Clinical trial NCT03320434
Conditions: Allergic Conjunctivitis
Sponsor: ORA, Inc.
Start date: 2017-10-13; Completion date: 2018-02-18
Enrollment: 120 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy and safety of two concentrations of PRT-2761 as a topical ophthalmic solution for the treatment of the signs and symptoms of acute and chronic allergic conjunctivitis.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: PRT-2761 0.5% intervention 2: PRT-2761 1% intervention 3: Patanol intervention 4: Pred-forte intervention 5: PRT-2761 0%
Intervention descriptions: intervention 1: Six drops in each eye over a 17 day period. intervention 2: Six drops in each eye over a 17 day period. intervention 3: Six drops in each eye over a 17 day period. intervention 4: Four drops in each eye over a 3 day period. intervention 5: Six drops in each eye over a 17 day period.

Protocol documents:
Prot_000.pdf: 
PRT-2761 Ophthalmic Solution 
Ora, Inc. 
Clinical Trial Protocol: 17-100-0008 
Amendment 2.0, 18-Oct-2017 
CONFIDENTIAL 
Page 1 of 80 
1 CLINICAL TRIAL PROTOCOL: 17-100-0008 
Protocol Title: 
A Single-Center, Randomized, Double-Masked, Vehicle 
and Active-Controlled, Dose-Ranging Phase 2 Study 
Evaluating the Efficacy and Safety of PRT-2761 for the 
Treatment of Acute and Chronic Allergic Conjunctivitis 
Using the Conjunctival Allergen Challenge Model (Ora-
CAC®)   
Protocol Number: 
17-100-0008 
Name of Test Drug 
/Investigational Product: 
PRT-2761 Ophthalmic Solution 
IND/IDE/PMA Number: 
130,141 
Indication Studied: 
Acute and chronic allergic conjunctivitis 
Development Phase: 
2 
Brief Description: 
This is a prospective, single-center, randomized, double-
masked, vehicle and active-controlled, dose-ranging 
design study. 
Name of Sponsor: 
Ora, Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico, Suite C, #497 
San Clemente, CA 92673 
949-542-3882 
www.alphairb.com  
 
 Date 
Original Protocol: 
Amendment 1.0 Date: 
29-Aug-2017 
26-Sep-2017 
Amendment 2.0 Date: 
18-Oct-2017 
 
 
Statement of Compliance with Good Clinical Practice 
This study will be performed in compliance with the ethical principles of the Declaration of Helsinki and the International 
Conference on Harmonization (ICH) Harmonized Tripartite Guideline for Good Clinical Practice (GCP). 
Confidentiality Statement 
This protocol is confidential and the information available within it may not be reproduced or otherwise disseminated. 


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Clinical Trial Protocol: 17-100-0008 
Amendment 2.0, 18-Oct-2017 
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ORA PERSONNEL 
Chief Medical Officer: 
David Hollander, M.D., M.B.A. 
Phone: 949-231-0004 
Fax: 978-689-0020 
Department Vice President: 
Paul J. Gomes, MS 
Phone: 978-685-8900 ext. 9429 
Fax: 978-689-0020 
Project Lead: 
Caitlin Pearson, MS 
Phone: 978-685-8900 ext. 9414 
Fax: 978-689-0020 
 
Medical Monitor: 
Joseph Ciolino, M.D. 
Phone: 617-573-5575 
Fax: 617-573-4324 
 
 
 


















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Clinical Trial Protocol: 17-100-0008 
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TABLE OF CONTENTS 
1 CLINICAL TRIAL PROTOCOL: 17-100-0008 .......................................................1 
2 SYNOPSIS ....................................................................................................................3 
TABLE OF CONTENTS ................................................................................................11 
LIST OF ABBREVIATIONS .........................................................................................14 
3 INTRODUCTION......................................................................................................15 
4 STUDY OBJECTIVES ..............................................................................................16 
5 CLINICAL HYPOTHESES .....................................................................................17 
6 OVERALL STUDY DESIGN ...................................................................................17 
7 STUDY POPULATION ............................................................................................17 
 
Number of Subjects (approximate) ..................................................................17 
7.1
 
Study Population Characteristics .....................................................................18 
7.2
 
Inclusion Criteria ...............................................................................................18 
7.3
 
Exclusion Criteria ..............................................................................................19 
7.4
 
Withdrawal Criteria (if applicable) ..................................................................20 
7.5
8 STUDY MEASURES .................................................................................................20 
 
Efficacy Measures ..............................................................................................20 
8.1
 Primary Efficacy Measure(s) ..........................................................................20 
8.1.1
 Secondary Efficacy Measure(s) ......................................................................20 
8.1.2
 Criteria for Effectiveness ................................................................................21 
8.1.3
 
Safety Measures ..................................................................................................21 
8.2
 
Tolerability Measures ........................................................................................22 
8.3
 
Exploratory Measures........................................................................................22 
8.4
9 STUDY MATERIALS ...............................................................................................23 
 
Study Treatment(s) ............................................................................................23 
9.1
 Study Treatment(s)/ Formulation(s)/ Medical Device Composition or 
9.1.1
Design .............................................................................................................23 
 Instructions for Use and Administration ........................................................23 
9.1.2
 
Other Study Supplies .........................................................................................24 
9.2
10 STUDY METHODS AND PROCEDURES ............................................................24 
 Subject Entry Procedures ..................................................................................24 
10.1
 Overview ........................................................................................................24 
10.1.1
 Informed Consent ...........................................................................................24 
10.1.2
 Washout Intervals ...........................................................................................25 
10.1.3
 Procedures for Final Study Entry ...................................................................25 
10.1.4
 Methods for Assignment to Treatment Groups: .............................................25 
10.1.5
 Concurrent Therapies ........................................................................................27 
10.2
 Prohibited Medications/Treatments ...............................................................27 
10.2.1
 Escape Medications ........................................................................................27 
10.2.2
 Special Diet or Activities ...............................................................................27 
10.2.3
 Examination Procedures....................................................................................28 
10.3
 Procedures to be Performed at Each Study Visit with Regard to Study 
10.3.1
Objective(s) ....................................................................................................28 
 Schedule of Visits, Measurements and Dosing ................................................38 
10.4
 Scheduled Visits .............................................................................................38 
10.4.1


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 Unscheduled Visits .........................................................................................39 
10.4.2
 Compliance with Protocol .................................................................................39 
10.5
 Subject Disposition .............................................................................................39 
10.6
 Completed Subjects ........................................................................................39 
10.6.1
 Discontinued Subjects ....................................................................................39 
10.6.2
 Study Termination .............................................................................................40 
10.7
 Study Duration ...................................................................................................40 
10.8
 Monitoring and Quality Assurance ..................................................................40 
10.9
11 ADVERSE EVENTS .................................................................................................40 
 Severity ................................................................................................................41 
11.1
 Relationship to Investigational Product ...........................................................41 
11.2
 Expectedness .......................................................................................................42 
11.3
 Serious Adverse Events ......................................................................................43 
11.4
 Procedures for Reporting Adverse Events.......................................................44 
11.5
 Reporting a Suspected Unexpected Adverse Reaction ..................................44 
11.5.1
 Reporting a Serious Adverse Event ................................................................44 
11.5.2
 Procedures for Unmasking (if applicable) .......................................................44 
11.6
 Type and Duration of the Follow-up of Subjects after Adverse Events ........45 
11.7
12 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES...................45 
 Intent-to-Treat Population ................................................................................45 
12.1
 Per Protocol Population .....................................................................................45 
12.2
 Safety Population................................................................................................46 
12.3
 General Imputation Methods ............................................................................46 
12.4
 Primary Efficacy Endpoints ..............................................................................46 
12.5
 Criteria for Efficacy ...........................................................................................46 
12.6
 Secondary Efficacy Endpoints ..........................................................................47 
12.7
 Statistical Hypotheses ........................................................................................47 
12.8
 Sample Size .........................................................................................................48 
12.9
 Demographic and Baseline Medical History ...................................................48 
12.10
 Primary Efficacy Analyses ................................................................................48 
12.11
 Secondary Efficacy Analysis .............................................................................49 
12.12
 Adjustment for Multiplicity ..............................................................................49 
12.13
 Safety Analysis ....................................................................................................50 
12.14
 Tolerability Measures ........................................................................................50 
12.15
 Subgroup Analysis .............................................................................................50 
12.16
 Interim Analysis .................................................................................................50 
12.17
13 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ...................................50 
 Protection of Human Subjects ..........................................................................51 
13.1
 Subject Informed Consent ..............................................................................51 
13.1.1
 Institutional Review Board (IRB) Approval ..................................................51 
13.1.2
 Ethical Conduct of the Study ............................................................................51 
13.2
 Subject Confidentiality ......................................................................................51 
13.3
 Documentation ....................................................................................................52 
13.4
 Retention of Documentation ..........................................................................52 
13.4.1
 Photography and Videos ................................................................................52 
13.4.2


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 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
13.5
Investigational Product ......................................................................................52 
 Labeling/Packaging ........................................................................................52 
13.5.1
 Storage of Investigational Product .................................................................53 
13.5.2
 Accountability of Investigational Product ......................................................53 
13.5.3
 Return or Disposal of Investigational Product ...............................................53 
13.5.4
 Recording of Data on Source Documents and Case Reports Forms (CRFs) 53 
13.6
 Handling of Biological Specimens .....................................................................53 
13.7
 Publications .........................................................................................................53 
13.8
14 REFERENCES ...........................................................................................................55 
Appendix 1:  Schedule of Visits and Measurements .....................................................56 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ..............58 
Appendix 3: Investigational Product composition /design ...........................................70 
Appendix 4:  Handling of Biological Specimens ...........................................................71 
Appendix 5:  Protocol Amendment 2 Summary ...........................................................72 
Appendix 6:  ORA APPROVALS ..................................................................................79 
Appendix 7:  INVESTIGATOR’S SIGNATURE .........................................................80 
 
 
 
 
 
 
 
 
 
 
 


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Clinical Trial Protocol: 17-100-0008 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
CRF 
Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
IOP 
Intraocular Pressure 
ICH 
International Conference on Harmonization 
IP 
Investigational Product 
IRB 
Institutional/Independent Review Board 
ITT 
Intent To Treat 
logMAR 
Logarithm of the Minimum Angle of Resolution 
mmHg 
Millimeters of Mercury 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
PV 
Placebo Vehicle 
Ora-CAC® 
Ora Conjunctival Allergen Challenge (CAC) 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent adverse event 
VA 
Visual Acuity 
 
 


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3 INTRODUCTION 
Most approved treatments for ocular allergy are antihistamines, mast cell stabilizers, or 
both, and these drugs act primarily to reduce the signs and symptoms of the early phase 
allergic reaction.  There is, however, evidence that suggests that many ocular allergy 
patients exhibit a persistent late phase reaction.  The contribution of this underlying late-
phase inflammatory response to the clinical signs and symptoms of chronic and/or severe 
ocular allergy requires that an anti-allergy product must be effective not only in the 
treatment of the acute allergic reaction, but also of the more complex chronic 
inflammatory environment that results from overlapping and continual allergen exposure.  
The conjunctival allergen challenge (CAC)-induced allergic response mimics the acute 
response that is triggered by intermittent exposure to allergen.  The Ora-CAC® model has 
been used to evaluate anti-allergic agents and to identify the cellular and mediator 
responses seen in allergic conjunctivitis.4   
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.5  Following antigen exposure, 
conjunctival mast cells degranulate and release newly formed and pre-existing 
inflammatory mediators.6  Histamine is the primary preformed mediator responsible for 
the typical early phase reaction that triggers itching, vasodilation and vascular leak 
leading to ocular redness, chemosis, and blepharitis.  The early phase response occurs 
within minutes to hours following allergen exposure.  Mast cells also synthesize and 
release cytokines, chemokines, and growth factors that initiate a cascade of inflammatory 
events leading to a late phase reaction characterized by recruitment of eosinophils, 
neutrophils, and subsequent lymphocytes and macrophages into the conjunctival 
tissues.7,8 
                                                 
4 Abelson, M. B., W. A. Chambers and L. M. Smith (1990). Conjunctival allergen 
challenge. A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol 
108(1): 84-88. 
5 Abelson, M. B., L. Smith and M. Chapin (2003). Ocular Allergic Disease: Mechanisms, 
Disease Sub-types, Treatment. The Ocular Surface 1(3): 38-60 
6 Ono, S. J. and M. B. Abelson (2005). Allergic conjunctivitis: update on pathophysiology 
and  prospects for future treatment. J Allergy Clin Immunol 115(1): 118-122 
7 Bacon, A. S., P. Ahluwalia, A. M. Irani, L. B. Schwartz, S. T. Holgate, M. K. Church 
and J. I. McGill (2000). Tear and conjunctival changes during the allergen-induced early- 
and late-phase responses. J Allergy Clin Immunol 106(5): 948-954. 


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Clinical Trial Protocol: 17-100-0008 
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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.  
Following the CAC, the principal sign and symptom of acute allergic reaction, ocular 
itching and conjunctival redness, are typically monitored over time periods of 3-10 
minutes and 7-20 minutes, respectively. 
Modifying the conventional CAC model is useful for assessment of drug efficacy against 
more chronic states of inflammation than that observed after only one allergen challenge. 
The present protocol involves two parts: in the first part, the conventional method will be 
used in that duration and onset of action of PRT-2761 will be assessed after only one 
challenge. Subsequent to Visit 4a, four additional challenges will be conducted in 
subjects to mimic the chronic phase of ocular allergy. Subjects will enter a state of 
incrementally increasing allergic chronicity, and will be dosed prior to each of these 
challenges to assess drug onset of efficacy.  This repeat-CAC model provides the 
opportunity to investigate the effects of the underlying inflammatory reaction on the 
ability of the tissues to mount a robust acute response to a subsequent allergen challenge.  
The repeat-CAC model also provides a means to investigate the mechanism(s) of action 
of anti-inflammatory agents in the treatment of both acute and chronic allergic reactions.   
The Ora-CAC® model has been clinically validated and has been recognized by the US 
Food and Drug Administration (FDA) as a reliable method for evaluating novel 
ophthalmic pharmaceutical drugs.9,10  Since changes in the signs and symptoms of ocular 
allergy are captured on standardized severity scales, the CAC model allows for precise 
comparisons of the effects of ocular allergy drugs among study subjects with a high level 
of internal control, sensitivity, and reproducibility. 
4 STUDY OBJECTIVES 
To evaluate the efficacy and safety of two concentrations of PRT-2761 as a topical 
ophthalmic solution for the treatment of the signs and symptoms of acute and chronic 
allergic conjunctivitis.  
                                                                                                                                                 
8 Ciprandi, G., S. Buscaglia, G. P. Pesce, M. Bagnasco and G. W. Canonica (1993). 
Ocular challenge and hyperresponsiveness to histamine in patients with allergic 
conjunctivitis. J Allergy Clin Immunol 91(6): 1227-1230. 
9 Abelson, M. B., W. A. Chambers and L. M. Smith (1990). Conjunctival allergen 
challenge. A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol 
108(1): 84-88. 
10 Abelson, M. B. and O. Loeffler (2003a). Conjunctival allergen challenge: models in the 
investigation of ocular allergy. Curr Allergy Asthma Rep 3(4): 363-368. 


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5 CLINICAL HYPOTHESES 
It is hypothesized that at least one concentration of PRT-2761 will be as safe as and more 
effective than vehicle treatment in the prevention of ocular itching and conjunctival 
redness associated with acute and/or chronic allergic conjunctivitis. 
6 OVERALL STUDY DESIGN 
This is a prospective, single-center, randomized, double-masked, vehicle and active-
controlled, dose-ranging study to evaluate the efficacy and safety of PRT-2761 in two 
concentrations compared to Placebo Vehicle (PV), Patanol® and Patanol®/Pred forte® 
for the treatment of the signs and symptoms of chronic allergic conjunctivitis.   
The trial will comprise of 10 office visits over a period of up to 9 weeks. Part 1 will be a 
conventional CAC protocol. Subjects who meet the entry criteria for itching and redness 
response to the CAC at Visits 2 and 3 will be randomized at Visit 4a (Day 1, Duration of 
Action Visit) in a 1:1:1:1 (PRT-2761 0.5%: PRT-2761 1%: PV:Patanol®) assignment 
ratio in the acute phase. Subjects randomized to the Patanol® treatment for the acute 
phase will further be randomized using a 1:1 (Patanol®: Pred forte®) assignment ratio 
for the chronic phase.  After 8 hours, subjects will return for Visit 4b to be challenged 
with signs and symptoms assessed post-CAC. Subjects will return 14 days later for Visit 
5a (Day 15, Onset of Action Visit), at which time they will be challenged 15 minutes 
after dosing with the same concentration of PRT-2761, PV, or Patanol® as randomized at 
Visit 4a.  This will conclude Part 1 of the study.  
Part 2 will be the assessment of chronic allergy and subjects will be challenged 15 
minutes after dosing. If subjects were randomized to receive PRT-2761 0.5%, PRT-2761 
1%, or PV at Visit 4a, subjects will continue to receive the same treatment at (Visits 5b, 
6a, 6b and 7 at 8, 24, 32 and 48 hours from Visit 5a, respectively). Subjects who were 
randomized to receive Patanol® at Visit 4a will be further randomized into 2 groups. One 
group will continue to receive Patanol® through Visit 7.  The other group will be dosed 
with Pred forte® at Visits 5b through 7. At Visit 7, final exit procedures will also be 
conducted and subjects will exit the study.  
7 STUDY POPULATION 
 
NUMBER OF SUBJECTS (APPROXIMATE) 
7.1
Approximately 240 subjects will be screened to enroll 120 subjects and complete 
approximately 112 subjects.  
Randomization will be stratified by average post-CAC itching scores
 at 
baseline (Visit 3), by qualifying allergen type 
 and by confocal 
participation (yes and no).  


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STUDY POPULATION CHARACTERISTICS 
7.2
Subjects of at least 18 years of age of either sex and any race, who meet all of the 
inclusion criteria and none of the exclusion criteria. 
 
Inclusion Criteria 
7.3
Subjects must: 
1. be at least 18 years of age of either sex 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. (for females capable of becoming pregnant) agree to have urine pregnancy testing 
performed at screening (must be negative) and at exit visit11; must not be lactating; 
and must agree to use a medically acceptable form of birth control12 throughout the 
study duration and for at least 14 days prior to initiation of the investigational 
product (IP) treatment (Visit 4a) and for one month after cessation of IP treatment. 
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); 
5. have a positive history of allergic conjunctivitis and a positive skin test reaction to 
a 
 
allergen 
. Testing will be 
provided at Visit 1 if the subject has never been tested o
 
 
6. have a calculated visual acuity of 0.7 logMAR or better in each eye as measured 
using an ETDRS chart;   
7. have a positive bilateral CAC reaction13 to allergen within 10 (±2) minutes of 
instillation of the last titration of allergen at Visit 2;  
8. have a positive bilateral CAC reaction15 to allergen for at least two out of the three 
time points following challenge at Visit 3;  
9. be able and willing to avoid all disallowed medication for the appropriate washout 
period and during the study (see exclusion 6); 
10. be able and willing to discontinue wearing contact lenses for at least 72 hours prior 
to Visit 2 and during the study trial period. 
                                                 
11  The subject must choose an acceptable method of birth control as specified in inclusion criterion d) in order to 
continue in the study.  
12 Acceptable forms of birth control are spermicide with barrier, oral contraceptive, injectable or implantable method of 
contraception, transdermal contraceptive, intrauterine device, or surgical sterilization of partner.  For non-sexually 
active females, abstinence will be considered an acceptable form of birth control.  
13
.  


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EXCLUSION CRITERIA 
7.4
Subjects may not: 
1. have known contraindications or sensitivities to the use of any of the IP treatment 
or components;  
2. have any ocular condition in either eye 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, trichiasis, follicular 
conjunctivitis, iritis, pterygium or a diagnosis of dry eye); 
3. have had ocular surgical intervention in either eye within three (3) months prior to 
Visit 1 or during the study and/or a history of refractive surgery within the past 6 
months; 
4. have a known history of retinal detachment, diabetic retinopathy, or active retinal 
disease in either eye; 
5. have the presence of an active ocular infection in either eye (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 2 and during the study. Washout periods prior to Visit 2 are as 
follows: 
7 Days: 
 systemic or ocular H1 antihistamine, H1 antihistamine/mast-cell stabilizer drug 
combinations, H1 antihistamine- vasoconstrictor drug combinations; 
 decongestants; 
 monoamine oxidase inhibitors; 
 all other topical ophthalmic preparations (including artificial tears); 
 lid scrubs; 
 prostaglandins or prostaglandin derivatives; 
 ocular, topical, or systemic nonsteroidal anti-inflammatory drugs (NSAIDs); 
14 Days: 
 inhaled, ocular or topical corticosteroids or mast cell stabilizers;  
45 Days: 
 depot-corticosteroids; 
2 Months: 
 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 at the end of Visit 2, Visit 3, Visit 4b, or Visit 7, after 
all evaluations are completed;  
7. have any significant illness [e.g., an autoimmune disease, severe cardiovascular 
disease (including arrhythmias)] the Investigator feels could expect to interfere 
with the subject’s safety or study parameters and/or put the subject at any 
unnecessary risk.  This includes but is not limited to: alcohol or drug abuse, 


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poorly controlled hypertension or poorly controlled diabetes, a history of status 
asthmaticus, 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. 
 
  
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 IP trial; 
11. be a female who is currently pregnant, planning a pregnancy, lactating, not using 
a medically acceptable form of birth control throughout the study duration and for 
at least 14 days prior to initiation of IP treatment and for one month after 
cessation of treatment, or has a positive urine pregnancy test at Visit 2; 
12. have a history of ocular hypertension (OHT), glaucoma, or an intraocular pressure 
(IOP) that is less than 8 millimeters Mercury (mmHg) or greater than 22 mmHg in 
either eye at Visit 2. 
 
WITHDRAWAL CRITERIA (IF APPLICABLE) 
7.5
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. 
Sponsor and/or Investigator may discontinue any patient for non-compliance or any valid 
medical reason (see Section 10.6.2). 
8 STUDY MEASURES 
 
EFFICACY MEASURES  
8.1
 Primary Efficacy Measure(s) 
8.1.1
 Ocular itching evaluated by the subject at Visits 4b and 5a (for Duration and Onset of 
action, respectively) at 5(±1), 7(±1), and 10(±1) minutes post-CAC  (0-4 scale, 
allowing half-unit increments)  
 Conjunctival redness evaluated by the Investigator at Visits 4b and 5a (for Duration 
and Onset of action, respectively) at 7(±1), 15(±1), and 20(±1) minutes post-CAC (0-
4 scale, allowing half-unit increments) 
 Secondary Efficacy Measure(s) 
8.1.2
 Ocular itching evaluated by the subject at Visits 5b, 6a, 6b, and 7 at 5(±1), 7(±1), and 
10(±1) minutes post-CAC (0-4 scale, allowing half-unit increments) 




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The eyelids, conjunctiva, cornea, lens, and anterior chamber will be examined as part 
of the Slit Lamp Biomicroscopy exam. 
 Dilated Ophthalmoscopy 
Dilated ophthalmoscopy will be performed by the Investigator to evaluate the 
presence or absence of clinically significant fundus abnormalities and vitreous 
pathology. 
 Distance VA using an ETDRS chart 
A worsening of acuity of greater than 10 letters from Visit 2 will be considered an 
adverse event (AE) 
 IOP 
 AEs (reported, elicited, and observed) 
 
TOLERABILITY MEASURES 
8.3
 Drop comfort assessment (0-10 unit scale) assessed by subject immediately upon 
instillation, at 30 seconds, and 1 minute post-instillation at Visit 4a 
 Drop comfort descriptor questionnaire at 3 minutes post-instillation at Visit 4a 
 
EXPLORATORY MEASURES 
8.4
 Ocular itching evaluated by the subject at Visit 5b, 6a, 6b, and 7 at 15(±1), 20(±1), 
25(±1) and 30(±1) minutes post-CAC (0-4 scale, allowing half-unit increments). 
 Tearing evaluated by the subject at Visits 5b, 6a, 6b, and 7 at 25(±1) and 30(±1) 
minutes post-CAC (0-4 scale, NOT allowing half-unit increments) 
 Eyelid swelling evaluated by the subject at Visits 5b, 6a, 6b, and 7 at 25(±1) and 
30(±1) minutes post-CAC (0-3 scale, NOT allowing half-unit increments) 
 Rhinorrhea, nasal pruritis, ear or palate pruritis, and nasal congestion evaluated by the 
subject at Visits 5b, 6a, 6b, and 7 at 25(±1) and 30(±1) minutes post-CAC (0-4 scale, 
NOT allowing half-unit increments) 
 Conjunctival, episcleral, and ciliary redness evaluated by the investigator at Visit 5b, 
6a, 6b, and 7 at 25(±1) and 30(±1) minutes post-CAC (0-4 scale, allowing half-unit 
increments). 
 Chemosis evaluated by the investigator at Visit 5b, 6a, 6b, and 7 at 25(±1) and 30(±1) 
minutes post-CAC (0-4 scale, allowing half-unit increments). 
 In a subset of approximately 36 subjects who agree to undergo confocal microscopy, 
Conjunctival Inflammation as measured by confocal microscopy (0-4 scale, NOT 
allowing half-unit increments) at Visits 3, 4b, and 7. This number is estimated to be 
sufficient to ensure approximately 30 subjects in the confocal microscopy subset 
complete the trial. 


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 In this same subset of subjects who undergo confocal microscopy, tears will be 
collected from both eyes (prior to confocal microscopy) at Visit 3, 4a, 4b and 7. At 
Visit 3, tears will be collected both pre- and post-CAC. At Visit 4a tears will be 
collected prior to dosing. Tears will be analyzed for cytokine levels. 
 Diary assessments for subset of subjects undergoing confocal microscopy at Visits 3 
and 4b. Additionally, all subjects will be dispensed diaries at Visits 5b and 6b. 
Assessments of ocular itching, ocular redness, and eyelid swelling will occur prior to 
bedtime and upon awakening (all use a 0 to 4 scale, except eyelid swelling, 0 to 3).  
 Digital photographs will be taken at-home of each eye (for subset of subjects 
undergoing confocal microscopy) prior to subjects completing diary assessments 
following Visits 5b and 6b. 
 Digital photographs will be taken in-office of all subjects pre-CAC and within 30 
minutes of the last post-CAC assessment at Visit 4b and Visit 5a 
9 STUDY MATERIALS 
 
STUDY TREATMENT(S) 
9.1
 Study Treatment(s)/ Formulation(s)/ Medical Device Composition or Design 
9.1.1
PRT-2761 will be assessed in two concentrations as an ophthalmic solution: 
 Concentration 1: PRT-2761 0.5%, n = 30 
 Concentration 2: PRT-2761 1%, n = 30 
The following will be the Reference Therapy:  
 PV (vehicle), n = 30 
 Patanol® (active), n = 15 
 Patanol® during acute phase/Pred forte® during chronic phase (active), n = 15 
 Instructions for Use and Administration 
9.1.2
 At Visit 4a, a trained study technician will instill 1 drop of assigned 
investigational product into each eye.  
 At Visit 5a, a trained study technician will instill the assigned investigational 
product in each eye and subjects will return 8 hours later for a second in-office 
dose that same day at Visit 5b. 
 At Visit 6a, a trained study technician will instill the assigned investigational 
product in each eye approximately 24 hours from in-office dose at Visit 5a and 
subjects will return 8 hours later for a second in-office dose that same day at Visit 
6b. 
 At Visit 7, a trained study technician will instill the assigned investigational 
product in each eye 15 minutes prior to CAC.  
The trained study technician instilling the investigational product will be considered 
unmasked since all bottles are not identical in appearance. This technician will not be 


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involved in any other procedures for this trial. During dosing, subjects will be called 
into a room out of view from other subjects and staff. Subjects will be instructed to 
look at the ceiling during instillation. The technician will instill the study medication 
in a manner which will minimize the chance of the subject seeing the bottle. All 
bottles will be kept out of direct view of the subjects. 
 
OTHER STUDY SUPPLIES 
9.2
Clarity HCG (RAC Medical Boca Raton, FL) will be used for pregnancy tests. Ora, Inc. 
will supply these pregnancy kits. 
 
 
 
The ocular anesthetic agent (Fluress) and dilating drops used for the IOP and dilated 
ophthalmoscopy respectively will be supplied by Ora, Inc. 
The ocular anesthetic agent (proparacaine hydrochloride ophthalmic solution) used for 
the confocal microscopy will be supplied by Ora, Inc. 
10 STUDY METHODS AND PROCEDURES 
 SUBJECT ENTRY PROCEDURES 
10.1
 Overview 
10.1.1
Subjects as defined by the criteria in Section 7.3 and 7.4 will be considered for entry into 
this study. 
 Informed Consent 
10.1.2
Prior to a subject’s participation in the trial (ie, 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, 3, 4a, 4b, 5a, 5b, 6a, 6b, and 7. 
Prior to the completion of Visit 1 (Screening), 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.   


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 Washout Intervals 
10.1.3
Subjects will adhere to the following medication washout intervals during the period 
indicated prior to Visit 2 and will refrain from using these medications 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 NSAIDs; 
14 Days 
 inhaled, ocular or topical corticosteroids or mast cell stabilizers;  
45 Days 
 depot-corticosteroids; 
2 Months 
 immunosuppressive or cancer chemotherapeutic agents. 
 Procedures for Final Study Entry 
10.1.4
Subjects must meet all of the inclusion criteria and none of the exclusion criteria prior to 
Visit 4a to be enrolled in the study. 
 Methods for Assignment to Treatment Groups: 
10.1.5
All subjects screened for the study who sign an ICF will be assigned a 3-digit screening 
number that will be entered in the Screening and Enrollment Log. Screening numbers 
will be assigned in sequential order beginning with 001. Randomization will be used to 
avoid bias in the assignment of subjects to treatment and time point, to increase the 
likelihood that known and unknown subject attributes (e.g., demographics and baseline 
characteristics) are evenly balanced across treatment groups and across time points, and 
to enhance the validity of statistical comparisons.  
Once a subject meets all qualification criteria at Visit 4a, they will be enrolled and 
randomly assigned to masked treatment using a 1:1:1:1 (PRT-2761 0.5%: PRT-2761 
1%:PV:Patanol®) assignment ratio for the acute phase. Subjects randomized to the 
Patanol® treatment in the acute phase will further be randomized using a 1:1 


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(Patanol®:Pred forte®) assignment ratio for the chronic phase. Subjects will be 
randomized at Visit 4a (Day 1) by assignment of the lowest 4-digit randomization 
number available within the appropriate stratum. Randomization will be stratified by 
average post-CAC itching scores 
 at baseline (Visit 3), by qualifying 
allergen type (seasonal and perennial) and by confocal participation (yes and no) to 
ensure balance for the primary endpoint of ocular itching.  The randomization numbers 
will start from x001, where x refers to the subject’s stratum as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
The first 36 subjects who qualify after post-CAC assessments at Visit 3 and had tear 
collection at Visit 2, will be in the confocal microscopy subset. This number is estimated 
to ensure approximately 30 subjects in the confocal microscopy subset complete the trial. 
At Visit 4, these individuals will be assigned to a kit number from Stratum 5, 6, 7, or 8.  
Once 36 subjects have completed confocal microscopy at Visit 3, any subjects who had 
tear collection at Visit 2, will not have additional tear collections or confocal microscopy. 
At Visit 4, these individuals will be assigned to a kit number from Stratum 1, 2, 3, or 4. 
No randomization numbers will be skipped or omitted.  
At Visit 4a, if a subject requires a kit from their assigned stratum, based on the above 
criteria, and there are no longer any kits available for that stratum, the subject will be not 
be randomized and will be deemed a screen failure. 


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 CONCURRENT THERAPIES 
10.2
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. 
 Prohibited Medications/Treatments 
10.2.1
Refer to Section 10 for a complete list of washout periods for the following prohibited 
medications and 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 NSAIDs; 
 inhaled, ocular or topical corticosteroids or mast cell stabilizers;  
 depot-corticosteroids; 
 immunosuppressive or cancer chemotherapeutic agents. 
If a subject uses a disallowed medication, this will be recorded as a protocol violation. 
Protocol violations must be reported to the IRB in accordance with their standard 
operating procedures. 
 Escape Medications 
10.2.2
Cold compresses should first be used in the management of allergic symptoms. Subjects 
may be prescribed anti-inflammatory or anti-allergy medication at the Investigator’s 
discretion. Subjects will be discontinued if prescribed such anti-inflammatory or anti-
allergy medication.  
Currently marketed over-the-counter anti-allergy eye drops (i.e., anti-histamine/ 
vasoconstrictor combination products such as Visine®-A®) may be administered to 
subjects at the end of Visit 2, Visit 3, Visit 4b, or Visit 7, after all evaluations are 
completed. 
 Special Diet or Activities 
10.2.3
Not Applicable. 


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 EXAMINATION PROCEDURES 
10.3
The following procedures will be conducted at one or more visits, as listed below.  
 Procedures to be Performed at Each Study Visit with Regard to Study 
10.3.1
Objective(s) 
10.3.1.1 VISIT 1 (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 Visit 1 (Screening), 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: A diagnostic test for allergic disease (skin test) will be performed 
for subjects without documentation of a positive test within the past 24 months. 
 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 thirty 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 screening.  
 Review of Inclusion/Exclusion Criteria: Confirm if subject needs to washout from 
any current medications and instruct he/she to follow the appropriate washout time 
periods (refer to Section 10.1.3).  
 Adverse Event Query: Adverse Events/Adverse Device Effects (both elicited and 
observed; expected and unexpected; suspected relationship to the treatment, suspected 
unrelated, and not related) will be monitored throughout the study.  All adverse 
events (both elicited and observed) will be promptly reviewed by the Investigator for 
accuracy and completeness.   
 Scheduling of Next Visit (Visit 2) 
10.3.1.2 VISIT 2 (Day -21±3): Titration CAC 
 Update of Medical/Medication History 
 Adverse Event Query 
 Urine Pregnancy Test (for females of childbearing potential): Women of childbearing 
potential must have a negative urine pregnancy test to continue in the study and must 


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agree to use an adequate method of contraception for the duration of the study in 
order to be enrolled. 
 Visual Acuity Utilizing an ETDRS Chart: Subjects must have a score of 0.7 logMAR 
or better in each eye in order to qualify.  
 Initial Ocular and Nasal Allergic Signs and Symptoms Assessment: 
 
 
 
 
 
 
 Slit Lamp Biomicroscopy: A slit-lamp examination will be performed in both eyes to 
exclude subjects with disallowed ocular conditions. Findings of abnormality which 
are not exclusionary should be recorded as Medical History.  
 Tear Collection: Tears will be collected from up to 60 subjects to ensure there are 
enough potential subjects at Visit 3 for the confocal microscopy subset. If 5µl of tears 
is not collected at Visit 2, the subject will not have any additional tears collected for 
this trial and will not be a member of the confocal subset. The technician collecting 
tears will note the subject’s reflex tearing, if applicable (see Appendix 2). There will 
be at least a 30 minute wait period between Tear Collection and the Titration CAC.  
 
 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
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Upon 
completion of the initial titration CAC, subjects will receive an ocular examination by 
the Investigator to evaluate all Investigator-evaluated efficacy measures and confirm 


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the subject’s qualification. Subjects will be asked to assess their ocular and nasal 
symptoms. 
 IOP Measurement: Intraocular Pressure (IOP) will be measured in each eye by 
contact tonometry, for qualified subjects. 
 Dilated Ophthalmoscopy: A dilated ophthalmoscopy will be performed by the 
Investigator to evaluate the presence or absence of clinically significant fundus 
abnormalities and vitreous pathology, for qualified subjects. 
 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  
 Scheduling of Next Visit (Visit 3) 
10.3.1.3 VISIT 3 (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 (defined as an increase of 0.22 or greater in logMAR score) from Visit 2 will 
be considered an adverse event. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: 
 
 
 
 
 
   
 Slit Lamp Biomicroscopy  
 Digital Imaging: Digital photographs may be taken of each eye. 
 Review of Inclusion/Exclusion Criteria  
 Confirmation CAC: 
 
 
  
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment 
of itching will be made by the subject at 5(±1), 7 (±1), and 10(±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, 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 


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to react positively 
 
in both eyes in at least two (2) out of the first three (3) time points14, he/she will 
be excluded from the study.  
Digital Imaging: Digital photographs may be taken of each eye within 30 minutes of 
the last post-CAC assessment. 
 Tear Collection: Tears will be collected from the subset of subjects (approximately 
36) that agree to receive confocal microscopy. 5µL of tears will be collected from 
each eye prior to confocal microscopy procedures. If 5µl of tears is not collected at 
Visit 3 post-CAC, the subject will remain in the confocal microscopy subset but no 
further tear collections will be performed. The technician collecting tears will note the 
subject’s reflex tearing, if applicable (see Appendix 2). 
 Confocal Microscopy: The first 36 subjects who qualify after post-CAC assessments, 
and had tears successfully collected at Visit 2, will be in the confocal subset to ensure 
that approximately 30 subjects complete the trial. Confocal microscopy of the left eye 
will be performed following tear collection. 
 Diary Dispensation: The subset of subjects undergoing tear collection and confocal 
microscopy will be dispensed a diary to complete daily assessments prior to bedtime 
on the evening of Visit 3 and upon awakening the next morning. Subjects will be 
given a mailing label and instructed to mail the diary back to the site following their 
morning assessments.  
 Tear Collection: Tears (5µL from each eye) will be collected from the confocal 
subset at 2 (+1) hours after instillation of the anesthetic used for confocal microscopy 
procedures. If 5µl of tears from each eye is not collected, the subject will remain in 
the confocal microscopy subset but no further tear collections will be performed. The 
technician collecting tears will note the subject’s reflex tearing, if applicable (see 
Appendix 2).  
 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 4a): Subjects will be asked to return to the office 7 days later for Visit 
4a, the Duration of Action Visit.  
                                                 
14 Not necessarily at the same time point  


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10.3.1.4 VISIT 4a (Day 1): 1st Dose, Enrollment / Randomization to PRT-2761, PV 
or Patanol® & in-office instillation 
 Update of Medical/Medication History 
 Adverse Event Query  
 Assessments Diary Review and Collection: Diary will be collected (if not mailed in) 
and reviewed. 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease (defined as an increase of 0.22 or greater in logMAR score) from Visit 2 will 
be considered an adverse event. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: 
 
 
 
 
 
      
 Slit Lamp Biomicroscopy  
 Review Inclusion and 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 randomly assigned to 
masked treatment using a 1:1:1:1 (PRT-2761 0.5%: PRT-2761 1%: PV: Patanol®) 
assignment ratio for the acute phase. Subjects randomized to the Patanol® treatment 
in the acute phase will further be randomized using a 1:1 (Patanol®: Pred forte®) 
assignment ratio for the chronic phase. Subjects will be randomized by assignment of 
the lowest randomization number available within the appropriate stratum. 
Randomization will be stratified by average post-CAC itching scores 
 
at baseline (Visit 3), by qualifying allergen type (seasonal and perennial), and by 
confocal participation (yes and no) to ensure balance for the primary endpoint of 
ocular itching.  No numbers will be skipped or omitted. If a subject requires a kit 
from their assigned stratum, based on the above criteria, and there are no longer any 
kits available for that stratum, the subject will be not be randomized and will be 
deemed a screen failure.  
 Investigational Product Instillation: A
 
 
  
 Drop Comfort Assessment: Drop comfort will be assessed immediately upon 
instillation, at 30 seconds, and 1 minute post-instillation (0 – 10 scale). 
 Drop Comfort Descriptor Questionnaire: The subject will select 3 descriptor terms 
for drop comfort at 3 minutes post-instillation. 
 Adverse Event Query  


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 Scheduling of Next Visit (Visit 4b): Subjects will be asked to return to the office 7.5 
hours later for Visit 4b, the Duration of Action CAC Visit.  
10.3.1.5 VISIT 4b (8 [+1] Hours Post-Dose): Duration of Action, CAC #1 
 Update of Medical/Medication History 
 Adverse Event Query 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease (defined as an increase of 0.22 or greater in logMAR score) from Visit 2 will 
be considered an adverse event. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: 
 
 
 
    
 Slit Lamp Biomicroscopy  
 Digital Imaging: Digital photographs may be taken of each eye. 
 Conjunctival Allergen Challenge (CAC): 
 
 
  
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment 
of itching will be made by the subject at 5(±1), 7(±1), and 10(±1) minutes following 
allergen challenge. Assessments of redness and chemosis will be graded by the 
Investigator and assessments of eyelid swelling, tearing/watery eyes, and nasal 
symptoms will be made by the subject at 7(±1), 15(±1) and 20(±1) minutes post-
challenge (Appendix 2).  
 Digital Imaging: Digital photographs may be taken of each eye within 30 minutes of 
the last post-CAC assessment. 
 Tear Collection: Tears will be collected from the subset of subjects (up to 36) that 
agree to receive confocal microscopy. 5µL of tears will be collected from each eye 
prior to confocal microscopy procedures. If 5µl of tears is not collected at Visit 4b 
post-CAC, the subject will remain in the confocal microscopy subset but no further 
tear collections will be performed.  The technician collecting tears will note the 
subject’s reflex tearing, if applicable (see Appendix 2). 
 Confocal Microscopy: Following digital photographs, the same subset of subjects that 
underwent confocal at Visit 3 will undergo confocal microscopy of the left eye.   
 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 


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 Scheduling for Next Visit (Visit 5a): Subjects will be asked to return to the office 14 
days later for Visit 5a, the Onset of Action CAC Visit.  
10.3.1.6 VISIT 5a (Day 15±3): Onset of Action Visit, 2nd Dose/CAC #2 
 Update of Medical/Medication History 
 Adverse Event Query 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease (defined as an increase of 0.22 or greater in logMAR score) from Visit 2 will 
be considered an adverse event. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment  
 Slit Lamp Biomicroscopy 
 Digital Imaging: Digital photographs may be taken of each eye.  
 Investigational Product Instillation: A
 
 
. 
 Conjunctival Allergen Challenge (CAC): 
 
 
.  
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment 
of itching will be made by the subject at 5(±1), 7(±1), and 10(±1) minutes following 
allergen challenge. Assessments of redness and chemosis will be graded by the 
Investigator and assessments of eyelid swelling, tearing/watery eyes, and nasal 
symptoms will be made by the subject at 7(±1), 15(±1) and 20(±1) minutes post-
challenge (Appendix 2).  
 Digital Imaging: Digital photographs may be taken of each eye within 30 minutes of 
the last post-CAC assessment.  
 Adverse Event Query 
 Scheduling for Next Visit, 8 hours later (Visit 5b): Subjects will be asked to return to 
the office 7.5 hours later for Visit 5b, start of Part 2, Chronic Ocular Allergy Visits.  
10.3.1.7 VISIT 5b (8 [+1] Hours Post-Dose at Visit 5a) 3rd Dose/CAC #3 
 Update of Medical/Medication History 
 Adverse Event Query 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease (defined as an increase of 0.22 or greater in logMAR score) from Visit 2 will 
be considered an adverse event. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment  


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 Slit Lamp Biomicroscopy 
 Investigational Product Instillation: A
 
 
 
  
 Conjunctival Allergen Challenge (CAC): 
 
 
  
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment 
of itching will be made by the subject at 5(±1), 7(±1), 10(±1), 15(±1), 20(±1), 25(±1), 
and 30(±1) minutes following allergen challenge. Assessments of redness and 
chemosis will be graded by the Investigator at 7(±1), 15(±1), 20(±1), 25(±1) and 
30(±1) minutes post-challenge. Assessments of eyelid swelling, tearing/watery eyes, 
and nasal symptoms will be made by the subject at 7(±1), 15(±1), 20(±1), 25(±1), and 
30(±1) minutes post-challenge (Appendix 2).  
 Diary Dispensation: All subjects will be dispensed a diary to complete daily 
assessments prior to bedtime and upon awakening beginning the evening of Visit 5b. 
Subjects will be instructed to bring the diary to the next visit (Visit 6a) for a 
compliance check.  
 Ora Photography System: The subset of subjects who underwent confocal 
microscopy will be dispensed cameras for at home assessments, to be done alongside 
diary assessments. 
 Adverse Event Query 
 Scheduling for Next Visit (Visit 6a): Subjects will be asked to return to the office the 
following day (Day 16), approximately 24 hours from Visit 5a.  
10.3.1.8 VISIT 6a (24 hours (±6 hrs) Post-Dose at Visit 5a): 4th Dose/CAC #4 
 Update of Medical/Medication History 
 Adverse Event Query 
 Assessments Diary Review and Collection: Assessments diary will be collected and 
reviewed for compliance from Visit 5b to Visit 6a and to address any queries. 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease (defined as an increase of 0.22 or greater in logMAR score) from Visit 2 will 
be considered an adverse event. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment  
 Slit Lamp Biomicroscopy 
 Investigational Product Instillation: 
 
 




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 Diary Dispensation: All subjects will be dispensed a diary to complete daily 
assessments prior to bedtime and upon awakening until the morning of Visit 7. 
Subjects will be instructed to bring the diary to the next visit (Visit 7) for a 
compliance check.  
 Ora Photography System: The subset of subjects who underwent confocal 
microscopy will be dispensed cameras for at home assessments, to be done alongside 
diary assessments. 
 Adverse Event Query 
 Scheduling of next visit (Visit 7): Subjects will be asked to return to the office the 
following day (Day 17) Visit 7. 
10.3.1.10 Visit 7(24 hours (±6 hrs) Post-Dose at Visit 6a): 6th Dose/CAC #6 
 Update of Medical/Medication History 
 Adverse Event Query 
 Assessments Diary Review and Collection: Assessments diary will be collected and 
reviewed for compliance from Visit 6b to Visit 7 and to address any queries. 
 Urine Pregnancy Testing: This will be given to all women of childbearing potential 
 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease (defined as an increase of 0.22 or greater in logMAR score) from Visit 2 will 
be considered an adverse event. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment  
 Slit Lamp Biomicroscopy 
 Digital Imaging: Digital photographs may be taken of each eye. 
 Investigational Product Instillation: 
 
 
 
  
 Conjunctival Allergen Challenge (CAC): 
 
 
  
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment 
of itching will be made by the subject at 5(±1), 7(±1), 10(±1), 15(±1), 20(±1), 25(±1), 
and 30(±1) minutes following allergen challenge. Assessments of redness and 
chemosis will be graded by the Investigator at 7(±1), 15(±1), 20(±1), 25(±1) and 
30(±1) minutes post-challenge. Assessments of eyelid swelling, tearing/watery eyes, 
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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 Visual Acuity Utilizing an ETDRS Chart: A clinically significant visual acuity 
decrease (defined as an increase of 0.22 or greater in logMAR score) from Visit 2 will 
be considered an adverse event. 
 Slit Lamp Biomicroscopy 
 Digital Imaging: Digital photographs may be taken of each eye within 30 minutes of 
the last post-CAC assessment. 
 Confocal Microscopy: Following digital photographs, the same subset of subjects that 
underwent confocal at Visit 3 will undergo confocal microscopy of the left eye. 
 Tear Collection: Tears (5µL from each eye) will be collected from the confocal 
subset 2 hours (+1 hours) after instillation of the anesthetic used for confocal 
microscopy procedures. The technician collecting tears will note the subject’s reflex 
tearing, if applicable (see Appendix 2). 
 IOP Measurement: Intraocular Pressure (IOP) will be measured in each eye by 
contact tonometry.  
 Dilated Ophthalmoscopy: A dilated ophthalmoscopy will be performed by the 
Investigator to evaluate the presence or absence of clinically significant fundus 
abnormalities and vitreous pathology. 
 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  
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 
10.4
 Scheduled Visits 
10.4.1
Refer to Appendix 1 for a schedule of visits and measurements. 
If a subject is discontinued at a scheduled study visit, the remaining assessments should 
be captured on the Unscheduled Visit/ Early Exit Visit pages of the source document and 
corresponding eCRF. 


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 Unscheduled Visits 
10.4.2
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 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:  
 Update of Medical/Medication History 
 Assessment of AEs 
 Visual Acuity Using an ETDRS chart 
 Pregnancy Testing 
 Slit Lamp Examination 
 Digital Imaging 
 IOP Measurement 
 Dilated Ophthalmoscopy Examination 
 COMPLIANCE WITH PROTOCOL 
10.5
Site staff will review concomitant medication use at each visit.  
If at any point during treatment the subject is experiencing discomfort or an undesirable 
reaction due to PRT-2761, PV, Patanol®, or Pred forte®, drug should be discontinued 
and the subject will exit the study.  
Subjects who are inappropriately enrolled will 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 CRF.  
 SUBJECT DISPOSITION 
10.6
 Completed Subjects 
10.6.1
A completed subject is one who has not been discontinued from the study. 
 Discontinued Subjects 
10.6.2
Subjects may be discontinued prior to their completion of the study due to: 
 AEs 


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 protocol violations 
 administrative reasons (eg, inability to continue, lost to follow up) 
 manifest clinically active signs and symptoms of allergic conjunctivitis during the 
ocular and nasal allergic signs and symptoms assessment at Visit 5a 
 
 
 
 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 will be clearly documented on the eCRF. 
 STUDY TERMINATION 
10.7
The study may be stopped at any time by the investigator and/or Ora with appropriate 
notification. 
 STUDY DURATION 
10.8
10 office visits over a period of up to 9 weeks.  
 MONITORING AND QUALITY ASSURANCE 
10.9
During the course of the study an Ora monitor, or designee, will make routine site visits 
to review protocol compliance, assess study drug 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. 
11 ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence associated with the use of an 
investigational product (IP) in humans, whether or not considered IP-related. An AE can 
be any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an IP, without any judgment about 


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causality. An AE can arise from any use of the IP (eg, off-label use, use in combination 
with another drug or medical device) and from any route of administration, formulation, 
or dose, including an overdose. 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 (eg, anatomical limitations), and therapeutic 
parameters (eg, energy applied, sizing, dose release) associated with medical device. 
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 CRF. 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 1 comprehensive event. 
Collection of AEs/SAEs will begin at the time of informed consent. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to IP, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the physician or reported by the subject upon indirect questioning.  
 SEVERITY 
11.1
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. 
 RELATIONSHIP TO INVESTIGATIONAL PRODUCT 
11.2
The relationship of each AE to the IP should be determined by the investigator using 
these explanations: 
 Suspected:  A reasonable possibility exists that the IP caused the AE. A suspected AE 
can be further defined as:  
 Definite:  Relationship exists when the AE follows a reasonable sequence from 
the time of IP administration, follows a known response pattern of the drug 


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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 administration, but could also have been produced by the subject’s 
clinical state or by other drugs administered to the subject. 
 Not Suspected:  A reasonable possibility does not exist that the IP caused the AE. A 
not suspected AE cab further be defined as: 
 Not Related:  Concurrent illness, concurrent medication, or other known cause 
is clearly responsible for the AE, the administration of the IP and the occurrence 
of the AE are not reasonably related in time, OR exposure to IP has not 
occurred. 
Types of evidence that would suggest a causal relationship between the IP and the AE 
include:  a single occurrence of an event that is uncommon and known to be strongly 
associated with IP exposure (eg, angioedema, hepatic injury, Stevens-Johnson 
Syndrome); one or more occurrences of an event that is not commonly associated with IP 
exposure, but is otherwise uncommon in the population exposed to the IP (eg, tendon 
rupture); an aggregate analysis of specific events observed in a clinical trial (such as 
known consequences of the underlying disease or condition under investigation or other 
events that commonly occur in the study population independent of drug therapy) that 
indicates those events occur more frequently in the IP-treatment group than in a 
concurrent or historical control group. 
 EXPECTEDNESS 
11.3
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 
 Unexpected:  an AE that is not listed in the Investigator’s Brochure (IB) or Report of 
Prior Investigations (ROPI) or is not listed at the specificity or severity that has been 
observed. 
 Expected:  an AE that is listed in the IB or ROPI at the specificity and severity that 
has been observed. 
 Not applicable: an AE unrelated to the IP. 
AEs that are mentioned in the IB or ROPI as occurring with a class of products or as 
anticipated from the pharmacological/ mechanical (or other) properties of the product, but 


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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 
11.4
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 (eg, 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic 
nerve). 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 


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 PROCEDURES FOR REPORTING ADVERSE EVENTS 
11.5
All AEs and their outcomes must be reported to Ora and the IRB/IEC as required by the 
IRB/IEC, federal, state, or local regulations and governing health authorities and recorded 
on the appropriate eCRF. 
 Reporting a Suspected Unexpected Adverse Reaction 
11.5.1
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora and the IRB/IEC 
as required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities. 
 Reporting a Serious Adverse Event 
11.5.2
To ensure subject safety, all SAEs, regardless of relationship to the IP, must be 
immediately reported.  All information relevant to the SAE must be recorded on the 
appropriate case report forms.  The investigator is obligated to pursue and obtain 
information requested by Ora and/or the sponsor in addition to that information reported 
on the case report form.  All subjects experiencing a SAE must be followed up and the 
outcome reported. 
In the event of a SAE, the investigator must notify Ora 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 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. 
Contact information for reporting SAEs and ADEs: 
 
 
 
 
 
 
 
         
 
          
 
 PROCEDURES FOR UNMASKING (IF APPLICABLE) 
11.6
When medically necessary, the Investigator may need to determine what treatment has 
been assigned to a subject. The Investigator will contact Ora with the details of the 
emergency unmasking request. Ora will make the final determination if the unmasking 
request will be granted. If granted, the Investigator will be permitted to use the code-
break instructions available on site. 


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Each kit will be labeled with a two panel scratch off label. The right panel of the label, 
containing the scratch off portion, should be placed in the corresponding subject binder. 
If the Investigator determines that emergency unmasking is necessary, the Investigator 
should locate the subject binder containing the label and scratch off the laminate section 
to reveal the assigned treatment. The Investigator must also indicate in source documents 
and in the CRF that the mask was broken and provide the date, time, and reason for 
breaking the mask. Any AE or SAE associated with breaking the mask must be recorded 
and reported as specified in this protocol. 
Subjects will have the IP treatment discontinued immediately if treatment assignment is 
unmasked. 
 TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECTS 
11.7
AFTER ADVERSE EVENTS 
AEs will be followed until:  
 Resolution (return to baseline status or to ‘normal’) 
 Stabilization of the event has occurred (no 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. 
If the subject is lost to follow-up, the investigator should make 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 CRF with the status noted.  
12 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
 INTENT-TO-TREAT POPULATION 
12.1
The Intent-to-Treat (ITT) population consists of all subjects who are randomized.  All 
data will be included and no subjects will be excluded because of protocol violations.  
The ITT population will be analyzed as randomized and will be used for the efficacy 
analyses.  
 PER PROTOCOL POPULATION 
12.2
The Per Protocol (PP) population is a subset of the ITT population and includes the 
subjects who completed the study through Visit 5a (Day 15) with no major protocol 
violations. This population will be analyzed as treated using observed data only for 
confirmatory analyses. 


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 SAFETY POPULATION 
12.3
The safety population includes all randomized subjects who received at least one dose of 
investigational treatment. 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  
12.4
 
 
 
 
 
 
 
 
 
 
 
 
 
 PRIMARY EFFICACY ENDPOINTS 
12.5
The primary efficacy endpoints are: 
 Ocular itching evaluated by the subject at 5(±1), 7(±1), and 10(±1) minutes post-CAC 
(0-4 scale, allowing half-unit increments) at Visits 4b and 5a. 
 Conjunctival redness evaluated by the Investigator at 7(±1), 15(±1), and 20(±1) 
minutes post-CAC (0-4 scale, allowing half-unit increments) at Visits 4b and 5a. 
 CRITERIA FOR EFFICACY  
12.6
To demonstrate efficacy for ocular itching, PRT-2761 in any concentration needs to show 
clinical superiority over PV 
 
s, 5(±1), 7(±1), 10(±1) minutes post-CAC 
of 
the post-CAC time points. 
To demonstrate efficacy for conjunctival redness, PRT-2761 in any concentration needs 
to show clinical superiority over PV 
 7(±1), 15(±1), 20(±1) minutes post-CAC 
 
of the post-CAC time points. 
If ocular itching meets the efficacy measures as defined above with statistical 
significance, then the study will be considered a success for ocular itching.  


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If conjunctival redness meets the efficacy measures as defined above with statistical 
significance, then the study will be considered a success for conjunctival redness.  
If both ocular itching and conjunctival redness meets the efficacy measures as defined 
above with statistical significance, then the study will be considered a success for both 
ocular itching and conjunctival redness. 
 SECONDARY EFFICACY ENDPOINTS 
12.7
Secondary efficacy endpoints include the following:  
 Ocular Itching at 5(±1), 7(±1) and 10(±1) minutes post-CAC evaluated by the subject 
(0-4 scale, allowing half-unit increments) at Visits 5b, 6a, 6b and 7 
 Conjunctival Redness at 7(±1), 15(±1), and 20(±1) minutes post-CAC evaluated by 
the Investigator (0-4 scale, allowing half-unit increments) at Visits 5b, 6a, 6b and 7 
 Ciliary and episcleral redness at 7(±1), 15(±1), and 20(±1) minutes post-CAC 
evaluated by the Investigator (0-4 scale, allowing half-unit increments) at all dosing 
Visits (4b, 5a, 5b, 6a, 6b, 7) 
 Chemosis evaluated at 7(±1), 15(±1), and 20(±1) minutes post-CAC by the 
Investigator (0-4 scale, allowing half-unit increments) at all dosing Visits (4b, 5a, 5b, 
6a, 6b, 7) 
 Eyelid swelling evaluated at 7(±1), 15(±1), and 20(±1) minutes post-CAC by the 
subject (0-3 scale, NOT allowing half-unit increments) at all dosing Visits (4b, 5a, 5b, 
6a, 6b, 7) 
 Tearing/watery eyes evaluated at 7(±1), 15(±1), and 20(±1) minutes post-CAC by the 
subject (0-4 scale, NOT allowing half unit increments) at all dosing Visits (4b, 5a, 5b, 
6a, 6b, 7) 
 Rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal congestion evaluated at 
7(±1), 15(±1), and 20(±1) minutes post-CAC by the subject (0-4 scale, NOT allowing 
half-unit increments) at all dosing Visits (4b, 5a, 5b, 6a, 6b, 7) 
 STATISTICAL HYPOTHESES 
12.8
  
 
 
  
 
 


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 SAMPLE SIZE 
12.9
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 DEMOGRAPHIC AND BASELINE MEDICAL HISTORY  
12.10
The demographic and baseline medical history data will be summarized descriptively. 
For quantitative variables, the summaries will include the number of observations, mean, 
SD, median, minimum, and maximum. Qualitative variables will be summarized using 
counts and percentages.  
 PRIMARY EFFICACY ANALYSES  
12.11
The primary efficacy endpoints are ocular itching assessed at 5(±1), 7(±1), 10(±1) 
minutes post-CAC (0-4 scale, allowing half-unit increments) and conjunctival redness 
evaluated by the Investigator at 7(±1), 15(±1), 20(±1) minutes post-CAC (0-4 scale, 
allowing half-unit increments) at Visit 4b (Duration of Action Visit) and 5a (Onset of 
Action Visit).  The average of each subject’s eyes at each post-CAC time point will be 
used as the unit of analysis for both ocular itching and conjunctival redness.  Ocular 
itching and conjunctival redness will each be analyzed using an analysis of covariance 
(ANCOVA) model for each post-CAC time point at each visit, with the time appropriate 
post-CAC scores at Visit 3 as a covariate and treatment group (including all four 
treatments: PRT-2761 0.5%, PRT-2761 1%, PV, Patanol®), as the sole factor. Least 
square (LS) means will be used to compare each concentration of PRT-2761 to PV. Two-
sample t-tests will be used as unadjusted sensitivity analyses at each post-CAC time 
point, as well as a non-parametric Wilcoxon rank sum tests (comparing each 
concentration of PRT-2761 to PV). At each post-CAC time point, treatment differences 


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Treatment success is defined as PRT-2761, for at least one concentration, showing 
clinical superiority over PV 
 
 5(±1), 7(±1), 10(±1) minutes post-CAC for ocular itching and 7(±1), 15(±1), 
20(±1) minutes post-CAC for conjunctival redness, a
 
 of the post-CAC time points measured for both ocular itching and 
conjunctival redness. 
The primary efficacy analyses will be conducted on the ITT population using the last 
observation carried forward method for missing data as described in Section 12.4. 
Sensitivity or supportive analyses will be performed on the ITT population using 
observed data only, 
 
 
 
 
 SECONDARY EFFICACY ANALYSIS 
12.12
Analyses will be performed on quantitative secondary endpoints in a manner similar to 
primary endpoints. Qualitative measures will be analyzed using Fisher’s exact test or 
Chi-Square test as appropriate (comparing PRT-2761 to PV).  Secondary endpoints 
include ocular itching (at Visits 5b, 6a, 6b, 7), conjunctival redness (at Visits 5b, 6a, 6b, 
7), episcleral and ciliary redness, chemosis, eyelid swelling, tearing/watery eyes, 
rhinorrhea, nasal pruritus, ear or palate pruritus, nasal congestion (at Visits (4b, 5a, 5b, 
6a, 6b, 7). The secondary endpoints will be analyzed for the ITT population with 
observed data only and for the PP population with observed data only. The exploratory 
measure, conjunctival inflammation, at Visits 3, 4b, and 7, will be analyzed as described 
above. 
 
 
 
 
 
Additionally, similar analyses will be completed on all efficacy endpoints secondarily to 
compare each concentration of PRT-2761 to Patanol® [acute and chronic phase] and 
Pred forte® [chronic phase]. 
 ADJUSTMENT FOR MULTIPLICITY 
12.13
 
 


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.  
 SAFETY ANALYSIS 
12.14
The primary safety variable is the incidence of subjects with any AE during the entire 
study. The percentage of subjects with specific treatment-emergent adverse events 
(TEAEs) will be summarized for each treatment group. Incidence will be tabulated by 
Medical Dictionary for Regulatory Activities System Organ Class and preferred term 
within each system organ class. The secondary safety variables of slit lamp 
biomicroscopy, dilated fundoscopy, VA, and IOP will be summarized descriptively using 
quantitative and qualitative summary statistics as appropriate. 
 TOLERABILITY MEASURES 
12.15
Drop comfort and drop descriptor assessments will be used to assess tolerability.  Drop 
comfort will be summarized using number of observations, mean, median, standard 
deviation, minimum and maximum, and will be analyzed with two-sample t-tests. The 
drop descriptor assessment will be summarized using counts and percentages and will be 
analyzed using Fisher’s exact or Chi-Square tests as appropriate. 
 SUBGROUP ANALYSIS 
12.16
No subgroup analyses are planned. 
  INTERIM ANALYSIS 
12.17
No interim analyses are planned. 
13 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonization (ICH) 
Guidelines, and in general, consistent with the Declaration of Helsinki.  In addition, all 
applicable local, state, and federal requirements relevant to the use of investigational 
products in the countries involved will be adhered to. 


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 PROTECTION OF HUMAN SUBJECTS 
13.1
 Subject Informed Consent 
13.1.1
Informed consent must take place before any study specific procedures are initiated.  
Signed and dated written informed consent must be obtained from each subject prior to 
enrollment into the study.   
All informed consent forms must be approved for use by the sponsor and receive 
approval/favorable opinion from an IRB/IEC prior to their use.  If the consent form 
requires revision (eg, due to a protocol amendment or significant new safety 
information), it is the investigator’s responsibility to ensure that the amended informed 
consent is reviewed and approved by Ora prior to submission to the governing IRB/IEC 
and that it is read, signed and dated by all subjects subsequently enrolled in the study as 
well as those currently enrolled in the study. 
If informed consent is taken under special circumstances (oral informed consent), then 
the procedures to be followed must be determined by Ora and provided in writing by Ora 
and/or study sponsor prior to the consent process. 
 Institutional Review Board (IRB) Approval 
13.1.2
This study is to be conducted in accordance with Institutional Review Board regulations 
(U.S. 21 CFR Part 56.103).  The investigator must obtain appropriate IRB approval 
before initiating the study and re-approval at least annually. 
Only an IRB/ERC approved version of the ICF will be used. 
 ETHICAL CONDUCT OF THE STUDY 
13.2
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 SUBJECT CONFIDENTIALITY 
13.3
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data in accordance with local, state, and federal laws 
and regulations. 
Monitors, auditors and other authorized representatives of Ora, the IRB/IEC approving 
this study, the Food and Drug Administration, the Department of Health and Human 
Services, other domestic government agencies, and other foreign regulatory agencies will 
be granted direct access to the study subject’s original medical and study records for 
verification of the data and/or clinical trial procedures.  Access to this information will be 
permitted to the aforementioned individuals to the extent permitted by law. 


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Clinical Trial Protocol: 17-100-0008 
Amendment 2.0, 18-Oct-2017 
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A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the investigational product may ultimately be 
marketed, but the subject’s identity will not be disclosed in these documents. 
 DOCUMENTATION 
13.4
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s study subject files, as well as the results of diagnostic tests such as X-
rays, laboratory tests, and electrocardiograms.  The investigator’s copy of the eCRFs 
serves as the investigator’s record of a subject’s study-related data. 
 Retention of Documentation 
13.4.1
All study related correspondence, subject records, ICFs, record of the distribution and use 
of all IPs and copies of eCRFs should be maintained on file for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region; or until at least 2 years have 
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. 
 Photography and Videos 
13.4.2
Photographs and/or videos may be taken of each subject’s eyes prior to CAC and/or 
instillation of investigational product and/or post-CAC (prior to confocal microscopy) at 
Visits 3, 4b, 7, and early exit/unscheduled visit. 
Digital photographs may also be taken at home by the subset of subjects undergoing 
confocal after Visit 5b and 6b.  
 LABELING, PACKAGING, STORAGE, ACCOUNTABILITY, AND 
13.5
RETURN OR DISPOSAL OF INVESTIGATIONAL PRODUCT 
 Labeling/Packaging 
13.5.1
Investigational product will be packaged into clinical kits. Each kit will be labeled with 
the study information on a double panel, scratch off label and the kit will contain two 
bottles of investigational product. Each bottle will be labeled with a kit number and visit 
number range (4a-5a and 5b-7).  


PRT-2761 Ophthalmic Solution 
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Clinical Trial Protocol: 17-100-0008 
Amendment 2.0, 18-Oct-2017 
CONFIDENTIAL 
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All clinical labels will meet applicable regulatory requirements. Investigational product 
will be packaged and labeled based on the randomization schedule generated prior to the 
start of the study.  
 Storage of Investigational Product 
13.5.2
 The study drugs must be stored in a secure area accessible only to the investigator and 
his/her designees. Study drug(s) must be kept at room temperature (15-25°C), and 
secured at the investigational site in a locked container.  
 Accountability of Investigational Product 
13.5.3
The IP is to only be prescribed by the principal investigator or his/her named sub 
investigator(s), and is to only be used in accordance with this protocol.  The IP must only 
be distributed to subjects properly qualified under this protocol to receive IP. 
The investigator must keep an accurate accounting of the IP received from the supplier. 
This includes the amount of IP dispensed to subjects, amount of IP returned to the 
investigator by the subjects, and the amount returned or disposed upon the completion of 
the study.  A detailed inventory must be completed for the IP. 
 Return or Disposal of Investigational Product 
13.5.4
All IP will be returned to the sponsor or their designee or destroyed at the study site.  The 
return or disposal of IP will be specified in writing. 
 RECORDING OF DATA ON SOURCE DOCUMENTS AND CASE 
13.6
REPORTS FORMS (CRFS) 
The investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s eCRF, source document, and all study-related material.  All 
study data should also be attributable, legible, contemporaneous, and original.  Recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or render 
illegible the previous entry (eg, by drawing a single line through the incorrect entry and 
writing the revision next to the corrected data).  An individual who has corrected a data 
entry should make clear who made the correction and when, by adding to the correction 
his/her initials as well as the date of the correction. 
 HANDLING OF BIOLOGICAL SPECIMENS 
13.7
Not Applicable. 
 PUBLICATIONS 
13.8
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study.  Authorship will be established before writing the manuscript.  Ora 


PRT-2761 Ophthalmic Solution 
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Clinical Trial Protocol: 17-100-0008 
Amendment 2.0, 18-Oct-2017 
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and the study sponsor will have the final decision regarding the manuscript and 
publication. 
 
 


PRT-2761 Ophthalmic Solution 
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Clinical Trial Protocol: 17-100-0008 
Amendment 2.0, 18-Oct-2017 
CONFIDENTIAL 
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14 REFERENCES 
See footnotes throughout this document. 
 






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Clinical Trial Protocol: 17-100-0008 
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APPENDIX 2: EXAMINATION PROCEDURES, TESTS, EQUIPMENT, 
AND TECHNIQUES 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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Clinical Trial Protocol: 17-100-0008 
Amendment 2.0, 18-Oct-2017 
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Amendment 2.0, 18-Oct-2017 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
                                                                                                                        
  
 
                                                                                 
  
 
 
                                                                                                                        
  
 
                                                                                 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 


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APPENDIX 4:  HANDLING OF BIOLOGICAL SPECIMENS 
Not Applicable. 










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SAP_001.pdf: 
 
27NOV2017 
Confidential and Proprietary 
Page 1 of 38 
 
STATISTICAL ANALYSIS PLAN  
A Single-Center, Randomized, Double-Masked, Vehicle and Active-
Controlled, Dose-Ranging Phase 2 Study Evaluating the Efficacy and 
Safety of PRT-2761 for the Treatment of Acute and Chronic Allergic 
Conjunctivitis Using the Conjunctival Allergen Challenge Model 
(Ora-CAC®)   
 
 
 
 
Sponsor:   
 
Ora, Inc. 
 
 
 
 
 
Protocol Number: 
17-100-0008 
 
 
Author:   
 
Lot Slade 
 
 
 
Associate Biostatistician 
Statistics & Data Corporation 
 
Date:    
 
27NOV2017 
Version:  
 
1.0 
 
 




 
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Table of Contents 
1. Introduction ..................................................................................................................................... 6 
2. Study Objectives ............................................................................................................................. 6 
2.1 Primary Efficacy Measures ...................................................................................................... 6 
2.2 Secondary Efficacy Measures ................................................................................................. 6 
2.3 Safety Measures ...................................................................................................................... 7 
2.4 Tolerability Measures ............................................................................................................... 7 
2.5 Exploratory Measures .............................................................................................................. 7 
2.6 Statistical Hypotheses .............................................................................................................. 8 
3. Study Design and Procedures ........................................................................................................ 9 
3.1 General Study Design .............................................................................................................. 9 
3.2 Schedule of Visits and Assessments ..................................................................................... 11 
4. Study Treatments .......................................................................................................................... 13 
4.1 Method of Assigning Subjects to Treatment Groups ............................................................. 13 
4.2 Masking and Unmasking ........................................................................................................ 14 
5. Sample Size and Power Considerations ...................................................................................... 14 
6. Data Preparation ........................................................................................................................... 15 
7. Analysis Populations ..................................................................................................................... 15 
7.1 Intent-to-Treat ........................................................................................................................ 15 
7.2 Per Protocol ........................................................................................................................... 16 
7.3 Safety ..................................................................................................................................... 16 
8. General Statistical Considerations ................................................................................................ 16 
8.1 Unit of Analysis ...................................................................................................................... 16 
8.2 Missing or Inconclusive Data Handling .................................................................................. 16 
8.3 Definition of Baseline ............................................................................................................. 18 
8.4 Data Analysis Conventions .................................................................................................... 18 
8.5 Adjustments for Multiplicity .................................................................................................... 19 
9. Disposition of Subjects .................................................................................................................. 19 
10. Demographic and Pretreatment Variables .................................................................................. 20 
10.1 Demographic Variables .......................................................................................................... 20 
10.2 Pretreatment Variables .......................................................................................................... 20 
11. Medical History and Concomitant Medications ........................................................................... 20 
11.1 Medical History ...................................................................................................................... 20 
11.2 Concomitant Medications ....................................................................................................... 21 
12. Exposure to Investigational Product ............................................................................................ 21 


 
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13. Efficacy Analyses ........................................................................................................................ 21 
13.1 Primary Analysis .................................................................................................................... 21 
13.2 Secondary Analyses .............................................................................................................. 24 
13.2.1 Ocular Itching ................................................................................................................. 25 
13.2.2 Conjunctival, Ciliary and Episcleral Redness ................................................................. 25 
13.2.3 Chemosis........................................................................................................................ 25 
13.2.4 Tearing/Watery Eyes ...................................................................................................... 26 
13.2.5 Eyelid Swelling ............................................................................................................... 26 
13.2.6 Rhinorrhea ...................................................................................................................... 26 
13.2.7 Nasal Pruritus and Ear or Palate Pruritus ...................................................................... 27 
13.2.8 Nasal Congestion ........................................................................................................... 27 
14. Safety Analyses ........................................................................................................................... 27 
14.1 Adverse Events ...................................................................................................................... 27 
14.2 Slit-Lamp Biomicroscopy Examination .................................................................................. 31 
14.3 Dilated Ophthalmoscopy ........................................................................................................ 31 
14.4 Visual Acuity .......................................................................................................................... 31 
14.5 Intraocular Pressure ............................................................................................................... 32 
15. Tolerability Analysis ..................................................................................................................... 32 
15.1 Drop Comfort Scale ............................................................................................................... 32 
15.2 Drop Comfort Questionnaire .................................................................................................. 33 
16. Exploratory Analysis .................................................................................................................... 33 
16.1 Conjunctival Inflammation ...................................................................................................... 34 
16.2 Tear Collection, Diary Assessments, Digital Photographs .................................................... 34 
17. Interim Analyses .......................................................................................................................... 34 
18. Changes from Protocol-Stated Analyses .................................................................................... 34 
19. Revision History........................................................................................................................... 34 
20. Tables .......................................................................................................................................... 34 
21. Listings ........................................................................................................................................ 37 
22. Figures ......................................................................................................................................... 38 
 
 
 


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


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol 17-100-0008, version Amendment 2.0 dated 18OCT2017. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports (CSR). 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated.  This SAP provides details of the specific statistical methods that 
will be used.  The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol.  If additional analyses are required to supplement 
the planned analyses described in this SAP they may be completed and will be identified in the CSR. 
2. Study Objectives 
The objective of this study is to evaluate the efficacy and safety of two concentrations of PRT-2761 
(0.5% and 1%) as a topical ophthalmic solution for the treatment of the signs and symptoms of acute 
and chronic allergic conjunctivitis. 
2.1 
Primary Efficacy Measures 
The primary efficacy measures are:  
• 
Ocular itching evaluated by the subject at Visits 4b and 5a (for Duration and Onset of action, 
respectively) at 5(±1), 7(±1), and 10(±1) minutes post-Conjunctival Allergen Challenge (CAC, 
0-4 scale, allowing half-unit increments)  
• 
Conjunctival redness evaluated by the Investigator at Visits 4b and 5a (for Duration and Onset 
of action, respectively) at 7(±1), 15(±1), and 20(±1) minutes post-CAC (0-4 scale, allowing 
half-unit increments)  
2.2 
Secondary Efficacy Measures 
The secondary efficacy measures are:  
• 
Ocular itching evaluated by the subject at Visits 5b, 6a, 6b, and 7 at 5(±1), 7(±1), and 10(±1) 
minutes post-CAC (0-4 scale, allowing half-unit increments) 
• 
Conjunctival redness evaluated by the Investigator at Visits 5b, 6a, 6b, and 7 at 7(±1), 15(±1), 
and 20(±1) minutes post-CAC (0-4 scale, allowing half-unit increments) 
• 
Episcleral and ciliary redness evaluated by the Investigator at all dosing Visits (4b, 5a, 5b, 6a, 
6b, 7) at 7(±1), 15(±1), and 20(±1) minutes post-CAC (0-4 scale, allowing half-unit increments) 


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• 
Chemosis evaluated by the Investigator at all dosing Visits (4b, 5a, 5b, 6a, 6b, 7) at 7(±1), 
15(±1), and 20(±1) minutes post-CAC (0-4 scale, allowing half-unit increments) 
• 
Tearing evaluated by the subject at all dosing Visits (4b, 5a, 5b, 6a, 6b, 7) at 7(±1), 15(±1), and 
20(±1) minutes post-CAC (0-4 scale, NOT allowing half-unit increments) 
• 
Eyelid swelling evaluated by the subject at all dosing Visits (4b, 5a, 5b, 6a, 6b, 7) at 7(±1), 
15(±1), and 20(±1) minutes post-CAC (0-3 scale, NOT allowing half-unit increments) 
• 
Rhinorrhea, nasal pruritis, ear or palate pruritis, and nasal congestion evaluated by the subject 
at all dosing Visits (4b, 5a, 5b, 6a, 6b, 7) at 7(±1), 15(±1), and 20(±1) minutes post-CAC (0-4 
scale, NOT allowing half-unit increments) 
2.3 
Safety Measures 
The safety measures include the following: 
• 
Slit Lamp Biomicroscopy conducted at Visits 2, 3, 4a, 4b, 5a, 5b, 6a, 6b and 7 
• 
Dilated Ophthalmoscopy conducted at Visits 2 and 7 
• 
Distance Visual Acuity (VA) using an Early Treatment of Diabetic Retinopathy Study (ETDRS) 
chart conducted at Visits 2, 3, 4a, 4b, 5a, 5b, 6a, 6b and 7 
• 
Intraocular Pressure (IOP) Visits 2 and 7 
• 
Adverse Events (AE) (reported, elicited, and observed) assessed at Visits 1, 2, 3, 4a, 4b, 5a, 
5b, 6a, 6b and 7 
2.4 
Tolerability Measures 
The tolerability measures include the following: 
• 
Drop comfort assessment (0-10 unit scale) assessed by subject immediately upon instillation, 
at 30 seconds, and 1 minute post-instillation at Visit 4a  
• 
Drop comfort descriptor questionnaire at 3 minutes post-instillation at Visit 4a  
2.5 
Exploratory Measures 
The exploratory measures include the following: 
• 
Ocular itching evaluated by the subject at Visit 5b, 6a, 6b, and 7 at 15(±1), 20(±1), 25(±1) and 
30(±1) minutes post-CAC (0-4 scale, allowing half-unit increments) 
• 
Tearing evaluated by the subject at Visits 5b, 6a, 6b, and 7 at 25(±1) and 30(±1) minutes post-
CAC (0-4 scale, NOT allowing half-unit increments) 
• 
Eyelid swelling evaluated by the subject at Visits 5b, 6a, 6b, and 7 at 25(±1) and 30(±1) 
minutes post-CAC (0-3 scale, NOT allowing half-unit increments) 


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• 
Rhinorrhea, nasal pruritis, ear or palate pruritis, and nasal congestion evaluated by the subject 
at Visits 5b, 6a, 6b, and 7 at 25(±1) and 30(±1) minutes post-CAC (0-4 scale, NOT allowing 
half-unit increments). 
• 
Conjunctival, episcleral, and ciliary redness evaluated by the investigator at Visit 5b, 6a, 6b, 
and 7 at 25(±1) and 30(±1) minutes post-CAC (0-4 scale, allowing half-unit increments).  
• 
Chemosis evaluated by the investigator at Visit 5b, 6a, 6b, and 7 at 25(±1) and 30(±1) minutes 
post-CAC (0-4 scale, allowing half-unit increments). 
• 
In a subset of approximately 36 subjects who agree to undergo confocal microscopy, 
conjunctival inflammation as measured by confocal microscopy (0-4 scale, NOT allowing half-
unit increments) at Visits 3, 4b, and 7. 
• 
In the same subset of subjects who undergo confocal microscopy, tears will be collected from 
both eyes (prior to confocal microscopy) at Visit 3, 4b, and 7. At Visit 3, tears will be collected 
at two separate time points post-CAC: prior to the confocal microscopy procedures and again 
at 2 (+1) hours after instillation of the anesthetic used for the confocal microscopy procedures. 
At Visit 4b tears will be collected prior to the confocal microsopy procedures post-CAC. At Visit 
7 tears will be collected 2 (+1) hours after instillation of the anesthetic used for the confocal 
microscopy procedures post-CAC. Tears will be analyzed for cytokine levels. 
• 
Diary assessments for the subset of subjects undergoing confocal microscopy at Visits 3 and 
4b. Additionally, all subjects will be dispensed diaries at Visits 5b and 6b. Assessments of 
ocular itching, ocular redness, and eyelid swelling will occur prior to bedtime and upon 
awakening (all use a 0 to 4 scale, except eyelid swelling, 0 to 3). 
• 
In the same subset of subjects who undergo confocal microscopy, digital photographs will be 
taken at-home of each eye prior to subjects completing diary assessments following Visits 5b 
and 6b. 
• 
Digital photographs will be taken in-office of all subjects pre-CAC and within 30 minutes of the 
last post-CAC assessment at Visit 4b and Visit 5a. 
2.6 
Statistical Hypotheses 
 
 
 
 
 
 
 


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3. Study Design and Procedures 
3.1 
General Study Design 
This is a prospective, single-center, randomized, double-masked, vehicle and active-controlled, dose-
ranging study to evaluate the efficacy and safety of PRT-2761 in two concentrations compared to 
Vehicle, Patanol® and Patanol®/Pred forte® for the treatment of the signs and symptoms of chronic 
allergic conjunctivitis. 
The trial will comprise of 10 office visits over a period of up to 9 weeks. Part 1 will be a conventional 
CAC protocol. Subjects who meet the entry criteria for itching and redness response to the CAC at Visits 
2 and 3 will be randomized at Visit 4a (Day 1, Duration of Action Visit) in a 1:1:1:1 (PRT-2761 0.5%: 
PRT-2761 1%: Vehicle:Patanol®) assignment ratio in the acute phase. Subjects randomized to the 
Patanol® treatment for the acute phase will further be randomized using a 1:1 (Patanol®: Pred forte®) 
assignment ratio for the chronic phase. After 8 hours, subjects will return for Visit 4b to be challenged 
with signs and symptoms assessed post-CAC. Subjects will return 14 days later for Visit 5a (Day 15, 
Onset of Action Visit), at which time they will be challenged 15 minutes after dosing with the same 
concentration of PRT-2761, vehicle, or Patanol® as randomized at Visit 4a. This will conclude Part 1 of 
the study. 
Part 2 will be the assessment of chronic allergy and subjects will be challenged 15 minutes after dosing. 
If subjects were randomized to receive PRT-2761 0.5%, PRT-2761 1%, or vehicle at Visit 4a, subjects 
will continue to receive the same treatment at (Visits 5b, 6a, 6b and 7 at 8, 24, 32 and 48 hours from 
Visit 5a, respectively). Subjects who were randomized to receive Patanol® at Visit 4a will be further 
randomized into 2 groups. One group will continue to receive Patanol® through Visit 7. The other group 
will be dosed with Pred forte® at Visits 5b through 7. At Visit 7, final exit procedures will also be conducted 
and subjects will exit the study.  
Study visits will be referred to in all tables and listings with the expected visit and study day 
corresponding to the visit to enable reviewers to understand the assessment timing without referring to 
the protocol visit schedule.  The following table shows the scheduled study visits, their planned study 
day (note that there is no Day 0 and that Day 1 corresponds to the day of randomization), and the 
acceptable visit window for each study visit: 








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4. Study Treatments 
Subjects will be assigned to one of the following treatments: 
• 
PRT-2761 0.5% 
• 
PRT-2761 1% 
• 
Vehicle 
• 
Patonol® (active reference) 
• 
Patanol® during the acute phase / Pred forte® during the chronic phase (active reference) 
4.1 
Method of Assigning Subjects to Treatment Groups 
All subjects screened for the study who sign an informed consent form will be assigned a 3-digit 
screening number that will be entered in the Screening and Enrollment Log. Screening numbers will be 
assigned in sequential order beginning with 001. Randomization will be used to avoid bias in the 
assignment of subjects to treatment and time point, to increase the likelihood that known and unknown 
subject attributes (e.g., demographics and baseline characteristics) are evenly balanced across 
treatment groups and across time points, and to enhance the validity of statistical comparisons. 
Once a subject meets all qualification criteria at Visit 4a, they will be enrolled and randomly assigned to 
masked treatment using a 1:1:1:1 (PRT-2761 0.5%: PRT-2761 1%:Vehicle:Patanol®) assignment ratio 
for the acute phase. Subjects randomized to the Patanol® treatment in the acute phase will further be 
randomized using a 1:1 (Patanol®:Pred forte®) assignment ratio for the chronic phase. Subjects will be 
randomized at Visit 4a (Day 1) by assignment of the lowest 4-digit randomization number available 
within the appropriate stratum. Randomization will be stratified by average post-CAC itching scores 
at baseline (Visit 3), by qualifying allergen type 
 and by confocal 
participation (yes and no) to ensure balance for the primary endpoint of ocular itching. The 
randomization numbers will start from x001, where x refers to the subject’s stratum as follows: 
• 
x = 1 for subjects in the low baseline itching, seasonal allergy, no confocal participation stratum 
• 
x = 2 for subjects in the low baseline itching, perennial allergy, no confocal participation stratum 
• 
x = 3 for subjects in the high baseline itching, seasonal allergy, no confocal participation stratum 
• 
x = 4 for subjects in the high baseline itching, perennial allergy, no confocal participation stratum 
• 
x = 5 for subjects in the low baseline itching, seasonal allergy, confocal participation stratum 
• 
x = 6 for subjects in the low baseline itching, perennial allergy, confocal participation stratum 
• 
x = 7 for subjects in the high baseline itching, seasonal allergy, confocal participation stratum 
• 
x = 8 for subjects in the high baseline itching, perennial allergy, confocal participation stratum 
The first 36 subjects who qualify after post-CAC assessments at Visit 3 and had tear collection at Visit 
2, will be in the confocal microscopy subset. This number is estimated to ensure approximately 30 


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subjects in the confocal microscopy subset complete the trial. At Visit 4, these individuals will be 
assigned to a kit number from Stratum 5, 6, 7, or 8. 
Once 36 subjects have completed confocal microscopy at Visit 3, any subjects who had tear collection 
at Visit 2, will not have additional tear collections or confocal microscopy. At Visit 4, these individuals 
will be assigned to a kit number from Stratum 1, 2, 3, or 4. 
No randomization numbers will be skipped or omitted. 
At Visit 4a, if a subject requires a kit from their assigned stratum, based on the above criteria, and there 
are no longer any kits available for that stratum, the subject will not be randomized and will be deemed 
a screen failure. A five-digit subject ID (two-digit site number and the three-digit screening number 
separated by a hyphen [i.e., nn-nnn]) will be used to identify subjects in all datasets, listings, and tables 
for this study.  
4.2 
Masking and Unmasking 
When medically necessary, the Investigator may need to determine what treatment has been assigned 
to a subject. The Investigator will contact Ora with the details of the emergency unmasking request. Ora 
will make the final determination if the unmasking request will be granted. If granted, the Investigator 
will be permitted to use the code-break instructions available on site. 
Each kit will be labeled with a two panel scratch off label. The right panel of the label, containing the 
scratch off portion, should be placed in the corresponding subject binder. If the Investigator determines 
that emergency unmasking is necessary, the Investigator should locate the subject binder containing 
the label and scratch off the laminate section to reveal the assigned treatment. The Investigator must 
also indicate in source documents and in the CRF that the mask was broken and provide the date, time, 
and reason for breaking the mask. Any AE or serious AE (SAE) associated with breaking the mask must 
be recorded and reported as specified in this protocol. 
Subjects will have the investigational product (IP) treatment discontinued immediately if treatment 
assignment is unmasked. 
5. Sample Size and Power Considerations 
 
 
 
 
 
 
 


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6. Data Preparation 
All reported study data will be recorded on the electronic case report forms (eCRF) supplied by Statistics 
& Data Corporation (SDC) using iMedNetTM.  Data from source documents will be entered into the eCRF 
by site personnel.   
After data are entered into the clinical study database, electronic edit checks and data review will be 
performed.  All data validation specifications and procedures are detailed in the Data Validation Manual 
as a separate document.  When the database has been declared to be complete and accurate, the 
database will be locked.  Any changes to the database after data have been locked can only be made 
with the approval of the Sponsor and Ora in consultation with SDC.  
All final analyses outlined in this document will be carried out after the following have occurred: 
• 
All data management requirements are met according to SDC standard operating procedures, 
including data entry, performance of edit and validation checks, documentation and resolution 
of data queries, and database lock with written authorization provided by appropriate SDC and 
Sponsor personnel; 
• 
Protocol deviations have been identified and status defined (major/minor deviations);  
• 
Analysis populations have been determined; and 
• 
Randomized treatment codes have been unmasked. 
7. Analysis Populations 
7.1 
Intent-to-Treat 
The Intent-to-Treat (ITT) population consists of all subjects who are randomized. All data will be included 
and no subjects will be excluded because of protocol violations. The ITT population will be analyzed as 
randomized and will be used for the efficacy analyses. 


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7.2 
Per Protocol 
The Per Protocol (PP) population is a subset of the ITT population and includes the subjects who 
completed the study through Visit 5a (Day 15) with no major protocol violations. This population will be 
analyzed as treated using observed data only for confirmatory analyses. 
7.3 
Safety 
The safety population includes all randomized subjects who received at least one dose of investigational 
treatment. The safety population will be analyzed as treated and will be used for the safety analyses. 
No data will be excluded for any reason. 
8. General Statistical Considerations 
8.1 
Unit of Analysis 
The subject will be considered the unit of analysis for all variables with exceptions of slit-lamp 
biomicroscopy and dilated fundoscopy examination. For the variables using subject as the unit of the 
analysis, the average of both eyes of each subject will be used for statistical summaries and analyses 
in cases where data are collected for each eye. For slit-lamp biomicroscopy and dilated fundoscopy 
examination results, the eye will be the unit of analysis and summaries will be provided for all eyes 
combined. 
8.2 
Missing or Inconclusive Data Handling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






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reported in the raw values. Standard deviations will be presented to two additional decimal places than 
reported in the raw values. Summaries for discrete variables will include frequency counts and 
percentages. All percentages will be rounded to one decimal place (i.e., XX.X%).  Differences between 
active treatment groups and vehicle or active control will be calculated as active minus vehicle or active 
control and change from baseline will be calculated as follow-up visit minus baseline.  
All statistical tests will be two-sided with a significance level of 0.05 (α = 0.05) unless otherwise specified.  
Confidence intervals (CI) for differences between treatment groups will be two-sided at 95% confidence.  
All p-values will be rounded to four decimal places; p-values less than 0.0001 will be presented as 
“<0.0001”; p-values greater than 0.9999 will be presented as “>0.9999”. 
Unless otherwise specified, summaries will be presented by treatment group and, where appropriate, 
visit/time point. 
8.5 
Adjustments for Multiplicity 
There will be no adjustment for multiplicity for having two endpoints as statistical significance is required 
for both ocular itching and conjunctival redness for treatment success. There will also be no adjustment 
necessary for testing multiple time points within a given visit, as significance at all post-CAC time points 
is required. 
Since this is a proof of concept study, there will be no adjustment for multiplicity of testing two 
concentrations of PRT-2761 versus placebo. 
9. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized, completed the study, and discontinued from the study. Subjects who are not discontinued 
from the study will be considered study completers. Disposition will be summarized by treatment group 
and for all subjects.  
The number and percentage of subjects prematurely discontinued from the study and the reasons for 
study discontinuation will be summarized by treatment group for all randomized subjects. The reasons 
for study discontinuation that will be summarized include: AE, protocol deviation, administrative reasons, 
manifest signs of allergic conjunctivitis at Visit 5a , sponsor termination of study and other. A subject 
listing will be provided that includes the date of and reason for premature study discontinuation. 
Subject listings will be provided that include informed consent date, inclusion and exclusion criteria, 
deviations, and exclusions from the PP population. 
Protocol deviations will be summarized by treatment group for all randomized subjects for each deviation 
category (informed consent, inclusion/exclusion and randomization, test article/study drug instillation 
and assignment at site, improper protocol procedures at site, site failure to report SAE, visit out of 


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window [missed, early, late],  subject’s non-compliance with test article/study drug, subject use of 
prohibited concomitant medication, subject’s failure to follow instructions, other) and severity (minor, 
major) using counts and percentages. Percentages will be based on the total number of subjects 
randomized in each treatment group. A subject listing will be provided that includes the date of the 
deviation, the deviation description, and the classification of whether the deviation was judged to be 
major or minor. 
10. Demographic and Pretreatment Variables 
10.1 
Demographic Variables 
The demographic variables collected in this study include age, gender, race, ethnicity, and iris color.  
Subjects who record more than one race will be grouped into a single category denoted as multi-racial. 
Demographic variables will be summarized for the ITT and Safety populations, separately. 
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics.  Age 
will also be categorized as follows:  <65 years and ≥65 years.  Age will be reported in years and 
calculated using the following formula: 
Age = (informed consent date – date of birth) / 365.25 truncated as an integer 
The number and percentage of subjects will be presented, overall and by treatment, for age category, 
sex, race, ethnicity, iris color, average post-CAC itching scores at baseline 
 allergen 
type, and confocal participation.  
A subject listing that includes all demographic variables will be provided. 
10.2 
Pretreatment Variables 
At Visit 1 (Day -50 to -22), subjects signing the informed consent and Health Insurance Portability and 
Accountability Act (HIPAA) forms may be given a diagnostic test for allergic disease (skin test). Results 
from this test will be provided in a subject listing. 
11. Medical History and Concomitant Medications 
11.1 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1. 
Non-ocular medical history will be summarized using discrete summary statistics and presented by 
treatment group at the subject level by System Organ Class (SOC) and Preferred Term (PT) using the 
ITT population.  Ocular medical history will be similarly summarized at the subject level.  If a subject 
reports the same PT multiple times within the same SOC, that PT will only be reported once within that 
SOC.  As with the PT, if a subject reports multiple conditions within the same SOC, that SOC will only 
be reported once.   


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Listings of medical history will be generated separately for ocular and non-ocular data. 
11.2 
Concomitant Medications 
The use of any concurrent medication, prescription or over-the-counter, is to be recorded on the subject’s 
source document and corresponding eCRF along with the reason the medication was taken.  
Concomitant medications will be coded using the World Health Organization Drug Dictionary (WHO DD, 
Enhanced B2, September 2017) and summarized to the therapeutic drug class (Anatomical Therapeutic 
Chemical [ATC] 4 classification) and preferred name.  If the ATC 4 classification is not provided, the 
next lowest classification that is provided in the coding dictionary will be used.  The preferred name will 
be defined as the active ingredient; if the active ingredient is not provided or includes more than two 
ingredients (e.g., multivitamins) then the drug name will be summarized as the preferred name.   
Concomitant medications will be summarized using the ITT population. Medications will be tabulated for 
each treatment group using frequencies and percentages. Subjects may have more than one medication 
per ATC text.  At each level of subject summarization, a subject will be counted once if he/she reports 
one or more medications. Percentages will be based on the number of randomized subjects in each 
treatment group.  Listings of concomitant medications will be generated separately for ocular and non-
ocular data. 
12. Exposure to Investigational Product 
The number and percentage of subjects instilled with IP will be summarized by visit and treatment group 
for the Safety population. Percentages will be calculated based on the total number of subjects in each 
treatment group with responses. 
A listing of IP instillation for all subjects will also be provided. 
13. Efficacy Analyses 
13.1 
Primary Analysis 
The primary efficacy endpoints are ocular itching assessed by the subject at 5(±1), 7(±1), 10(±1) minutes 
post-CAC (0-4 scale, allowing half-unit increments) and conjunctival redness evaluated by the 
Investigator at 7(±1), 15(±1), 20(±1) minutes post-CAC (0-4 scale, allowing half-unit increments) at Visit 
4b (duration of action visit) and 5a (onset of action visit).  
Ocular itching will be evaluated by the subject using the following Ora Calibra® CAC Ocular Itching 
Scale: 
 
 
 
 






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subjects in each concentration of PRT-2761 and Patanol® will be compared to Pred forte® in addition to 
the treatment comparisons being made for the acute phase. A Fisher’s exact test will be used to compare 
treatments for the number of subjects in each category and the corresponding p-values will be reported. 
Conjunctival redness scores will be summarized in a similar manner using categories of scores less 
than or equal to one and scores equal to zero. 
Figures will be produced to show mean ocular itching score for each treatment arm by time point and 
visit (Visits 4b and 5a) for the ITT and PP populations with observed data only. Mean change from 
baseline of ocular itching scores for each treatment arm will be presented in a similar figure for the ITT 
population with observed data only. Mean conjunctival redness scores and mean change from baseline 
of conjunctival redness scores will also be presented in similar figures. 
Separate listings of ocular itching scores and conjunctival redness scores for all subjects will also be 
provided. 
13.2 
Secondary Analyses 
Secondary endpoints include ocular itching; conjunctival, episcleral, and ciliary redness; chemosis; 
tearing/watery eyes; eyelid swelling; rhinorrhea; nasal pruritus; ear or palate pruritus; and nasal 
congestion. All secondary endpoints will be analyzed in a manner similar to the primary endpoints for 
the ITT population with observed data only and for the PP population with observed data only. The 
ANCOVA models used will include treatment group (including all five treatments: PRT-2761 0.5%, PRT-
2761 1%, vehicle, Patanol®/Patanol®, Patanol®/Pred forte®) and the time point specific post-CAC scores 
at Visit 3 as a measure of baseline. For the acute phase (Part 1), LS means for each treatment, the 
estimated treatment differences and their corresponding 95% confidence intervals, and p-values will be 
used to compare each concentration of PRT-2761 and Patanol® to vehicle and each concentration of 
PRT-2761 to Patanol®. For the chronic phase (Part 2), LS means for each treatment, and the estimated 
treatment difference and their corresponding 95% confidence intervals, and p-values will be used to 
compare each concentration of PRT-2761, Patanol®/Patanol® and Patanol®/Pred forte® to vehicle. Each 
concentration of PRT-2761 will also be compared to Patanol®/Patanol® and Patanol®/Pred forte® 
separately. 
In addition, repeated measures ANCOVA models will be run for each visit, with treatment, time point, 
and time appropriate baseline as covariates. These models account for correlations between time points 
within each subject. LS means for each treatment, the estimated treatment differences and their 
corresponding 95% confidence intervals (as described previously for each phase) will be calculated from 
these repeated measures ANCOVA models. SAS code to implement this repeated measures ANCOVA 
model for each visit is as follows: 
 




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 described at the beginning of Section 13.2. 
13.2.4 Tearing/Watery Eyes 
Tearing/watery eyes will be evaluated by the subject at 7(±1), 15(±1) and 20(±1) post-CAC at all dosing 
visits (Visits 4b, 5a, 5b, 6a, 6b, and 7) using the following Ora Calibra CAC Tearing/Watery Eyes Scale 
(half unit increments are NOT allowed): 
 
 
 
 
 
Tearing/watery eyes will be analyzed as a quantitative variable as described at the beginning of Section 
13.2. 
13.2.5 Eyelid Swelling 
Eyelid swelling will be evaluated by the subject at 7(±1), 15(±1) and 20(±1) post-CAC at all dosing visits 
(Visits 4b, 5a, 5b, 6a, 6b, and 7) using the following Ora Calibra® CAC Eyelid Swelling Scale (half unit 
increments are NOT allowed): 
 
 
 
  
 
Eyelid swelling will be analyzed as a quantitative variable as described at the beginning of Section 13.2. 
13.2.6 Rhinorrhea 
Rhinorrhea (runny nose) will be evaluated by the subject at 7(±1), 15(±1) and 20(±1) post-CAC at all 
dosing visits (Visits 4b, 5a, 5b, 6a, 6b, and 7) using the following Ora Calibra® Rhinorrhea Scale (half 
unit increments are NOT allowed): 
 
 
 
 


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Rhinorrhea will be analyzed as a quantitative variable as described at the beginning of Section 13.2. 
13.2.7 Nasal Pruritus and Ear or Palate Pruritus 
Nasal pruritus (itchy nose) and ear or palate pruritus (itch ear or palate) will be evaluated by the subject 
at 7(±1), 15(±1) and 20(±1) post-CAC at all dosing visits (Visits 4b, 5a, 5b, 6a, 6b, and 7) using the 
following Ora Calibra® Nasal Pruritus / Ear or Palate Pruritus Scales (half unit increments are NOT 
allowed): 
 
 
 
 
 
Nasal pruritus and ear or palate pruritus will be analyzed as quantitative variables as described at the 
beginning of Section 13.2. 
13.2.8 Nasal Congestion 
Nasal congestion will be evaluated by the subject at 7(±1), 15(±1) and 20(±1) post-CAC at all dosing 
visits (Visits 4b, 5a, 5b, 6a, 6b, and 7) using the following Ora Calibra® Nasal Congestion Scale (half 
unit increments are NOT allowed): 
 
 
 
 
 
Nasal congestion will be analyzed as a quantitative variable as described at the beginning of Section 
13.2. 
14. Safety Analyses 
All safety analyses will be conducted using the Safety population. 
14.1 
Adverse Events 
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 


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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) 
associated with medical device. 
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 CRF. 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. 
Collection of AEs/SAEs will begin at the time of informed consent. Any AE that occurs or worsens after 
the first instillation of the IP will be classified as a treatment-emergent AE (TEAE). All AEs will be coded 
using the MedDRA Version 20.1. 
An AE is considered serious if, in the view of either the investigator or sponsor/designee, 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 an inpatient admission for more 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.  
An overnight stay in the hospital that is only due to transportation, organization or 
accommodation problems and without medical background does not need to be 
handled/documented as an SAE. Hospitalizations due to surgical procedures for pre-existing 
conditions that have been planned before enrolment of the subject are not considered SAEs.  


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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: An 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.  
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, requires no special treatment 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.  
The relationship of each AE to the IP should be determined by the investigator using these explanations: 
• Suspected: A reasonable possibility exists that the study drug caused the AE. A suspected AE can 
be further defined as: 
o 
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. 
o 
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. 


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o 
Possible: Relationship exists when the AE follows a reasonable sequence from the time of 
administration, but could also have been produced by the subject’s clinical state or by other 
drugs administered to the subject. 
• Not Suspected: A reasonable possibility does not exist that the study drug caused the AE. A not 
suspected AE can further be defined as: 
o 
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. 
An overall summary will be presented that includes the number of TEAEs and the number and 
percentage of subjects who experienced at least one TEAE, by treatment group.  This summary will also 
include breakdowns of TEAEs further categorized as ocular or non-ocular, serious TEAEs, TEAEs by 
maximum severity, TEAEs by maximum relationship to IP,  TEAEs leading to IP withdrawal, and number 
of subjects with TEAEs resulting in death.  
Additional summaries of AEs will be provided showing the number and percentage of subjects who 
experienced at least one AE. These summaries will be presented by SOC and PT. AEs will be 
summarized using counts and percentages and presented by treatment group at the subject level by 
SOC and PT.  If a subject reports the same PT multiple times within the same SOC, that PT will only be 
reported once within that SOC.  As with the PT, if a subject reports multiple conditions within the same 
SOC, that SOC will only be reported once.  In the summary, SOC will be listed in order of decreasing 
frequency for all subjects; PTs will be listed in order of descending frequency for all subjects within each 
SOC.  The occurrence of non-ocular and ocular AEs will also be tabulated by SOC, PT and maximal 
severity. If a subject has multiple AEs coded to the same PT within the same SOC, the subject will be 
counted once under the maximal severity. 
Separate summaries will be provided for the following categories of AEs:  
• 
All Ocular AEs 
• 
All Ocular AEs by Study Phase 
• 
All Non-Ocular AEs 
• 
All Ocular TEAEs 
• 
All Non-Ocular TEAEs 
• 
All Ocular SAEs 
• 
All Non-Ocular SAEs 
• 
All Ocular TEAEs by Maximal Severity 
• 
All Non-Ocular TEAEs by Maximal Severity 


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Subject listings will be provided for all AEs, SAEs, TEAEs, AEs leading to study treatment 
discontinuation and AEs leading to death. 
14.2 
Slit-Lamp Biomicroscopy Examination 
A slit-lamp biomicroscopy examination will be performed at Visits 2, 3, 4a, 4b, 5a,  5b, 6a, 6b, and 7 
prior to the CAC and again post-CAC at Visit 7, and will consist of the examination of the following items: 
• 
Anterior Chamber 
• 
Conjunctiva 
• 
Cornea 
• 
Eyelid 
• 
Lens 
The results will be graded as normal, abnormal not clinically significant (NCS), or abnormal clinically 
significant (CS). The results will be summarized using counts and percentages for each treatment 
group for all eyes combined. Percentages will be based on the number of subject eyes in each 
treatment group with responses.  A shift table will also be produced showing changes from baseline in 
slit-lamp examination results for each treatment and post-baseline assessment. 
A subject listing of the slit-lamp biomicroscopy parameters will also be produced. 
14.3 
Dilated Ophthalmoscopy  
Dilated fundoscopy examinations will be performed post-CAC at Visits 2 and 7. Counts and percentages 
of normal and abnormal results will be presented for all eyes combined by visit and treatment group for 
the following regions:  
• 
Choroid  
• 
Macula 
• 
Optic Nerve 
• 
Retina 
• 
Vitreous 
Percentages will be based on the number of subject eyes in each treatment group with responses.  A 
shift table will also be produced showing changes from baseline in dilated fundoscopy examination 
results for each treatment and post-baseline assessment. Results will be listed for both eyes at each 
visit. 
14.4 
Visual Acuity  
Visual acuity will be assessed using an ETDRS at Visits 2, 3, 4a, 4b, 5a,  5b, 6a, 6b, and 7 prior to the 
CAC. For Visit 7, it will be measured again post-CAC.  


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VA  for each eye will be calculated as the last line in which a letter is read correctly. To this value will be 
added the number “N x 0.02” where “N” represents the total number of letters missed up to and included 
in the last line read. This total sum represents the logarithm of the minimum angle of resolution (logMAR) 
VA for that eye. 
For Example: Subject correctly reads four (4) of five (5) letters on the 0.2 line, and two (2) of five (5) 
letters on the 0.1 line. 
Base logMAR 
= 0.1 
N (total number of letters incorrect on 
line 0.2 as well as 0.1) 
= 4 
N x T (T=0.2) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
VA in logMAR unit will be summarized by treatment using the average of both eyes for each subject 
with quantitative summary statistics. The number of subjects with worsening of acuity of 10 letters (0.2 
logMAR) or more from Visit 2 will also be summarized with counts and percentages based on the total 
number of subjects in each treatment group with responses. Results for VA will be presented in a data 
listing.  
14.5 
Intraocular Pressure 
Intraocular pressure will be measured and recorded in mmHg post-CAC at Visits 2 and 7 and will be 
summarized with quantitative summary statistics by treatment using the average of both eyes for each 
subject. The number of subjects at Visit 7 with an IOP greater than or equal to 30 mmHg and with an 
increase of at least 10 mmHg in IOP from baseline will be summarized separately with counts and 
percentages. IOP will be listed for each eye at each visit. 
15. Tolerability Analysis 
All tolerability analyses will be conducted using the Safety population. 
15.1 
Drop Comfort Scale 
Drop comfort will be assessed for each eye immediately upon instillation, at 30 seconds, and one minute 
post-instillation of the IP following initial dosing at Visit 4a using the Ora Calibra® Drop Comfort Scale 
which ranges from 0 (very comfortable) to 10 (very uncomfortable) in one unit increments. 
Subject response will be summarized with quantitative summary statistics by treatment using the 
average of both eyes for each subject in the Safety population. Two-sample t-tests will be used to 


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compare each active treatment to vehicle and each dose of PRT-2761 to Patanol® and the resulting p-
values will be reported. Drop comfort scale responses will be listed for each eye at each  time point. 
15.2 
Drop Comfort Questionnaire 
Description of drop comfort will be assessed at three minutes following initial dosing at Visit 4a using 
the Ora Calibra™ Drop Comfort Questionnaire. The subjects will be asked to choose three words that 
best describe how each eye drop feels in both of his/her eyes. The following list will be provided to each 
subject as possible descriptor words: 
• 
Burning 
• 
Comfortable 
• 
Cool 
• 
Filmy 
• 
Gentle 
• 
Gritty 
• 
Irritating 
• 
Refreshing 
• 
Smooth 
• 
Soothing 
• 
Sticky 
• 
Stinging 
The number and percentage of subjects in the Safety population selecting each of the descriptor words 
above (along with responses of “Other”) will be presented by treatment group. A listing of the drop 
comfort questionnaire responses will also be provided. 
16. Exploratory Analysis 
The following exploratory measures will be collected using the respective scales as previously defined; 
select measures will be listed and summarized by treatment group, visit and time point as applicable: 
• 
Ocular itching evaluated by the subject at Visit 5b, 6a, 6b, and 7 at 15(±1), 20(±1), 25(±1) and 
30(±1) minutes post-CAC (0-4 scale, allowing half-unit increments) 
• 
Tearing evaluated by the subject at Visits 5b, 6a, 6b, and 7 at 25(±1) and 30(±1) minutes post-
CAC (0-4 scale, NOT allowing half-unit increments) 
• 
Eyelid swelling evaluated by the subject at Visits 5b, 6a, 6b, and 7 at 25(±1) and 30(±1) 
minutes post-CAC (0-3 scale, NOT allowing half-unit increments) 
• 
Rhinorrhea, nasal pruritis, ear or palate pruritis, and nasal congestion evaluated by the subject 
at Visits 5b, 6a, 6b, and 7 at 25(±1) and 30(±1) minutes post-CAC (0-4 scale, NOT allowing 
half-unit increments). 
• 
Conjunctival, episcleral, and ciliary redness evaluated by the investigator at Visit 5b, 6a, 6b, 
and 7 at 25(±1) and 30(±1) minutes post-CAC (0-4 scale, allowing half-unit increments).  
• 
Chemosis evaluated by the investigator at Visit 5b, 6a, 6b, and 7 at 25(±1) and 30(±1) minutes 
post-CAC (0-4 scale, allowing half-unit increments).