety. All information gathered 
at unscheduled visits should be recorded on the Unscheduled Visit/Early Exit Visit pages 
of the source document and corresponding eCRF. 
Evaluations that may be conducted at an Unscheduled Visit (as appropriate, depending on 
the reason for the visit), include:  
 
Assessment of Adverse Events 
 
Assessment of Concomitant Medications 
 
Visual Acuity Utilizing an ETDRS chart 
 
Urine Pregnancy Test (for females of childbearing potential) 
 
Slit lamp Biomicroscopy  
If a randomized subject does not attend their scheduled visit, eCRF pages for missed 
visits will be skipped. All efforts should be made to schedule the subject for an Exit Visit 
to complete exit procedures.  
 Compliance with Protocol 
8.5
Subjects who are inappropriately enrolled or no longer fulfill the study eligibility criteria 
may be discontinued from the study. The reason for such discontinuation will be recorded 
as “protocol violation” in the source document and on the appropriate page in the eCRF.  
Site staff will review concomitant medication by asking subjects if they changed their 
dosing regimen since their previous visit. The response will be recorded in the source 
document and on the eCRF at Visits 1, 2, and 3.  
All protocol violations, regardless of causation, will be recorded in the subject’s source 
document as well as eCRF. Major protocol violations will be recorded in the subject’s 
source document, entered in the eCRF, and reported to the IRB, as per the applicable 
regulations.   
 Subject Disposition 
8.6
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
8.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
 
subject request/withdrawal 
 
AEs 
 
protocol violations 
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 
administrative reasons (e.g., inability to continue, lost to follow up) 
 
sponsor termination of study 
 
other 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to Ora and/or sponsor and will be clearly documented on the eCRF. Subjects who are 
discontinued from the study will not be replaced. 
 Study Termination 
8.7
The study may be stopped at any time by the investigator, the sponsor, and/or Ora with 
appropriate notification. 
 Study Duration 
8.8
This study consists of four (4) office visits (Screening Visit, Visit 1, Visit 2, and Visit 3) 
over a period of approximately three to five (3-5) weeks. 
 Monitoring and Quality Assurance 
8.9
During the course of the study, an Ora monitor, or designee, will make routine site visits 
to review protocol compliance, assess IP accountability, and ensure the study is being 
conducted according to the pertinent regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject 
confidentiality. Further details of the study monitoring will be outlined in a monitoring 
plan. 
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. 
9 ADVERSE EVENTS 
 Adverse Event 
9.1
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered IP-related. An AE can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP, without any judgment about causality. An AE can arise 
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from any use of the IP (e.g., off-label use, use in combination with another drug or 
medical device) and from any route of administration, formulation, or dose, including an 
overdose. An AE can arise from any delivery, implantation, or use of a medical device, 
including medical device failure, subject characteristics that may impact medical device 
performance (e.g., anatomical limitations), and therapeutic parameters (e.g., energy 
applied, sizing, dose release, and anatomic fit) associated with medical device use. 
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 comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, and 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.  
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). 
9.1.1 Severity 
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. 
 
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. 
9.1.2 Relationship to Investigational Product 
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 
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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 IP 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. 
 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. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the IP caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the IP and the AE. Types of evidence that would suggest a 
causal relationship between the IP and the AE event include: a single occurrence of an 
event that is uncommon and known to be strongly associated with IP exposure (e.g., 
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 (e.g., 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. 
9.1.3 Expectedness 
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 is not 
listed at the specificity or severity that has been observed. 
 Expected:  An AE that is listed in the IB at the specificity and severity that has been 
observed. 
 Not applicable: An AE unrelated to the IP. 
Adverse events that are mentioned in the IB as occurring with a class of products or as 
anticipated from the pharmacological/mechanical (or other) properties of the product, but 
are not specifically mentioned as occurring with the particular product under 
investigation are to be considered unexpected. 
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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 
9.2
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; 
Note: 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; 
Note: 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; 
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 (e.g., 
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 
9.3
All AEs and their outcomes must be reported to Ora, the 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.  
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Collection of AEs/SAEs will begin at the time of informed consent.  
9.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the sponsor and 
the IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities. 
9.3.2 Reporting a Serious Adverse Event 
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 eCRFs. 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. 
In the event of a SAE, the investigator must notify Ora and the sponsor 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 with a complete case history, which includes a 
statement as to whether the event was or was not suspected to be related to the use of the 
IP; and inform the IRB of the SAE within their guidelines for reporting SAEs. All SAEs, 
regardless of expectedness or relationship to the IP, will be reported to the FDA as soon 
as possible but no later than 15 calendar days after becoming aware of the event. 
Contact information for reporting SAEs: 
                       
                   
                   
 
 
 
 
 
 
 
        
         
 
 Procedures for Unmasking (if applicable) 
9.4
When medically necessary, the investigator may need to determine what treatment has 
been assigned to a subject. When possible (i.e., in non-emergent situations), Ora and/or 
the sponsor should be notified before unmasking IP. 
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 Type and Duration of the Follow-up of Subjects after Adverse 
9.5
Events 
AEs will be followed until: 
 Resolution (return to baseline status or to “normal”) 
 Stabilization of the event has occurred (no improvement or worsening expected 
by the investigator) 
 Event is otherwise explained, regardless of whether the subject is still 
participating in the study 
 Principal investigator determines, for events that do not end (i.e., metastasis), the 
condition to be chronic. The event can be determined to be resolved or resolved 
with sequelae.  
The Investigator will follow unresolved adverse events to resolution until the subject is 
lost to follow-up or until the adverse event is otherwise explained. If the subject is lost to 
follow-up, the Investigator should make three (3) reasonable attempts to contact the 
subject 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 and be followed as 
aforementioned.  
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. 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
 Study Populations 
10.1
10.1.1 Intent-to-Treat Population 
 
  
  
10.1.2 Per-Protocol Population 
 
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deviations. This population will be analyzed as treated using observed data only for 
confirmatory analyses. Major protocol deviations will be determined prior to 
unmasking any subject data. 
10.1.3 Safety Population 
The safety population includes all subjects who received the test article. The safety 
population will be analyzed as treated and will be used for the safety analyses. No 
data will be excluded for any reason. 
 General Imputation Methods 
10.2
Missing data is not expected in this single, post-randomization visit study.  
 
 
 
 
 
 
 
 Statistical Hypotheses 
10.3
The statistical hypotheses for the non-inferiority test between EM-100 ophthalmic 
solution and Zaditor® are as follows: 
PRIMARY: 
 
 
 
 
 
SECONDARY: 
Conditional upon H01 being rejected, the statistical hypothesis for the superiority test 
between EM-100 ophthalmic solution and vehicle solution will be tested as follows: 
H02: 
 
 
 
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Conditional upon H01 and H02 being rejected, the statistical hypothesis for the 
superiority test between Zaditor® and vehicle solution will be tested as follows: 
 
 
 
 
 
Conditional upon H01, H02, and H03 being rejected, the statistical hypothesis for the 
non-inferiority test between EM-100 ophthalmic solution and Zaditor® will be tested as 
follows: 
 
 
 
 
 
  
 Sample Size 
10.4
The following treatment combinations will be randomized.  The eye receiving each test 
article will also be randomized: 
 
 with EM-100 in right eye and Zaditor® in left eye 
 
 with Zaditor® in right eye and EM-100 in left eye 
 
 with EM-100 in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and EM-100 in left eye 
 
 with Zaditor® in right eye and Vehicle in left eye 
 
 with Vehicle in right eye and Zaditor® in left eye 
This sample size requires a total of 60 randomized subjects, while providing 
 
 
   
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This sample size will provide
 
 
 
 
 
   
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 Primary Efficacy Analyses  
10.5
The primary efficacy endpoint is ocular itching assessed at 3(±1), 5(±1), and 7(±1) 
minutes post-CAC 
 
 
 
 
 
 
 
 
 
 
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 Secondary Efficacy Analyses 
10.6
Analyses will be performed on the secondary endpoint of conjunctival redness in a 
manner similar to the non-inferiority test of the primary endpoint.
 
 
 
 
 
 
 
 
 
 
 
 
. 
 Adjustment for Multiplicity 
10.7
 
 
 
 
 
 
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 Demographic and Baseline Medical History  
10.8
The demographic and baseline medical history data will be summarized descriptively 
overall subjects and for each treatment combination. For quantitative variables, the 
summaries will include the number of observations, mean, standard deviation, median, 
minimum, and maximum. Qualitative variables will be summarized using counts and 
percentages.  
 Safety Analysis 
10.9
Safety will be assessed by evaluating the incidence of subjects with any adverse events 
during the entire study.  The percentage of subjects with any AEs will be summarized, 
as well as the percentage of subjects with any treatment-emergent adverse events 
(TEAEs), summarized for each treatment combination.  Ocular TEAEs will similarly be 
summarized by eye for each treatment group.  Incidence will be tabulated by MedDRA 
System Organ Class and preferred term within each system organ class.  Adverse events 
will also be summarized for treatment-related TEAEs, SAEs, by maximal severity, and 
by day of onset relative to the start of treatment. 
The additional safety variables of slit lamp biomicroscopy and visual acuity will be 
summarized descriptively using quantitative and qualitative summary statistics as 
appropriate.  In all cases, outcomes will be summarized by eye for each treatment 
group. Changes and shifts from baseline will also be summarized where applicable. 
 Interim Analysis 
10.10
No interim analyses are planned. 
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11 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 IP in the countries 
involved will be adhered to. 
 Protection of Human Subjects 
11.1
11.1.1 Subject Informed Consent 
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 (e.g., 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 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. 
 
11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB 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 approved version of the informed consent form will be used. 
 Ethical Conduct of the Study 
11.2
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 Subject Confidentiality 
11.3
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 is in accordance with local, state, and federal 
laws and regulations. 
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Monitors, auditors and other authorized representatives of Ora, the sponsor, the IRB 
approving this study, the FDA, the DHHS, other domestic government agencies, and 
other foreign regulatory agencies will be granted direct access to the 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 IP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
 Documentation 
11.4
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 EKGs. The investigator’s copy of the eCRFs serves as the 
investigator’s record of a subject’s study-related data. 
11.4.1 Retention of Documentation 
All study related correspondence, subject records, consent forms, record of the 
distribution and use of all IP, and copies of eCRFs should be maintained on file for at 
least two 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 two years have 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, and Return or 
11.5
Disposal of Investigational Product 
11.5.1 Labeling/Packaging 
Each kit will contain the 3 treatments labeled A, B, and C.  The EM-100 and vehicle will 
consist of five single use 0.4mL vials packaged in an aluminum pouch.  Zaditor® will be 
in its original bottle with the label removed.  A label containing the letter A, B, or C will 
be on the bottles of Zaditor® and the pouches of both EM-100 and vehicle of EM-100. 
There will be 485 kits created.  Kits will be labeled on the outside with a kit number 
ranging from 001-485.  Each kit will be sealed with tamper evident tape.    
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11.5.2 Storage of Investigational Product 
The IP must be stored in a secure area accessible only to the investigator and his/her 
designees. Kits will be left unopened until the authorized unmasked technicians open the 
assigned kit for administration to each randomized subject.  Following administration to 
the subject, the technicians will return the product to the kit and seal the kit with tamper 
evident tape.   
Investigational product must be stored at room temperature between 20-25°C (68-77°F). 
All investigational product will be returned to inventory after use. 
Upon receiving the shipment of IP, the investigator or his/her designee will select at 
random the appropriate number of units to be designated as the retain samples. A label 
will be affixed to the designated units to identify these as “retain samples.” These retain 
samples will not be assigned to study subjects for clinical use. All of the retain samples 
will be stored in a secure area accessible only to the investigator and his/her designees. 
The retain samples will be segregated from the investigational product to be assigned to 
study subjects for clinical use, but will be stored in the same area and under the same 
conditions for the duration of the study.   
 
11.5.3 Accountability of Investigational Product 
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 administered 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 returned or disposed upon the completion of the study. A 
detailed inventory must be completed for the IP.  Note only the kit number and number of 
kits will be tallied.  The kits will remain sealed prior to and following Visit 3. There will 
be no counting of individual IP inside the kit.   
 
The investigator must also keep an accurate accounting of the retain samples and must 
properly document the inventory.  
 
11.5.4 Return or Disposal of Investigational Product 
All IP used in the clinical trial 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. All of 
the retain samples will be shipped to a third party vendor for long-term storage.   
 Recording of Data on Source Documents and Case Reports Forms 
11.6
(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 
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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 (e.g., 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 
11.7
Not Applicable. 
 Publications 
11.8
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript. Ora 
and the sponsor will have the final decision regarding the manuscript and publication. 
 
 
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12 REFERENCES 
1. 
Bielory L. Allergic and immunologic disorders of the eye. Part II: ocular allergy. 
The Journal of allergy and clinical immunology. 2000;106(6):1019-32. 
2. 
Abelson MB, Loeffler O. Conjunctival allergen challenge: models in the 
investigation of ocular allergy. Current allergy and asthma reports. 2003;3(4):363-8. 
3. 
Ciprandi G, Buscaglia S, Pesce GP, Bagnasco M, Canonica GW. Ocular 
challenge and hyperresponsiveness to histamine in patients with allergic conjunctivitis. 
The Journal of allergy and clinical immunology. 1993;91(6):1227-30. 
4. 
Bacon AS, Ahluwalia P, Irani AM, Schwartz LB, Holgate ST, Church MK, et al. 
Tear and conjunctival changes during the allergen-induced early- and late-phase 
responses. The Journal of allergy and clinical immunology. 2000;106(5):948-54. 
5. 
Greiner JV, Mundorf T, Dubiner H, Lonsdale J, Casey R, Parver L, et al. Efficacy 
and safety of ketotifen fumarate 0.025% in the conjunctival antigen challenge model of 
ocular allergic conjunctivitis. American journal of ophthalmology. 2003;136(6):1097-
105. 
6. 
Abelson MB, Chapin MJ, Kapik BM, Shams NB. Efficacy of ketotifen fumarate 
0.025% ophthalmic solution compared with placebo in the conjunctival allergen 
challenge model. Archives of ophthalmology. 2003;121(5):626-30. 
7. 
Leonardi A, Busca F, Tavolato M, Secchi AG. The anti-allergic effects of a 
cromolyn sodium-chlorpheniramine combination compared to ketotifen in the 
conjunctival allergen challenge model. European journal of ophthalmology. 
2003;13(2):128-33. 
8. 
Crampton HJ. Comparison of ketotifen fumarate ophthalmic solution alone, 
desloratadine alone, and their combination for inhibition of the signs and symptoms of 
seasonal allergic rhinoconjunctivitis in the conjunctival allergen challenge model: a 
double-masked, placebo- and active-controlled trial. Clinical therapeutics. 
2003;25(7):1975-87. 
9. 
Crampton HJ. A comparison of the relative clinical efficacy of a single dose of 
ketotifen fumarate 0.025% ophthalmic solution versus placebo in inhibiting the signs and 
symptoms of allergic rhinoconjunctivitis as induced by the conjunctival allergen 
challenge model. Clinical therapeutics. 2002;24(11):1800-8. 
10. 
Greiner JV, Minno G. A placebo-controlled comparison of ketotifen fumarate and 
nedocromil sodium ophthalmic solutions for the prevention of ocular itching with the 
conjunctival allergen challenge model. Clinical therapeutics. 2003;25(7):1988-2005. 
11. 
D'Arienzo PA, Leonardi A, Bensch G. Randomized, double-masked, placebo-
controlled comparison of the efficacy of emedastine difumarate 0.05% ophthalmic 
solution and ketotifen fumarate 0.025% ophthalmic solution in the human conjunctival 
allergen challenge model. Clinical therapeutics. 2002;24(3):409-16. 
12. 
Greiner JV, Michaelson C, McWhirter CL, Shams NB. Single dose of ketotifen 
fumarate .025% vs 2 weeks of cromolyn sodium 4% for allergic conjunctivitis. Advances 
in therapy. 2002;19(4):185-93. 
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13. 
Kidd M, McKenzie SH, Steven I, Cooper C, Lanz R, Australian Ketotifen Study 
G. Efficacy and safety of ketotifen eye drops in the treatment of seasonal allergic 
conjunctivitis. The British journal of ophthalmology. 2003;87(10):1206-11. 
14. 
ZADITOR. Ketotifen Fumarate Ophthalmic Solution, 0.035% [package insert]. 
In: Ophthalmics N, editor. East Hanover, NJ: CIBA Vision Sterile Mfg; 2006. 
 
 
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13 
APPENDICES 
APPENDIX 1: SCHEDULE OF VISITS AND MEASUREMENTS 
  
 
 
 
                                                 
1 Informed consent must be signed before any study-related procedure can be performed. 
2 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 surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy).   
3 Instilled 15(+1) minutes prior to CAC 
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APPENDIX 2: EXAMINATION PROCEDURES, TESTS,  
Visual Acuity Procedures (ETDRS Chart) 
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Slit Lamp Biomicroscopy  
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
Amendment 2.0/04Apr2018 
 
Confidential 
Page 59 
 
 
APPENDIX 3: PACKAGE INSERT 
Drug Facts 
Active ingredients 
Ketotifen (0.025%) 
(equivalent to ketotifen fumarate 0.035%) 
Purpose 
Antihistamine 
  
Uses 
Temporarily relieves itchy eyes due to pollen, ragweed, grass, animal hair, and dander. 
  
Warnings 
For external use only 
 
Do not use 
 
if solution changes color or becomes cloudy 
 
if you are sensitive to any ingredient in this product 
 
to treat contact lens related irritation 
 
When using this product 
 
do not touch tip of container to any surface to avoid contamination 
 
remove contact lenses before use 
 
wait at least 10 minutes before reinserting contact lenses after use 
 
replace cap after each use 
 
Stop use and ask doctor if you experience any of the following: 
 
eye pain 
 
changes in vision 
 
redness of the eyes 
 
itching worsens or lasts for more than 72 hours 
 
Keep out of reach of children. 
If swallowed, get medical help or contact a Poison Control Center right away. 
  
Directions 
 
Adults and children 3 years of age and older: 
Put 1 drop in the affected eye(s) twice daily, every 8–12 hours, no more than twice per day. 
 
Children under 3 years of age: Consult a doctor. 
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Clinical Study Report
EyeMax, LLC 
Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
Amendment 2.0/04Apr2018 
 
Confidential 
Page 60 
 
 
  
Other information 
 
Only for use in the eye. 
 
Store between 4°–25°C (39°–77°F). 
  
Inactive ingredients 
benzalkonium chloride 0.01%, glycerol, purified water, sodium hydroxide, and/or hydrochloric acid 
 
 
 
 
 
 
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Clinical Study Report
EyeMax, LLC 
Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
Amendment 2.0/04Apr2018 
 
Confidential 
Page 61 
 
 
APPENDIX 4: HANDLING OF BIOLOGICAL SPECIMENS 
Not Applicable. 
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Clinical Study Report
EyeMax, LLC 
Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
Amendment 2.0/04Apr2018 
 
Confidential 
Page 62 
 
 
APPENDIX 5: PROTOCOL AMENDMENT 2 SUMMARY 
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Clinical Study Report
EyeMax, LLC 
Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
Amendment 2.0/04Apr2018 
 
 
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EyeMax, LLC 
Study # 17-100-0011
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EM-100 Topical Ophthalmic Solution  
EyeMax, LLC  
Clinical Trial Protocol: 17-100-0011 
Amendment 2.0/04Apr2018 
 
Confidential 
Page 65 
 
 
APPENDIX 8: INVESTIGATOR’S SIGNATURE 
 
Protocol Title: 
A Single-Center Evaluation of the Relative Efficacy of EM-100 
Compared to Zaditor® (Ketotifen Fumarate Ophthalmic Solution 
0.035%) and Vehicle in the Treatment of Ocular Itching 
Associated with Allergic Conjunctivitis as Induced by the 
Conjunctival Allergen Challenge Model (Ora-CAC®) 
Protocol Number: 
17-100-0011 
Amendment Date: 
04 April 2018 
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> 
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