A Phase 2, Multicenter, Randomized, Double-Masked and Placebo-Controlled Study Evaluating the Efficacy of Two Concentrations (0.10%, 0.25%) of HL036 Ophthalmic Solution Compared to Placebo in Subjects With Dry Eye
Phase: PHASE2
Conditions: Dry Eye
Sponsor: HanAll BioPharma Co., Ltd.

CLINICAL TRIAL PROTOCOL 
Study Title: 
A Phase 2, Multicenter, Randomized, Double–
Masked and Placebo–Controlled Study Evaluating 
the Efficacy of Two Concentrations (0.10%, 
0.25%) of HL036 Ophthalmic Solution Compared 
to Placebo in Subjects with Dry Eye  
Protocol Number: 
HL036-DED-US-P201 
Development Phase: 
Phase 2 
Investigational Product: 
HL036 Ophthalmic Solution 
IND Number: 
135371 
Indication: 
Dry eye disease 
Investigators 
Multi-centered (Up to 3 sites) 
Sponsor: 
HanAll Biopharma, Co., Ltd.  
12th Floor, Gyeonggi Bio-Center, 
147 Kwangkyo-ro, Yeongtong-gu 
Suwon, Gyeonggi-do, 16229 
Korea 
Contract Research Organization 
Ora, Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 
HanAll Biopharma’s Responsible 
Medical Officer: 
 
General Manager, Product and Business 
Development 
HPI, Inc. 
HanAll BioPharma Co., Ltd 
1 Church Street, Suite #103 
Rockville, MD 20850 
 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico 
Suite C, #497 
San Clemente, CA 92673 
USA 
Date of Protocol: 
Original Protocol: 
22 Sep 2017 
Amendment 1: 
31 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. 
HL036 Ophthalmic Solution 
Clinical Trial Protocol HL036-DED-US-P201
Sponsor: HanAll Biopharma, Co., Ltd
31 OCTOBER 2017
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SPONSOR PERSONNEL 
General Manager, Product and 
Business Development, HPI, Inc: 
 
General Manager, Product and Business 
Development 
HPI, Inc. 
 
HanAll BioPharma Co., Ltd 
1 Church Street, Suite #103 
Rockville, MD 20850 
 
 
MEDICAL MONITOR 
Medical Monitor:  
 
 
 
 
ORA PERSONNEL 
Department Vice President: 
 
 
 
 
Department Senior Manager: 
 
 
 
 
Clinical Project Manager: 
 
 
 
 
 
 
HL036 Ophthalmic Solution 
Clinical Trial Protocol HL036-DED-US-P201
Sponsor: HanAll Biopharma, Co., Ltd
31 OCTOBER 2017
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Page 2 of 81

SYNOPSIS 
NAME OF COMPANY 
HanAll Biopharma, Co., Ltd.  
12th Floor, Gyeonggi Bio-Center 
147 Kwangkyo-ro, Yeongtong-gu,  
Suwon, Gyeonggi-do, Korea 
NAME OF DRUG PRODUCT 
HL036 Ophthalmic Solution for Treatment of Dry Eye 
 
TITLE OF STUDY:  
A Phase 2, Multicenter, Randomized, Double–Masked and Placebo–Controlled Study Evaluating 
the Efficacy of Two Concentrations (0.10% and 0.25%) of HL036 Ophthalmic Solution Compared 
to Placebo in Subjects Diagnosed with Dry Eye   
PROTOCOL NUMBER: 
HL036-DED-US-P201 
STUDY SITES: 
Multicenter study involving up to 3 sites located in the United 
States 
STUDY PERIOD: 
Approximately 70 days 
PHASE OF DEVELOPMENT: 
Phase 2 
STUDY FORMULATIONS: 
 
0.10% HL036 Ophthalmic Solution  
0.25% HL036 Ophthalmic Solution 
Placebo Vehicle Solution 
OBJECTIVE: 
The objective of this study is to compare the safety and efficacy of 0.10% and 0.25% HL036 
Ophthalmic Solutions to placebo for the treatment of the signs and symptoms of dry eye. 
DOSE, ROUTE AND REGIMEN:  
Screening: Between Visits 1 and 2, all subjects will receive 14 consecutive days (± 2) of open–label 
placebo ocular drops self–administered BID in both eyes in the morning and the evening. 
Treatment: During the 8–week (56 ± 2 days) treatment period, HL036 Ophthalmic Solution at 
concentrations of 0.25%, 0.10% or placebo solution will be administered BID by bilateral topical 
ocular dosing. Subjects will be randomized to one of three treatment arms (1:1:1) to receive study 
drug administered by trained study personnel after the Post–CAE® #2 assessments at Visit 2.  
DURATION OF TREATMENT:  
Approximately 56 days (8 weeks) 
REFERENCE THERAPY, DOSE, ROUTE AND REGIMEN:  
Open–label placebo solution (placebo) will be provided to subjects from Day –14 to Day 0. Placebo 
ocular drops will be self–administered BID in both eyes in the morning and the evening. 
Following randomization, placebo will be dosed according to the same schedule as the HL036 
Ophthalmic Solution concentrations.  
NUMBER OF SUBJECTS PLANNED:  
Approximately 150 subjects will be enrolled in the study. The total number of expected participants, 
including screen failures, is approximately 375 subjects. 
 
 
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DIAGNOSIS AND ALL CRITERIA FOR INCLUSION AND EXCLUSION:  
INCLUSION CRITERIA: 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Be at least 18 years of age; 
2. Provide written informed consent; 
3. Be willing and able to comply with all study procedures; 
4. Have a patient-reported history of dry eye for at least 6 months prior to enrollment; 
5. Have a history of use or desire to use eye drops for dry eye symptoms within 6 months of Visit 
1; 
6. Have a best corrected visual acuity of 
 logMAR or better (Snellen equivalent score of 
 
) in each eye at Visit 1; 
7. Report in the study eye DVFRUHRI
DFFRUGLQJWRthe Ora Calibra® Ocular Discomfort and 4-
Symptom Questionnaire in at least one of the dry eye symptoms at Visits 1 and 2; 
8. Have in the study eye D6FKLUPHU¶V7HVWVFRUHRIPPDQGPPDW9LVLWVDQG 
9. Have in the study eye DFRUQHDOIOXRUHVFHLQVWDLQLQJVFRUHRI
in at least one region of the 
cornea (
) according to the Ora Calibra® Corneal and Conjunctival 
Staining Scale for Grading of Fluorescein Staining in at least one eye at Visits 1 and 2; 
10. Have in the study eye DFRQMXQFWLYDOUHGQHVVVFRUH DFFRUGLQJWRthe Ora Calibra® 
Conjunctival Redness for Dry Eye Scale in at least one eye at Visits 1 and 2;  
11. Demonstrate in the study eye a response to the CAE® at Visits 1 and 2 as defined by: 
a) 
 
 
 
 
 
 
 
 
  
12. A negative urine pregnancy test if female of childbearing potential (those who are not surgically 
sterilized [bilateral tubal ligation, hysterectomy or bilateral oophorectomy] or post–menopausal 
[12 months after last menses]) and must use adequate birth control throughout the study period. 
Adequate birth control is defined as hormonal–oral, implantable, injectable, or transdermal 
contraceptives; mechanical–spermicide in conjunction with a barrier such as condom or 
diaphragm; intrauterine device (IUD); or surgical sterilization of partner. For non–sexually 
active females, abstinence may be regarded as an adequate method of birth control. 
EXCLUSION CRITERIA: 
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the 
study: 
1. Have any clinically significant slit lamp findings at Visit 1 that may include active blepharitis, 
meibomian gland dysfunction (MGD), lid margin inflammation or active ocular allergies that 
require therapeutic treatment, and/or in the opinion of the investigator may interfere with study 
parameters; 
2. Be diagnosed with an ongoing ocular infection (bacterial, viral, or fungal), or active ocular 
inflammation at Visit 1; 
3. Have worn contact lenses within 7 days of Visit 1 or anticipate using contact lenses during the 
study; 
4. Have previously had laser-assisted in situ keratomileusis (LASIK) surgery within the last 12 
HL036 Ophthalmic Solution 
Clinical Trial Protocol HL036-DED-US-P201
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31 OCTOBER 2017
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months; 
5. Have used Restasis® or Xiidra® within 60 days of Visit 1; 
6. Have any planned ocular and/or lid surgeries over the study period; 
7. Be using or anticipate using temporary punctal plugs during the study that have not been stable 
within 30 days of Visit 1; 
8. Be currently taking any topical ophthalmic prescription (including medications for glaucoma) or 
over-the-counter (OTC) solutions, artificial tears, gels or scrubs, and cannot discontinue these 
medications for the duration of the trial (excluding medications allowed for the conduct of the 
study); the respective wash-out periods are required for the following medications: 
a) Antihistamines (including ocular):  72 hours prior to Visit 1 
b) Oral aspirin or aspirin–containing products allowed if dose has been stable over past 
30 days prior to Visit 1 and no change in dose anticipated during the study period 
c) Corticosteroids or mast cell stabilizers (including ocular):  14 days prior to Visit 1 
d) Any medication (oral or topical) known to cause ocular drying that has not been 
administered as a stable dose for at least 30 days prior to Visit 1 and during the study 
e) All other topical ophthalmic preparations (including artificial tear substitutes) other than 
the study drops:  72 hours prior to Visit 1 
9. Have an uncontrolled systemic disease; 
10. Be a woman who is pregnant, nursing or planning a pregnancy;  
11. Be unwilling to submit a urine pregnancy test at Visit 1 and Visit 6 (or early termination visit) if 
of childbearing potential.  Non-childbearing potential is defined as a woman who is 
permanently sterilized (e.g. has had a hysterectomy or tubal ligation), or is post-menopausal 
(without menses for 12 consecutive months); 
12. Be a woman of childbearing potential who is not using an acceptable means of birth control; 
acceptable methods of contraception include: hormonal – oral, implantable, injectable, or 
transdermal contraceptives; mechanical – spermicide in conjunction with a barrier such as a 
diaphragm or condom; IUD; or surgical sterilization of partner.  For non-sexually active 
females, abstinence may be regarded as an adequate method of birth control; however, if the 
subject becomes sexually active during the study, she must agree to use adequate birth control 
as defined above for the remainder of the study; 
13. Have a known allergy and/or sensitivity to the test article or its components; 
14. Have a condition or be in a situation which the investigator feels may put the subject at 
significant risk, may confound the study results, or may interfere significantly with the subject’s 
participation in the study; 
15. Be currently enrolled in an investigational drug or device study or have used an investigational 
drug or device within 30 days of Visit 1; 
16. Be unable or unwilling to follow instructions, including participation in all study assessments 
and visits. 
METHODOLOGY:  
Study Design 
Multicenter, randomized, prospective, double–masked, placebo–controlled, parallel–arm design. 
Approximately 150 subjects will be randomly assigned to one of three treatment groups (1:1:1) to 
receive either HL036 Ophthalmic Solution (0.10%, 0.25%) or placebo solution as topical 
ophthalmic drops administered bilaterally BID. Subjects, Sponsor, CRO and site personnel will be 
masked to treatment assignments.  
The study will be conducted in two periods: screening and treatment. A total of two screening 
challenges with the Controlled Adverse Environment (CAE®) are scheduled during the screening 
period. The CAE will also be used to assess subjects during the treatment period at Visits 4, 5, and 
HL036 Ophthalmic Solution 
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31 OCTOBER 2017
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6. 
The total number of expected participants, including CAE® screen failures, is approximately 375 
subjects. 
The screening period consists of two visits (Visits 1 and 2). Each visit includes exposure to the 
CAE®. Subjects must have a positive response (defined below) in at least one eye at Visit 1 
(screening challenge #1) and replicate the response in the same eye at Visit 2 (confirmatory 
screening challenge #2) in order to continue to be eligible for the study. The specific eye meeting 
these requirements will be designated as the study eye. 
Visit 1: Day –14 CAE Screening  
x 
Evaluation (Pre– CAE® #1) 
o After informed consent is obtained from study subjects, subjects will undergo 
preliminary screening that includes obtaining demographic data, medical and 
medication history, inclusion/exclusion criteria evaluation, and urine pregnancy test 
(as appropriate). 
o Subjects will undergo preliminary screening as follows. 
¾ Completion of subject questionnaires  
o Ocular discomfort scoring :Ora Calibra® Ocular Discomfort Scale 
and Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire 
o Ocular discomfort using a visual analog scale (VAS) 
o OSDI 
¾ Ocular examination assessments  
o BCVA  
o Slit–lamp biomicroscopy 
o Conjunctival redness 
o TFBUT 
o Corneal and conjunctival staining (with fluorescein and lissamine 
green)  
x 
Screening Challenge  
o Subjects meeting all of the evaluation criteria at this visit will undergo further 
screening evaluation in the CAE®. Subjects will be exposed to the CAE for 
 
 Ocular discomfort self–assessment scores (ODS) will be obtained just 
prior to entering, during and just after the CAE® exposure.  
o During the CAE® exposure, ODS will be collected at 
 
. 
x 
Post- CAE®  
o Upon exiting the CAE®, subjects will complete as follows. 
¾ Inclusion/exclusion criteria evaluation 
¾ Discomfort questionnaires  
o Ora Calibra® Ocular Discomfort Scale and Ora Calibra® Ocular 
Discomfort and 4-Symptom Questionnaire 
o VAS discomfort scale 
¾ Ocular examination assessments  
o Slit lamp biomicroscopy 
o Conjunctival redness 
o TFBUT  
o Corneal and conjunctival staining (with fluorescein and lissamine 
HL036 Ophthalmic Solution 
Clinical Trial Protocol HL036-DED-US-P201
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31 OCTOBER 2017
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green) 
o Schirmer’s test 
o Intraocular pressure (IOP)  
o Dilated fundoscopy  
¾ AE review 
o Eligible subjects must have a positive response in at least one eye. A positive 
response is defined as meeting ALL of the following criteria in the same eye: 
¾ Having at least a 
 point increase in fluorescein staining in the inferior 
region in at least one eye following CAE® exposure; 
¾ Reporting an Ocular Discomfort score 
 at 2 or more consecutive time 
points in at least one eye during CAE® exposure (
 
  
 
o Following the screening procedures at this visit, all subjects who meet all eligibility 
criteria and have a positive response (as defined above) will self-administer their 
initial dose of placebo drops (open–label, single drop, OU), for training purposes, at 
the study site under supervision of trained study personnel following the last Post– 
CAE® #1 study assessment. Only a single dose of placebo drops will be 
administered OU on Day –14.  
o Prior to discharge from the study site on Day –14, subjects will be dispensed 
sufficient placebo supply to last until Visit 2 and will be educated in study drug 
diary recording and self–administration of placebo. Subjects will be instructed to 
self–administer one drop BID in each eye in the morning and the evening until 
screening Visit 2. Subjects will be scheduled for Visit 2 during Visit 1. Subjects will 
be instructed NOT to instill study drug on the morning of their next scheduled study 
visit (Visit 2, Day 1).  
 
Days –14 thru Day -1 
o Subjects will self-administer a single drop of open–label placebo treatment 
bilaterally in the morning and the evening (BID) from Day –14 and continue 
through Day 0. Placebo will be provided in single–use unit dose vials. Subjects will 
report AEs and record study drug dosing information in the study drug diary.  
Visit 2: Day 1 – CAE® Confirmation and Baseline 
o Placebo vials and study drug diaries will be collected. 
o Site staff must confirm subjects have NOT administered their morning placebo dose 
at home. 
x 
Pre– CAE® #2 
o Subjects will undergo preliminary screening as follows. 
¾ Inclusion/exclusion criteria evaluation 
¾ AE and concomitant medication review 
¾ Completion of subject questionnaires  
o Ocular discomfort scoring: Ora Calibra® Ocular Discomfort Scale 
and Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire 
o OSDI 
HL036 Ophthalmic Solution 
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31 OCTOBER 2017
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o VAS discomfort scale 
¾ Ocular examination assessments  
o BCVA  
o Slit–lamp biomicroscopy 
o Conjunctival redness 
o TFBUT 
o Corneal and conjunctival staining (with fluorescein and lissamine 
green)  
o Tear collection from both eyes 
x 
Confirmatory Screening Challenge (CAE® #2) 
o Ocular discomfort self–assessment scores (ODS) will be obtained just prior to 
entering, during and just after the CAE® exposure.  
o During the CAE® exposure, ODS will be collected at 
 
thereafter throughout the
. 
x 
Post– CAE® #2 
o Upon exiting the CAE®, subjects will complete the following assessments. 
¾ Inclusion/exclusion evaluation 
¾ Ocular discomfort scoring 
o Ora Calibra® Ocular Discomfort Scale and Ora Calibra® Ocular 
Discomfort and 4-Symptom Questionnaire 
o VAS discomfort scale 
¾ Ocular examination assessments  
o Slit lamp biomicroscopy 
o Conjunctival redness 
o TFBUT 
o Corneal and conjunctival staining (with fluorescein and lissamine 
green) 
o Schirmer’s test 
¾ AE review 
o Eligible subjects must replicate a positive response at this visit in the same eye as 
was elicited in Visit 1. A positive response is defined as meeting ALL of the 
following criteria in the same eye: 
¾ Having at least a 
 point increase in fluorescein staining in the inferior 
region in at least one eye following CAE® exposure; 
¾ Reporting an Ocular Discomfort score 
 at 2 or more consecutive time 
points in at least one eye during CAE® exposure
 
 
x 
Randomization 
o All subjects having a positive response (as defined above) and meeting all other 
screening eligibility criteria for Visit 2 will be randomized to one of three treatment 
arms.  
o Blood sampling for Immunogenicity testing 
o Randomized subjects will self-administer their initial study drug dose at the study 
HL036 Ophthalmic Solution 
Clinical Trial Protocol HL036-DED-US-P201
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31 OCTOBER 2017
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site. 
o A drop comfort evaluation will be performed immediately and then at 1, 2 and 3 
minutes following initial dosing (post–randomization).   
o Monitoring and query of AEs 
o Prior to discharge from the study site on Visit 2 (Day 1), randomized subjects will 
be educated in study drug diary recording and self–administration of study drug. 
Subjects will receive their assigned study drug kit with sufficient supply to last until 
Visit 3 and will be instructed NOT to self–administer study drug on the morning of 
their next scheduled study visit (Visit 3, Day 8).  
o Screening procedures must be completed within 2 days of Day 1. Subjects will be 
scheduled for Visit 3 during Visit 2. 
Days 1 to 7 
o Subjects will begin out–patient self–administered study drug treatment (BID) in the 
morning and the evening of Day 1 and continue through Day 7. Study drug will be 
provided in single–use unit dose vials. Subjects will administer a single drop 
bilaterally during waking hours in the morning and the evening. Subjects will be 
instructed to report AEs and record study drug dosing information in the study drug 
diary. 
Day 8±1 (Visit 3) 
There is no CAE® evaluation at Day 8, Visit 3.  
o Study drug vials and study drug diaries will be collected. Site staff must confirm 
that subjects have NOT administered their morning study drug dose at home. 
Subjects will undergo repeat assessments as follows.  
o AE and concomitant medication review 
o Completion of subject questionnaires  
¾ Ora Calibra® Ocular Discomfort Scale and Ora Calibra® Ocular Discomfort 
and 4-Symptom Questionnaire 
¾ OSDI 
¾ VAS discomfort scale 
o Ocular examination assessments  
¾ BCVA 
¾ Slit-lamp biomicroscopy 
¾ Conjunctival redness 
¾ TFBUT 
¾ Corneal and conjunctival staining (with fluorescein and lissamine green) 
o Subjects will self-administer their first study drug dose bilaterally for Day 8 at the 
study site following the last study assessment. The subject will administer the 
evening dose at home. 
o Monitoring and Query of AEs 
o Prior to discharge from the study site on Visit 3 (Day 8), subjects will be educated 
in study drug diary recording and self–administration of study drug.  
o Used vials will be collected from study kits and the remaining vials of study drug 
will be returned to subjects. Subjects will be instructed to NOT self–administer 
study drug on the morning of their next scheduled study visit (Visit 4, Day 15). 
o Subjects will be scheduled for Visit 4 during Visit 3.  
 
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31 OCTOBER 2017
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Day 8 thru 14 ± 2 
o Subjects will continue to self–administer study drug bilaterally in the morning and 
the evening (BID) of Day 8 and continue through Day 14 ± 2. Study drug will be 
provided in single–use unit dose vials.  
o Subjects will be instructed to report AEs and record study drug dosing information 
in the study drug diary. 
Visit 4, Day 15 ± 2 
x 
Pre- CAE® 
o Study drug vials and study drug diaries will be collected. Site staff must confirm 
that subjects have NOT administered their morning study drug dose at home.  
o Subjects will undergo repeat assessments as follows. 
¾ AE and concomitant medication review 
¾ Completion of subject questionnaires  
o Ora Calibra® Ocular Discomfort Scale and Ora Calibra® Ocular 
Discomfort and 4-Symptom Questionnaire 
o OSDI 
o VAS discomfort scale 
¾ Ocular examination assessments 
o BCVA 
o Slit-lamp biomicroscopy 
o Conjunctival redness 
o TFBUT 
o Corneal and conjunctival staining (with fluorescein and lissamine 
green) 
x 
CAE® 
o During the CAE® exposure, ODS will be collected at time
 
 
x 
Post-CAE® 
o Upon exiting the CAE®, subjects will complete the following assessments. 
¾ Ocular discomfort scoring  
o Ora Calibra® Ocular Discomfort Scale and Ora Calibra® Ocular 
Discomfort and 4-Symptom Questionnaire 
o VAS discomfort scale 
¾ Ocular examination assessments  
o Slit lamp biomicroscopy 
o Conjunctival redness 
o TFBUT 
o Corneal and conjunctival staining (with fluorescein and lissamine 
green) 
o Schirmer’s test 
¾ AE review 
o Blood sampling for Immunogenicity testing 
o Prior to discharge from the study site on Visit 4 (Day 15), subjects will be educated 
in study drug diary recording and self–administration of study drug. Subjects will 
receive their assigned study drug kit with sufficient supply to last until Visit 5 and 
HL036 Ophthalmic Solution 
Clinical Trial Protocol HL036-DED-US-P201
Sponsor: HanAll Biopharma, Co., Ltd
31 OCTOBER 2017
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will be instructed to NOT self–administer study drug on the morning of their next 
scheduled study visit (Visit 5, Day 29). Subjects will be scheduled for Visit 5 during 
Visit 4. 
Day 15 thru 28 ±2 
o Subjects will continue out–patient self–administered study drug treatment (BID) in 
the morning and the evening of Day 15 and continue through Day 28 ± 2. Study 
drug will be provided in single–use unit dose vials. Subjects will self–administer a 
single drop bilaterally during waking hours in the morning and the evening. 
Subjects will be instructed to report AEs and record study drug dosing information 
in the study drug diary. 
Visit 5, Day 29 ± 2  
x 
Pre-CAE®  
o Study drug vials and study drug diaries will be collected. Site staff must confirm 
that subjects have NOT administered their morning study drug dose at home.  
o Subjects will undergo repeat assessments as follows. 
¾ AE and concomitant medication review 
¾ Completion of subject questionnaires  
o Ora Calibra® Ocular Discomfort Scale and Ora Calibra® Ocular 
Discomfort and 4-Symptom Questionnaire 
o OSDI 
o VAS discomfort scale 
¾ Ocular examination assessments 
o BCVA 
o Slit–lamp biomicroscopy 
o Conjunctival redness 
o TFBUT 
o Corneal and conjunctival staining (with fluorescein and lissamine 
green) 
x 
CAE® 
o During the CAE® exposure, ODS will be collected at time
 
 
x 
Post-CAE® 
o Upon exiting the CAE®, subjects will complete the following assessments. 
¾ Ocular discomfort scoring  
o Ora Calibra® Ocular Discomfort Scale and Ora Calibra® Ocular 
Discomfort and 4-Symptom Questionnaire 
o VAS discomfort scale 
¾ Ocular examination assessments 
o Slit lamp biomicroscopy 
o Conjunctival redness 
o TFBUT 
o Corneal and conjunctival staining (with fluorescein and lissamine 
green) 
o Schirmer’s test 
¾ AE review  
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o Blood sampling for Immunogenicity testing 
o Prior to discharge from the study site on Visit 5 (Day 29), subjects will be educated 
in study drug diary recording and self–administration of study drug. Subjects will 
receive their assigned study drug kit with sufficient supply to last until Visit 6 and 
will be instructed to NOT self–administer study drug on the morning of their next 
scheduled study visit (Visit 6, Day 57).  
o Subjects will be scheduled for Visit 6 during Visit 5. 
Day 29 thru 56 ± 3 
o Subjects will continue out–patient self–administered study drug treatment (BID) in 
the morning and the evening of Day 29 and continue through Day 56 ± 3. Study 
drug will be provided in single–use unit dose vials. Subjects will self–administer a 
single drop bilaterally during waking hours in the morning and the evening. 
Subjects will be instructed to report AEs and record study drug dosing information 
in the study drug diary. 
Visit 6: Day 57  ± 3 
x 
Pre-CAE® 
o Study drug vials and study drug diaries will be collected. Site staff must confirm 
that subjects have NOT administered their morning study drug dose at home.  
o Subjects will undergo the following assessments. 
¾ AE and concomitant medication review  
¾ Pregnancy tests will be conducted, as appropriate 
¾ Completion of subject questionnaires 
o Ora Calibra® Ocular Discomfort Scale and Ora Calibra® Ocular 
Discomfort and 4-Symptom Questionnaire 
o OSDI 
o VAS discomfort scale 
¾ Ocular examination assessments 
o BCVA 
o Slit-lamp biomicroscopy 
o Conjunctival redness 
o Tears will be collected and frozen for subsequent analyses  
o TFBUT 
o Corneal and conjunctival staining (with fluorescein and lissamine 
green) 
x 
CAE® 
o During the CAE® exposure, ODS will be collected at 
 
. 
x 
Post-CAE® 
o Upon exiting the CAE®, subjects will complete the following assessments. 
¾ Ocular discomfort scoring 
o Ora Calibra® Ocular Discomfort Scale and Ora Calibra® Ocular 
Discomfort and 4-Symptom Questionnaire 
o VAS discomfort scale 
¾ Ocular examination assessments 
o Slit lamp biomicroscopy 
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o Conjunctival redness 
o TFBUT 
o Corneal and conjunctival staining (with fluorescein and lissamine 
green) 
o Schirmer’s test 
o IOP 
o Dilated fundoscopy  
¾ Blood sampling for Immunogenicity testing 
¾ AE review  
Subjects will then exit the study treatment. 
ENDPOINTS:  
The primary efficacy endpoints of the study are: 
x 
Inferior corneal staining (sign) at Day 57 (Week 8) 
x 
Ocular discomfort score (symptom) at Day 57 (Week 8) 
The secondary efficacy endpoints of the study are: 
x 
Fluorescein staining by region: central, superior, inferior, temporal, nasal, corneal sum, 
conjunctival sum and total staining 
x 
Lissamine green staining by region: central, superior, inferior, temporal, nasal, corneal sum, 
conjunctival sum and total staining 
x 
TFBUT 
x 
Conjunctival redness  
x 
Schirmer’s Test   
x 
Symptoms  
x 
OSDI  
x 
Drop comfort  
x 
Daily diary 
x 
Tear mediators 
The safety endpoints of the study are: 
x 
Visual acuity 
x 
Slit-lamp evaluation 
x 
Adverse event query 
x 
IOP 
x 
Dilated fundoscopy 
x 
Immunogenicity to HL036 in Serum 
STATISTICAL METHODS:  
Analysis Populations 
x 
Intent-to-Treat Population – The intent-to-treat (ITT) population includes all randomized 
subjects.  The primary analysis will be performed on the ITT population with the Last 
Observation Carried Forward (LOCF) imputation method for missing values.  The ITT 
population may also be analyzed with observed data only (i.e., without LOCF) to assess 
sensitivity.  Subjects in the ITT population will be analyzed as randomized. 
x 
Per Protocol Population – The per protocol (PP) population includes subjects in the ITT 
population who do not have significant protocol deviations and who complete the study.  
Protocol deviations will be assessed prior to database lock and unmasking.  The PP 
population will be analyzed using observed data only for efficacy variables.  Subjects in 
the PP population will be analyzed as treated. 
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x 
Safety Population – The safety population includes all subjects who have received at least 
one dose of the investigational product.  The safety population will be analyzed for all 
safety assessments.  Subjects in the Safety population will be analyzed as treated.  
Sample Size 
This study is expected to enroll 50 subjects in each of the three treatment arms, for a total of 150 
randomized subjects.  Assuming a 10% drop out rate, 45 subjects per group are expected to 
complete the study.   
Assuming a common standard deviation in the change from baseline for the pre-CAE® inferior 
corneal fluorescein staining of 0.72 units, a sample size of 45 subjects per group will have 90% 
power to detect a difference of 0.5 units between each of the active treatment groups and the placebo 
group using a two-sample t-test at a significance level of 0.05.  A sample size of 45 subjects per 
treatment arm will have 90% power to detect a mean difference of 0.80 units in the change from 
baseline for the pre-CAE® ocular discomfort as assessed by the Ora Calibra® Ocular Discomfort 
Scale, assuming a standard deviation of 1.15 units.  Therefore the power for each endpoint for both 
the sign and the symptom is 81%, assuming independence between the endpoints.  The power for 
both the sign and the symptom in both active treatments is 66%, assuming independence of 
treatments. 
Multiplicity Consideration: 
For success, significance is required for both the primary sign and the primary symptom, and for 
both active treatments, hence no multiplicity adjustment is necessary. 
Primary Efficacy Analyses:  
For both coprimary endpoints, pre-CAE® change from baseline will be calculated as visit – baseline 
such that a positive difference indicates a worsening of dry eye signs.  In addition, treatment 
comparisons between active and placebo will be calculated as active – placebo, such that a negative 
result indicates a better score for the active treatment (i.e., the active treatment had a smaller 
increase in dry eye signs than the placebo group).  The coprimary endpoints and changes from 
baseline will be summarized descriptively (n, mean, standard deviation, median, min and max) by 
visit and treatment group. 
ANCOVA models will be used to compare the change from baseline in the pre-CAE® inferior 
corneal fluorescein staining at Day 57 (Visit 6), as measured on the Ora Calibra® scale, between 
each dose of 0.25% and 0.10% HL036 Ophthalmic Solution and Placebo.  The ANCOVA models 
will include terms for baseline pre-CAE® inferior corneal fluorescein staining and study site.  In 
addition, the study site by treatment interaction will be explored in a separate model to evaluate how 
the treatment effect may differ across study sites.  As supportive analyses, two-sample t-tests and 
Wilcoxon rank sum tests will also be conducted.  The primary analysis will use MCMC multiple 
imputation to have a full accounting of the ITT population at the Day 57 visit, as described in 
Section 10.4.3. 
Ocular discomfort will be analyzed similarly.  ANCOVA models will be used to compare the 
change from baseline in the pre-CAE® ocular discomfort scores at Day 57 (Visit 6), as measured on 
the Ora Calibra® Ocular Discomfort Scale, between each dose of 0.25% and 0.10% HL036 
Ophthalmic Solution and Placebo.  The ANCOVA models will include terms for baseline (Visit 2) 
ocular discomfort and study site.  In addition, the study site by treatment interaction will be 
explored in a separate model to evaluate how the treatment effect may differ across sites.  As 
supportive analyses, two-sample t-tests and Wilcoxon rank sum tests will also be conducted.   
Secondary Efficacy Analyses: 
The continuous and ordinal secondary efficacy variables collected at each visit will be summarized 
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31 OCTOBER 2017
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descriptively (n, mean, standard deviation, median, min and max) by visit and treatment group, and 
analyzed with two-sample t-tests comparing each of the active treatment groups to placebo.  All 
visit-based data will be analyzed at each visit and change from baseline.  Change scores from pre- 
to post-CAE® will be calculated as Post-CAE® score – Pre-CAE® score.  A Wilcoxon rank sum test 
and an ANCOVA model adjusting for baseline and site will also be assessed where appropriate.  
No imputation will be performed for secondary efficacy variables. 
Fluorescein staining by region and total, Lissamine green staining by region, TFBUT, conjunctival 
redness, unanesthetized Schirmer’s test, Drop comfort assessment, OSDI, ocular discomfort and dry 
eye symptoms, ocular discomfort during CAE®, pre- to post-CAE® changes, and changes from 
baseline in these measures will be analyzed by visit using two-sample t-tests and Wilcoxon rank 
sum tests, as appropriate.   
The worst symptom for each subject will be identified as the symptom with the highest average 
score during the run-in period (Days -14 to -1) as recorded in the subject diary.  The worst 
symptom and each individual symptom will be analyzed per day using a two-sample t-test. 
Additionally, the average score for the worst symptom and each individual symptom will also be 
analyzed separately using a Wilcoxon rank sum test.  
Safety Variables 
Adverse events will be coded using the MedDRA dictionary.  Frequencies and percentages of 
subjects with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs causing 
premature discontinuation will be provided by treatment group.  An AE is treatment emergent if it 
occurs or worsens after the first dose of study treatment. Furthermore, frequencies will be given of 
subjects with TEAEs by system organ class, by system organ class and preferred term, by system 
organ class, preferred term and maximal severity, by system organ class, preferred term and 
strongest relationship, and by system organ class, preferred term, maximal severity, and strongest 
relationship.  Separate analyses will be performed for ocular specific and all AEs (including 
systemic). 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, dilated fundoscopy, and 
intraocular pressure will be summarized by treatment group and visit using descriptive statistics. 
Changes or shifts from baseline will also be summarized where appropriate.  For assessments 
performed by eye, study eye and fellow eye will be summarized separately.  In addition, shifts 
from baseline to worst on-treatment value for ocular safety assessments will be summarized. 
Immunogenicity will be summarized using discrete summary statistics.  Counts and proportions 
will be presented by visit and treatment group.  Exact 95% Clopper-Pearson confidence intervals 
will be presented.  Treatment groups will be compared using Fisher’s Exact Test, and exact 95% 
confidence intervals for the pairwise proportion differences will be constructed. 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ...................................................................................................16 
LIST OF ABBREVIATIONS ............................................................................................19 
1 INTRODUCTION .......................................................................................................21 
1.1 
Nonclinical Studies ..............................................................................................21 
1.2 
Previous Clinical Studies .....................................................................................22 
1.3 
Study Rationale ....................................................................................................22 
1.4 
Summary of Overall Risks and Benefits ..............................................................23 
2 STUDY OBJECTIVES ................................................................................................23 
3 CLINICAL HYPOTHESES ........................................................................................24 
4 OVERALL STUDY DESIGN .....................................................................................24 
5 STUDY POPULATION ..............................................................................................26 
5.1 
Number of Subjects ..............................................................................................26 
5.2 
Study Population Characteristics .........................................................................26 
5.3 
INCLUSION CRITERIA .....................................................................................26 
5.4 
Exclusion Criteria .................................................................................................27 
5.5 
Withdrawal Criteria ..............................................................................................28 
6 STUDY PARAMETERS .............................................................................................29 
6.1 
Efficacy Measures ................................................................................................29 
6.1.1 Primary Efficacy Endpoints ...........................................................................29 
6.1.2 Secondary Efficacy Endpoints .......................................................................30 
6.1.3 Criteria for Effectiveness ................................................................................30 
6.2 
Safety Measures ...................................................................................................31 
7 STUDY MATERIALS ................................................................................................31 
7.1 
Study Treatments..................................................................................................31 
7.1.1 Study Treatments ............................................................................................31 
7.1.2 Description and Justification for the Route of Administration, Dosage, 
Dosage Regimen, and Treatment Period ........................................................31 
7.1.3 Instructions for Use and Administration ........................................................31 
7.2 
Other Study Supplies ............................................................................................32 
8 STUDY METHODS AND PROCEDURES ...............................................................32 
8.1 
Subject Entry Procedures .....................................................................................32 
8.1.1 Overview ........................................................................................................32 
8.1.2 Informed Consent ...........................................................................................33 
8.1.3 Washout Intervals ...........................................................................................33 
8.1.4 Procedures for Final Study Entry ...................................................................33 
8.1.5 Methods for Assignment to Treatment Groups: .............................................33 
8.2 
Concurrent Therapies ...........................................................................................33 
8.2.1 Prohibited Medications/Treatments ...............................................................34 
8.2.2 Escape Medications ........................................................................................34 
8.2.3 Special Diet or Activities ...............................................................................34 
8.3 
Examination Procedures .......................................................................................34 
8.3.1 Visit 1: Day –14 ± 1 – CAE® Screening ........................................................34 
8.3.2 Visit 2:  Day 1 – CAE® Confirmation and Baseline ....................................37 
8.3.3 Visit 3 (Day 8) ................................................................................................38 
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8.3.4 Visit 4: Day 15 ± 2 .........................................................................................40 
8.3.5 Visit 5: Day 29 ± 2 .........................................................................................41 
8.3.6 Visit 6: Day 57 ± 3 .........................................................................................42 
8.4 
Schedule of Visits, Measurements and Dosing ....................................................43 
8.4.1 Scheduled Visits .............................................................................................43 
8.4.2 Unscheduled Visits .........................................................................................43 
8.5 
Compliance with Protocol ....................................................................................44 
8.6 
Subject Disposition ..............................................................................................44 
8.6.1 Completed Subjects ........................................................................................44 
8.6.2 Discontinued Subjects ....................................................................................44 
8.7 
STUDY TERMINATION ....................................................................................45 
8.8 
STUDY Duration .................................................................................................45 
8.9 
Monitoring and Quality Assurance ......................................................................45 
9 ADVERSE EVENTS ...................................................................................................46 
9.1.1 Severity ...........................................................................................................46 
9.1.2 Relationship to Investigational Product .........................................................46 
9.1.3 Expectedness ..................................................................................................47 
9.2 
Serious Adverse Events ........................................................................................48 
9.3 
Procedures for Reporting Adverse Events ...........................................................49 
9.3.1 Reporting a Suspected Unexpected Adverse Reaction ..................................49 
9.3.2 Reporting a Serious Adverse Event ................................................................49 
9.4 
Procedures for Unmasking (if applicable) ...........................................................50 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ..............50 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES ........................50 
10.1 Analysis Populations ............................................................................................50 
10.2 Statistical Hypotheses ..........................................................................................51 
10.3 Sample Size ..........................................................................................................51 
10.4 Statistical Analysis ...............................................................................................52 
10.4.1 General Considerations ..................................................................................52 
10.4.2 Unit of Analysis ..............................................................................................52 
10.4.3 Missing Data ...................................................................................................53 
10.4.4 Multiplicity Consideration .............................................................................53 
10.4.5 Primary Efficacy Analyses .............................................................................53 
10.4.6 Secondary Efficacy Analyses .........................................................................54 
10.4.7 Safety Variables .............................................................................................54 
10.4.8 Interim Analyses .............................................................................................55 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES .......................................55 
11.1 Protection of Human Subjects ..............................................................................55 
11.1.1 Subject Informed Consent ..............................................................................55 
11.1.2 Institutional Review Board (IRB) Approval ..................................................56 
11.2 Ethical Conduct of the Study ...............................................................................56 
11.3 Subject Confidentiality .........................................................................................56 
11.4 Documentation .....................................................................................................56 
11.4.1 Retention of Documentation ..........................................................................57 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product .........................................................................................57 
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11.5.1 Labeling/Packaging ........................................................................................57 
11.5.2 Storage of Investigational Product .................................................................57 
11.5.3 Accountability of Investigational Product ......................................................57 
11.5.4 Return or Disposal of Investigational Product ...............................................58 
11.6 Recording of Data on Source Documents and Case Reports Forms (CRFs) .......58 
11.7 Handling of Biological Specimens .......................................................................58 
11.8 Publications ..........................................................................................................58 
12 REFERENCES ............................................................................................................59 
13 APPENDICES .............................................................................................................60 
Appendix 1:  Schedule of Visits and Measurements .......................................................60 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ......................61 
Appendix 3:  Investigational Product Composition/ Design ...........................................74 
Appendix 4:  Protocol Amendment Summary .................................................................75 
Appendix 5:  Sponsor and Ora Approvals .......................................................................78 
Appendix 6:  Investigator’s Signature .............................................................................79 
 
 
 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
APC 
Antigen presenting cells 
API 
Active Pharmaceutical Ingredients 
BCVA 
Best Corrected Visual Acuity 
BID 
Bis In Die (Two Times Daily)  
CAE 
Controlled Adverse Environment 
CD 
Compact Disk 
CDA 
Clinical Data Analyst 
CDM 
Clinical Data Manager 
CFR 
Code of Federal Regulations 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
DCF 
Data Clarification Form 
DVM 
Data Validation Manual 
EC 
Ethics Committee 
e-CRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDTA 
Ethylenediaminetetraacetic Acid 
ET 
Early Termination 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
F/U 
Follow Up 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HAV 
Hepatitis A 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICS 
Inferior Corneal Staining 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine Device 
KCS 
Keratoconjunctivitis Sicca 
LASIK 
Laser–assisted in situ keratomileusis 
LDPE 
Low Density Polyethylene 
LOCF 
Last Observation Carried Forward 
LogMAR 
Minimum Angle of Resolution 
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MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Authorities 
MW 
Molecular Weight 
N 
Number 
ODS 
Ocular Discomfort Score 
OPI 
Ocular Protection Index 
OSDI 
Ocular Surface Disease Index 
OTC 
Over the Counter 
OU 
Oculus Uterque (Each eye or Both eyes) 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDC 
Statistics and Data Corporation, Inc. 
SEC 
Self-Evident Correction 
STT 
Schirmer’s Tear Test 
TFBUT 
Tear Film Break Up Time 
TM 
Trademark 
US 
United States 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
WOCF 
Worst Observation Carried Forward 
 
 
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1 INTRODUCTION 
Dry eye is a complex disease that results in symptoms of discomfort, visual disturbance, 
and tear film instability. It is accompanied by increased osmolarity of the tear film and 
inflammation of the ocular surface. Estimates of the prevalence of dry eye vary 
considerably, depending on the criteria used to define the syndrome, but in the U.S., as 
many as 3.2 million women and 1.7 million men over the age of 50 have dry eye, with a 
projected 40% increase in number of patients affected by 20301-3. With the aging 
population in the United States and other countries of the developed world, and with 
increasing computer use, dry eye is expected to become more prevalent and finding a 
treatment is becoming more important4. 
HL036 ophthalmic solution is a molecularly engineered TNF receptor 1 (TNFR1) 
fragment (HL036337).  Molecule fragmentation and engineering techniques are applied 
for enhanced tissue distribution, increased stability and potency.  
HL036337 is a TNFR1 fragment composed of 171 amino acids, from 41 ~ 211 residues 
of TNFR1 outside domain and a methionine residue added at the N-terminal.  
HL036337 is a protein molecularly engineered by amino acid substitution of the 29th 
leucine, 53rd histidine, 56th histidine, 58th arginine, 59th histidine, and 122nd lysine 
with valine, methionine, phenylalanine, proline, glycine, and asparagine respectively. 
HL036 eye drops demonstrated potent anti-inflammatory effects in a carrageenan-
induced acute in vivo model of inflammation, and significant efficacy in a collagen-
induced arthritis model.  HL036 ophthalmic solution has also been shown to cause 
statistically significant clinical improvements in a dry eye animal model. 
1.1 NONCLINICAL STUDIES 
 
 
 
 
  
 
 
 
 
 
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1.2 PREVIOUS CLINICAL STUDIES 
There is no information on the clinical efficacy of HL036 in dry eye. 
One Phase 1 clinical trial aimed to assess the safety, local tolerance, and pharmacokinetic 
properties of HL036 by topical ophthalmic instillation of HL036 twice in one day (12 
hours apart) into left eyes of healthy male volunteers, while right eyes received vehicle 
placebo. 
One drop (40 μl) of HL036 at either the 0.5 mg/mL or 5 mg/mL concentration topically 
instilled twice to healthy male volunteers resulted in no clinically significant systemic 
absorption observed in any of the subjects. Safety and local tolerance assessment results 
showed no clinically significant observations. 
1.3 STUDY RATIONALE 
HL036 ophthalmic solution is a molecularly engineered tumor necrosis factor (TNF) 
receptor 1 (TNFR1) fragment (active pharmaceutical ingredient also denoted as 
HL036337).  Molecule fragmentation and engineering techniques are applied for 
enhanced tissue distribution, increased stability and potency. 
Anti-TNF molecules have been approved for rheumatoid arthritis, psoriasis, ankylosing 
spondylitis, ulcerative colitis, and Crohn’s diseases.  They are also prescribed for off-
label use for uveitis, dry eye disease, macular degeneration, sciatic neuralgia, chronic 
obstructive pulmonary diseases and asthma. 
The role of TNF as a major cytokine in dry eye provides a rationale for use of TNF 
inhibitors in this disease.  However, the majority of TNF inhibitors are antibody-based 
with a large molecular size (~150 kDa) that limits tissue penetration.  Considering the 
limited ocular distribution and excessive toxicity of TNF-inhibitor therapies administered 
systemically, HL036 Ophthalmic Solution was developed as a TNF-inhibitor with 
increased penetration and distribution and minimal systemic side effects.   
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1.4 SUMMARY OF OVERALL RISKS AND BENEFITS 
 
 
 
 
 
 
 
One Phase 1 clinical trial aimed to assess the safety, local tolerance, and pharmacokinetic 
properties of HL036 by topical ophthalmic instillation of HL036 twice in one day (12 
hours apart) into left eyes of healthy male volunteers, while right eyes received vehicle 
placebo. 
The investigational product was administered to 20 subjects, and 27 AEs in 11 subjects 
were observed. Among the AEs, 20 were mild cases and the subjects recovered without 
sequelae. The remaining 7 were moderate events that occurred in a single subject, B010. 
Among the 7 moderate AEs, 6 were resolved without sequelae. One AE, corneal opacity, 
was unresolved and this subject was lost to follow-up. The causal relationship between 
the investigational product and all 7 moderate AEs in Subject B010 was found to be 
“unlikely.”  
There was no significant difference in the number of subjects with AEs or the frequency 
of AEs between treatment groups. The most frequent suspected AE was conjunctival 
hyperemia. There was no serious AE or unexpected adverse drug reaction reported, and 
no clinically significant changes were observed in vital signs, physical examinations, and 
medical laboratory tests. 
Local tolerance was assessed through observation of ophthalmologic symptoms, and 
symptoms were either none or mild. There were no moderate or severe ophthalmologic 
symptoms observed. Ophthalmologic symptoms that occurred more than once in this trial 
were dryness, ocular burning or pain and conjunctival hyperemia.  
In conclusion, 1 drop (40 μl) of HL036 at either the 0.5 mg/mL or 5 mg/mL 
concentration was topically instilled twice to healthy male volunteers. There was no 
clinically significant systemic absorption observed in any of the subjects. Safety and local 
tolerance assessment results showed no clinically significant observations. Overall, 
topical ophthalmic instillation of 0.5 mg/mL or 5 mg/mL of HL036 in healthy subjects 
twice a day is unlikely to result in any clinically significant local tolerance issue. 
2 STUDY OBJECTIVES 
The objective of this study is to compare the safety and efficacy of 0.10% and 0.25% 
HL036 Ophthalmic Solutions to placebo for the treatment of the signs and symptoms of 
dry eye. 
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3 CLINICAL HYPOTHESES 
The clinical hypotheses for this study are that 0.10% or 0.25% HL036 Ophthalmic 
Solution is superior to placebo for the primary endpoints of signs and symptoms, as 
follows:  
x Pre- CAE® inferior corneal fluorescein staining score on the Ora Calibra® scale, 
measured by mean change from baseline (Visit 2) to Visit 6; 
x Pre- CAE® ocular discomfort score on the Ora Calibra® Ocular Discomfort Scale, 
measured by mean change from baseline (Visit 2) to Visit 6; 
4 OVERALL STUDY DESIGN 
This is a Phase 2, multicenter, randomized, prospective, double–masked, 
placebo-controlled, parallel-arm design with block enrollment. Subjects will be 
randomized to one of the following treatment arms at Visit 2 and will be instructed to 
follow a BID-dosing regimen:  
x HL036 0.25% Ophthalmic Solution (N~50)  
x HL036 0.10% Ophthalmic Solution (N~50)  
x Placebo, HL036 Ophthalmic Solution (N~50) 
This study is multicenter, randomized, prospective, double–masked, placebo–controlled, 
parallel-arm design with block enrollment. Approximately 150 subjects will be randomly 
assigned to one of the three treatment groups (1:1:1) to receive either HL036 Ophthalmic 
Solution (0.10%, 0.25%) or placebo solution as topical ophthalmic drops administered 
bilaterally BID. Subjects, Sponsor, CRO and site personnel will be masked to treatment 
assignment.  
During the screening period, two 
 exposures to the CAE® will be conducted to 
ascertain eligibility to enter the study.  Those who qualify will be randomized to receive 
study drug in a double-masked fashion for 56 days. Subjects will self-administer drops 
twice daily and will complete daily diary assessments as instructed. 
At Visits 4 (Day 15), 5 (Day 29) and 6 (Day 57), CAE® exposure will occur, with pre-
CAE®, during CAE® (symptoms only) and post-CAE® assessments of ocular signs and 
symptoms. At Visit 3 only, no CAE® exposure will occur but signs and symptoms will be 
assessed. 
The total number of expected participants, including screen failures, is approximately 375 
subjects. 
A study flow chart appears below: 
Visit 1 
(Day -14 ± 1): 
CAE® Screening 
Informed Consent 
Demographics, Medical/Medication & Ocular History 
Urine Pregnancy Testing (as needed) 
Symptom Questionnaires, Visual Acuity 
Pre-CAE® Eye Evaluations 
CAE® Exposure 
Post-CAE® Eye Evaluations 
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Safety Assessments (IOP and Dilated Fundoscopy) 
Run-in & Subject Daily Diary Dispensed 
 
 
Placebo Run-in Period (14 ± 1 day) 
 
 
Visit 2 
(Day 1): 
CAE® Confirmation/ 
Baseline 
Collection of Run-in/Diary 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Visual Acuity 
Tear Collection 
Pre-CAE® Eye Evaluations 
CAE® Exposure 
Post-CAE® Eye Evaluations 
Randomization 
Blood sampling for Immunogenicity testing 
In-Office Dose & Drop Comfort Questionnaire 
Study Drug & Subject Daily Diary Dispensed 
 
 
Visit 3 
(Day 8±1): 
1-Week Follow Up 
Collection of Study Drug/Diary 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Visual Acuity 
Eye Evaluations 
In office Dose 
Study Drug & Subject Daily Diary Dispensed 
 
 
Visit 4 
(Day 15 ± 2): 
2-Week CAE®  Follow Up 
Collection of Study Drug/Diary 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Visual Acuity 
Pre-CAE® Eye Evaluations 
CAE® Exposure 
Post-CAE® Eye Evaluations 
Blood sampling for Immunogenicity testing 
Study Drug & Subject Daily Diary Dispensed 
 
Visit 5 
(Day 29 ± 2): 
4-Week CAE®  Follow Up 
Collection of Study Drug/Diary 
Medical/Medication Update: AE Query 
Symptom Questionnaires, Visual Acuity 
Pre-CAE® Eye Evaluations 
CAE® Exposure 
Post-CAE® Eye Evaluations 
Blood sampling for Immunogenicity testing 
Study Drug & Subject Daily Diary Dispensed 
 
Visit 6 
(Day 57 ± 3): 
8-Week CAE®  Follow-Up 
and Study Exit 
Collection of Study Drug/Diary 
Medical/Medication Update: AE Query 
Urine Pregnancy Testing (as needed) 
Symptom Questionnaires, Visual Acuity 
Tear Collection 
Pre-CAE® Eye Evaluations 
CAE® Exposure 
Post-CAE® Eye Evaluations 
Blood sampling for Immunogenicity testing 
Safety Assessments (IOP and Dilated Fundoscopy) 
Study Exit 
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Subjects who terminate early during the treatment period will be asked to complete safety 
assessments prior to commencement of any alternative dry eye therapy (if at all possible). 
Subjects who are terminated early from the study will not be replaced. 
5 STUDY POPULATION 
5.1 NUMBER OF SUBJECTS  
It is estimated that approximately 375 subjects will be screened to enroll approximately 
150 randomized subjects (50 in each arm). Subjects will be randomized in a 1:1:1 ratio of 
HL036 Ophthalmic Solution (0.25%) to HL036 Ophthalmic Solution (0.1%) to HL036 
Vehicle Ophthalmic Solution. 
5.2 STUDY POPULATION CHARACTERISTICS 
All subjects must be at least 18 years of age, of either gender, and of any race, and must 
meet all inclusion criteria and none of the exclusion criteria. 
5.3 INCLUSION CRITERIA 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Be at least 18 years of age; 
2. Provide written informed consent; 
3. Be willing and able to comply with all study procedures; 
4. Have a patient-reported history of dry eye for at least 6 months prior to enrollment; 
5. Have a history of use or desire to use eye drops for dry eye symptoms within 6 
months of Visit 1; 
6. Have a best corrected visual acuity of
 logMAR or better (Snellen equivalent score 
of 
) in each eye at Visit 1; 
7. Report in the study eye DVFRUHRI
DFFRUGLQJWR the Ora Calibra® Ocular 
Discomfort and 4-Symptom Questionnaire in at least one of the dry eye symptoms at 
Visits 1 and 2; 
8. Have in the study eye D6FKLUPHU¶V7HVWVFRUHRIPPDQGPPDW9LVLWVDQG
2; 
9. Have in the study eye a corneal fluorescein stDLQLQJVFRUHRI
in at least one region 
of the cornea (
 according to the Ora Calibra® Corneal and 
Conjunctival Staining Scale for Grading of Fluorescein Staining in at least one eye at 
Visits 1 and 2; 
10. Have in the study eye DFRQMXQFWLYDOUHGQHVVVFRUH
DFFRUGLQJWRthe Ora Calibra® 
Conjunctival Redness for Dry Eye Scale in at least one eye at Visits 1 and 2;  
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11. Demonstrate in the study eye a response to the CAE® at Visits 1 and 2 as defined by: 
a) 
 
 

 
 
 
  
12. A negative urine pregnancy test if female of childbearing potential (those who are not 
surgically sterilized [bilateral tubal ligation, hysterectomy or bilateral oophorectomy] 
or post–menopausal [12 months after last menses]) and must use adequate birth 
control throughout the study period. Adequate birth control is defined as hormonal–
oral, implantable, injectable, or transdermal contraceptives; mechanical–spermicide in 
conjunction with a barrier such as condom or diaphragm; intrauterine device (IUD); 
or surgical sterilization of partner. For non–sexually active females, abstinence may 
be regarded as an adequate method of birth control. 
5.4 EXCLUSION CRITERIA 
Individuals who meet any of the following exclusion criteria will not be eligible to 
participate in the study: 
1. Have any clinically significant slit lamp findings at Visit 1 that may include active 
blepharitis, meibomian gland dysfunction (MGD), lid margin inflammation or active 
ocular allergies that require therapeutic treatment, and/or in the opinion of the 
investigator may interfere with study parameters; 
2. Be diagnosed with an ongoing ocular infection (bacterial, viral, or fungal), or active 
ocular inflammation at Visit 1; 
3. Have worn contact lenses within 7 days of Visit 1 or anticipate using contact lenses 
during the study; 
4. Have previously had laser-assisted in situ keratomileusis (LASIK) surgery within the 
last 12 months; 
5. Have used Restasis® or Xiidra® within 60 days of Visit 1; 
6. Have any planned ocular and/or lid surgeries over the study period; 
7. Be using or anticipate using temporary punctal plugs during the study that have not 
been stable within 30 days of Visit 1; 
8. Be currently taking any topical ophthalmic prescription (including medications for 
glaucoma) or over-the-counter (OTC) solutions, artificial tears, gels or scrubs, and 
cannot discontinue these medications for the duration of the trial (excluding 
medications allowed for the conduct of the study); the respective wash-out periods are 
required for the following medications: 
a) Antihistamines (including ocular): 72 hours prior to Visit 1 
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b) Oral aspirin or aspirin–containing products allowed if dose has been stable 
over past 30 days prior to Visit 1 and no change in dose anticipated during 
the study period 
c) Corticosteroids or mast cell stabilizers (including ocular):  14 days prior 
to Visit 1 
d) Any medication (oral or topical) known to cause ocular drying that has not 
been administered as a stable dose for at least 30 days prior to Visit 1 and 
during the study 
e) All other topical ophthalmic preparations (including artificial tear 
substitutes) other than the study drops: 72 hours prior to Visit 1 
9. Have an uncontrolled systemic disease; 
10. Be a woman who is pregnant, nursing or planning a pregnancy;  
11. Be unwilling to submit a urine pregnancy test at Visit 1 and Visit 6 (or early 
termination visit) if of childbearing potential.  Non-childbearing potential is defined 
as a woman who is permanently sterilized (e.g. has had a hysterectomy or tubal 
ligation), or is post-menopausal (without menses for 12 consecutive months); 
12. Be a woman of childbearing potential who is not using an acceptable means of birth 
control; acceptable methods of contraception include: hormonal – oral, implantable, 
injectable, or transdermal contraceptives; mechanical – spermicide in conjunction 
with a barrier such as a diaphragm or condom; IUD; or surgical sterilization of 
partner.  For non-sexually active females, abstinence may be regarded as an 
adequate method of birth control; however, if the subject becomes sexually active 
during the study, she must agree to use adequate birth control as defined above for the 
remainder of the study; 
13. Have a known allergy and/or sensitivity to the test article or its components; 
14. Have a condition or be in a situation which the investigator feels may put the subject 
at significant risk, may confound the study results, or may interfere significantly with 
the subject’s participation in the study; 
15. Be currently enrolled in an investigational drug or device study or have used an 
investigational drug or device within 30 days of Visit 1; 
16. Be unable or unwilling to follow instructions, including participation in all study 
assessments and visits. 
5.5 WITHDRAWAL CRITERIA  
Subjects (or their legally authorized representative) may withdraw their consent to 
participate in the study at any time without prejudice. The Investigator must withdraw 
from the study any subject who requests to be withdrawn. A subject’s participation in the 
study may be discontinued at any time at the discretion of the Investigator and/or Sponsor 
and in accordance with his/her clinical judgment. However, it is encouraged that the 
Investigator contact the Sponsor, when possible, to discuss possible reasons for 
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discontinuation prior to withdrawing a subject from the study. When possible, the tests 
and evaluations listed for the termination visit should be carried out. 
HanAll Biopharma, Co., Ltd. and Ora must be notified of all subject withdrawals as soon 
as possible. HanAll Biopharma, Co., Ltd. also reserves the right to discontinue the study 
at any time for either clinical or administrative reasons and to discontinue participation 
by an individual Investigator or site for poor enrollment or noncompliance. 
Reasons for which the Investigator or HanAll Biopharma, Co., Ltd. may withdraw a 
subject from the study include, but are not limited to, the following: 
x Subject experiences a serious or intolerable AE 
x Subject requires medication prohibited by the protocol 
x Subject does not adhere to study requirements specified in the protocol 
x Subject was erroneously admitted into the study or does not meet entry criteria 
x Subject is lost to follow–up 
x Subject becomes pregnant 
If a subject fails to return for scheduled visits, a documented effort must be made to 
determine the reason. If the subject cannot be reached by telephone after two attempts, a 
certified letter should be sent to the subject (or the subject’s legally authorized 
representative, if appropriate) requesting contact with the Investigator. This information 
should be recorded in the study records.  
The Investigator or designee must explain to each subject, before enrollment into the 
study, that for evaluation of study results, the subject’s protected health information 
obtained during the study may be shared with the study sponsor, regulatory agencies, and 
IRB/EC. It is the Investigator’s (or designee’s) responsibility to obtain written permission 
to use protected health information per country–specific regulations, such as HIPAA in 
the US, from each subject, or if appropriate, the subject’s legally authorized 
representative. If permission to use protected health information is withdrawn, it is the 
Investigator’s responsibility to obtain a written request, to ensure that no further data will 
be collected from the subject and the subject will be removed from the study. 
6 STUDY PARAMETERS 
6.1 EFFICACY MEASURES  
6.1.1 Primary Efficacy Endpoints 
The primary efficacy outcome endpoints are: 
x Inferior corneal staining score in the designated study eye as assessed by the Ora 
Calibra® Corneal and Conjunctival Staining Scale for Grading of Fluorescein 
Staining at Visit 6 (Day 57, Week 8) 
and  
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x Ocular discomfort in the designated study eye as assessed by the Ora Calibra® 
Ocular Discomfort Scale at Visit 6 (Day 57, Week 8) 
6.1.2 Secondary Efficacy Endpoints 
x Fluorescein staining by region: central, superior, inferior, temporal, nasal and corneal 
sum as assessed by the Ora Calibra® Corneal and Conjunctival Staining Scale for 
Grading of Fluorescein Staining at all other time points 
x Lissamine green staining by region: central, superior, inferior, temporal, nasal, and 
conjunctival sum as assessed by the Ora Calibra® Corneal and Conjunctival Staining 
Scale for Grading of Lissamine Staining at all time points 
x TFBUT© at all timepoints assessed 
x Conjunctival redness as assessed by the Ora Calibra® Conjunctival Redness Scale for 
Dry Eye at all timepoints assessed 
x Schirmer’s Test (unanesthetized) at all timepoints assessed 
x Symptoms as assessed by the Ora Calibra® Ocular Discomfort Scale and Ora 
Calibra® Ocular Discomfort and 4-Symptom Questionnaire at all other timepoints 
x Visual Analog Scale (VAS) Ocular Discomfort at all timepoints assessed 
x OSDI© at all timepoints assessed 
x Drop comfort as assessed by the Ora Calibra® Drop Comfort Scale, and the Ora 
Calibra® Drop Comfort Questionnaire at all timepoints assessed 
x Daily diary  
x Tear mediators 
Change from baseline and pre- to post-CAE® changes will also be assessed where 
appropriate. 
6.1.3 Criteria for Effectiveness 
The specific criteria for effectiveness for the endpoints derived from the measures 
described above are: 
x Mean change from baseline to Day 57 (Week 8) in inferior corneal staining Pre-
CAE in the designated study eye as assessed by the Ora Calibra® Corneal and 
Conjunctival Staining Scale for Grading of Fluorescein Staining 
and  
x Mean change from baseline to Day 57 (Week 8) in ocular discomfort Pre-CAE in 
the designated study eye as assessed by the Ora Calibra® Ocular Discomfort Scale 
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6.2 SAFETY MEASURES 
x Incidence and severity of ocular AEs 
x Incidence and severity of non-ocular AEs 
x BCVA at all visits 
x Slit-lamp biomicroscopy at all visits 
x Drop comfort assessment (Visits 2) 
x Intraocular pressure (Visits 1 and 6) 
x Dilated fundoscopy (Visits 1 and 6) 
x Immunogenicity to HL036 in Serum (Visits 2, 4, 5, and 6) 
7 STUDY MATERIALS 
7.1 STUDY TREATMENTS 
7.1.1 Study Treatments 
Subjects will receive twice-daily doses (BID) of either HL036 Ophthalmic Solution 
(0.25%, 0.10%) or placebo administered to the ocular surface as an eye drop. 
HL036 ophthalmic solution is a molecularly engineered TNF receptor 1 (TNFR1) 
fragment (HL036337).  Molecule fragmentation and engineering techniques are applied 
for enhanced tissue distribution, increased stability and potency.  
7.1.2 Description and Justification for the Route of Administration, Dosage, 
Dosage Regimen, and Treatment Period 
Topical ophthalmic dosing is the optimal route of administration for dry eye treatments. 
The dosage and dosage regimen was selected based on nonclinical studies described in 
Section 1.1. The proposed treatment period of 8 weeks is also based on nonclinical 
studies and on the anti-inflammatory mechanism of action of the drug.  
7.1.3 Instructions for Use and Administration 
x Study drug will be supplied as a sterile, clear, colorless liquid solution containing 
0.25% or 0.10% API (HL036) 5 cavity, 0.5 mL low–density polyethylene (LDPE) 
unit dose vials with a fill volume of approximately 0.25 mL. Each mL of the 
0.25% solution contains 2.5 mg of the API, and each mL of the 0.10% solution 
contains 1.0 mg of the API. In addition to HL036, the components of the drug 
product solution are: sodium chloride (tonicity adjusting agent), citric acid 
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monohydrate (buffering solution), sodium hydroxide solution and hydrochloric 
acid 1% (both for pH adjustments), and sterile water for injection as a solvent.   
x The placebo solution consists of all components of the drug product solution with 
the exception of HL036. 
x At the study site, all IP must be stored under the conditions specified in the 
Investigator’s Brochure in a secure area accessible only to the designated 
qualified clinical site personnel. All IP must be stored, inventoried and the 
inventories carefully and accurately documented according to applicable state, 
federal and local regulations, ICH GCPs and study procedures. 
x HL036 and placebo solutions should be stored refrigerated (2–8° C). Subjects will 
be instructed to store HL036 and placebo solutions in a refrigerator (2–8° C). It is 
recommended that HL036 and placebo solutions be placed at room (ambient) 
temperature at least 1 ± 0.5 hours prior to administration to subjects. Sterile drug 
product and placebo solutions are packaged into single–use 0.5 mL LDPE unit 
dose vials that deliver an approximate per drop volume of 50 μL. Two cavity unit 
dose vials are packaged in aluminum foil pouches under nitrogen. Unit dose vials 
are for SINGLE USE ONLY. 
x At a minimum, the immediate or secondary study drug packaging will provide the 
following information: study sponsor identification, batch number, directions for 
use, required storage conditions, caution statements (including “New Drug–
Limited by Federal Law to Investigational Use” language), study identification 
and product retest date.  
7.2 OTHER STUDY SUPPLIES 
Urine pregnancy tests, Schirmer’s test strips, sodium fluorescein, lissamine green, Fluress, 
tear collection supplies. 
8 STUDY METHODS AND PROCEDURES 
8.1 SUBJECT ENTRY PROCEDURES 
8.1.1 Overview 
Subjects as defined by the criteria in Sections 5.3, 5.4, and 5.5 will be considered for 
entry into this study. 
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8.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., prior to changes in a subject’s medical 
treatment and/or prior to 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 informed consent form must be the most recent 
version that has received approval/favorable review by a properly constituted Institutional 
Review Board (IRB). 
8.1.3 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in the Exclusion Criteria 
(Section 5.4). 
8.1.4 Procedures for Final Study Entry 
Subjects must meet all inclusion and none of the exclusion criteria. 
8.1.5 Methods for Assignment to Treatment Groups: 
Prior to initiation of study run-in (at Visit 1), each subject who qualifies for entry will be 
assigned a screening number. All screening numbers will be assigned in strict numerical 
sequence at a site and no numbers will be skipped or omitted. If all inclusion and 
exclusion criteria are met at Visits 1 and 2, each qualifying subject will then be assigned 
a randomization number at the end of Visit 2.  
A randomization schedule will be generated using block randomization. Blocks of 
randomization numbers will be distributed to sites, such that there will be an approximate 
equal number of subjects assigned to each of the three treatment arms at each site. The 
site staff will dispense to the patient the study kit labeled with the corresponding 
randomization number. The randomization number will be recorded on the patient’s 
source document and eCRF. A new kit will be dispensed at Visits 2, 4, and 5 based on the 
subject’s randomization. The visit 2 kit will be re-dispensed at Visit 3. The Sponsor, 
Investigators, and study staff will be masked during the randomization process and 
throughout the study.  
8.2 CONCURRENT THERAPIES 
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 device study is not permitted. 
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8.2.1 Prohibited Medications/Treatments 
Disallowed medications/treatments during the study are outlined in the Exclusion Criteria 
(Section 5.4).  
8.2.2 Escape Medications 
No escape medications are required for this study. 
8.2.3 Special Diet or Activities 
No special diets or activities are required for this study. 
8.3 EXAMINATION PROCEDURES 
An ICF must be signed and dated by the subject, the PI or designee and witness (if 
required) before any study–related procedures are performed. 
Procedures listed below should be performed in the given order. See Appendix 2 for 
details on methodologies and grading systems. 
8.3.1 Visit 1: Day –14 ± 1 – CAE® Screening  
All subjects will undergo the following screening assessments: 
Pre–CAE®  
x Informed Consent/HIPAA Prior to any changes in a subject’s medical treatment 
and/or invasive procedures (e.g., controlled adverse environment), the study will be 
discussed with each subject and subjects wishing to participate must give written 
informed consent and sign a HIPAA form.  
x Demographic Data and Medical/Medication/Ocular History Collect and record all 
demographic data, medical history, any medications and any underlying condition(s). 
Significant non–ocular medical history only within the past year and medications 
within the past 30 days will be captured. Record any medications the subject is 
taking, as well as those the subject may have taken but discontinued within 30 days 
prior to screening. 
x Review of Inclusion/Exclusion Criteria 
x Urine Pregnancy Test (for females of childbearing potential) Women of childbearing 
potential must have a negative urine pregnancy test to continue in the study.  
x Ora Calibra® Ocular Discomfort Scale  
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x Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score  
x Ocular discomfort using a visual analog scale (VAS) 
x OSDI© 
x BCVA Utilizing an ETDRS Chart Subjects must have a score of 
 logMAR or 
better (Snellen equivalent score of 
) in each eye at Visit 1. 
x Slit Lamp Biomicroscopy A slit lamp exam will be performed at the beginning of the 
visit and again Post–CAE® to exclude subjects with disallowed ocular conditions. 
x Conjunctival Redness Score An objective measure used to score redness on the Ora 
Calibra® Conjunctival Redness Scale for Dry Eye. Half point increments (0.5) may be 
used. 
x TFBUT 
x Corneal and Conjunctival Staining (fluorescein) as assessed by the Ora Calibra® 
Corneal and Conjunctival Staining Scale for Grading of Fluorescein Staining 
x Corneal and Conjunctival Staining (lissamine green) as assessed by the Ora Calibra® 
Corneal and Conjunctival Staining Scale for Grading of Lissamine Green Staining 
x Monitoring and Query AEs Report any AEs that occur after signing the ICF. 
Screening Challenge (CAE® #1) 
Subjects meeting all of the above evaluation (Pre–CAE® #1) criteria will undergo further 
screening evaluation in the CAE®. Subjects will be exposed to the CAE® for 
 
. Ocular discomfort self-assessment scores (ODS) will be obtained just prior to 
entering, during and just after the CAE® exposure. During the CAE® exposure, ODS will 
be collected at
. 
Post–CAE® 
x Ora Calibra® Ocular Discomfort Scale  
x Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score  
x VAS discomfort scale 
x Slit lamp biomicroscopy 
x Conjunctival redness 
x TFBUT 
x Fluorescein Staining 
x Lissamine Green Staining 
x Schirmer’s test 
x IOP 
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x Dilated Fundoscopy 
x Review of Inclusion/Exclusion Criteria  
o Eligible subjects must have a positive response in at least one eye. A positive 
response is defined as meeting ALL of the following criteria in the same eye: 
¾ +DYLQJDWOHDVWD
SRLQWLQFUHDVHLQIOXRUHVFHLQVWDLQLQJLQWKH
inferior region in at least one eye following CAE® exposure; 
¾ 5HSRUWLQJDQ2FXODU'LVFRPIRUWVFRUH
DWRUPRUHFRQVHFXWLYH
time points in at least one eye during CAE® exposure (
 
 
 
) 
o Following the screening procedures at this visit, all subjects who meet all 
eligibility criteria and have a positive response (as defined above) will self-
administer their initial dose of placebo drops (open–label, single drop, OU), for 
training purposes, at the study site under supervision of trained study personnel 
following the last Post– CAE® #1 study assessment. Only a single dose of placebo 
drops will be administered OU on Day –14.  
x Placebo and Diary Dispensation and Administration. Prior to discharge from the 
study site on Day –14, subjects will be dispensed sufficient placebo supply to last 
until Visit 2 and will be educated in study drug diary recording and self–
administration of placebo. Subjects will be instructed to self–administer one drop BID 
in each eye in the morning and the evening until screening Visit 2. Subjects will be 
instructed NOT to instill study drug on the morning of their next scheduled study visit 
(Visit 2, Day 1).  
x Monitoring and Query of AEs Report any AEs that occur after signing the ICF. 
x Schedule Next Visit Subjects will be scheduled for Visit 2. 
 
 
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8.3.2 Visit 2:  Day 1 – CAE® Confirmation and Baseline  
Pre–CAE®  
x Study Diary/Placebo Collection Subject study diaries and all used/unused placebo 
vials dispensed for Days –14 to 1 should be collected and reviewed by a trained study 
technician. 
x Site staff must confirm subjects have NOT administered their morning placebo dose 
at home. 
x Review of Inclusion/Exclusion Criteria  
x Monitoring and Query of AEs Report any AEs that occur after signing the ICF. 
x Record all Changes in Concomitant Medications 
x Ora Calibra® Ocular Discomfort Scale  
x Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score  
x VAS discomfort scale 
x OSDI 
x BCVA Utilizing an ETDRS Chart  
x Slit Lamp Biomicroscopy  
x Conjunctival redness  
x Tear sample collection from both eyes 
x TFBUT 
x Fluorescein Staining 
x Lissamine Green Staining 
Confirmatory Screening Challenge (CAE® #2) 
Subjects will be exposed to the CAE® for 
. Ocular discomfort self–
assessment scores (ODS) will be obtained just prior to entering, during and just after the 
CAE® exposure. During the CAE® exposure, ODS will be collected at 
 
. 
Post–CAE® 
x Inclusion/Exclusion Evaluation 
x Ora Calibra® Ocular Discomfort Scale  
x Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score  
x VAS discomfort scale 
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x Slit Lamp Biomicroscopy 
x Conjunctival redness 
x TFBUT 
x Fluorescein Staining 
x Lissamine Green Staining 
x Schirmer’s test  
x Review of Inclusion/Exclusion Criteria  
x Eligible subjects must replicate a positive response at this visit in the same eye as 
was elicited in Visit 1. A positive response is defined as meeting ALL of the 
following criteria in the same eye: 
¾ Having at least a 
 point increase in fluorescein staining in the 
inferior region in at least one eye following CAE® exposure; 
¾ Reporting an Ocular Discomfort score 
at 2 or more consecutive 
time points in at least one eye during CAE® exposure 
 
 
 
 
Randomization 
x Blood sampling for Immunogenicity testing 
x Study Drug Instillation at the Study Site All subjects having a positive response (as 
defined above) and meeting all other screening eligibility criteria after Visit 2 will be 
randomized to one of three treatment arms. Randomized subjects will self-administer 
their initial study drug dose bilaterally at the study site.  
x Drop Comfort Assessment A drop comfort evaluation will be performed immediately 
and then at 1, 2 and 3 minutes following initial dosing.  
x Monitoring and Query of AEs  
x Study Drug Diary/Study Drug Dispensation Prior to discharge from the study site on 
Visit 2 (Day 1), randomized subjects will be educated in study drug diary recording 
and self–administration of study drug. Subjects will receive their assigned study drug 
kit with sufficient supply to last until Visit 3 and will be instructed NOT to self–
administer study drug on the morning of their next scheduled study visit (Visit 3, Day 
8).  
x Schedule Next Visit Subjects will be scheduled for Visit 3. 
8.3.3 Visit 3 (Day 8) 
There is no CAE® evaluation at Day 8, Visit 3.  
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x Study Drug Diary/Study Drug Collection. Site staff must confirm that subjects have 
NOT administered their morning study drug dose at home. Subjects will undergo 
repeat assessments as follows. 
x Monitoring and Query AEs 
x Recording of all Changes in Concomitant Medications 
x Ora Calibra® Ocular Discomfort Scale  
x Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire  
x VAS discomfort scale 
x OSDI 
x BCVA Utilizing an ETDRS Chart  
x Slit Lamp Biomicroscopy  
x Conjunctival redness  
x TFBUT 
x Fluorescein Staining 
x Lissamine Green Staining 
x Study Drug Instillation at the Study Site Subjects will self-administer their first study 
drug dose bilaterally for Day 8 at the study site following the last study assessment. 
The evening dose will be administered at home, by the subject. 
x Monitoring and Query AEs 
x Study Drug Re-Dispensation. Prior to discharge from the study site on Visit 3 (Day 
8), study drug kits from Day 1 will be re-dispensed to subjects with the remaining 
study drug to complete up to Day 15. Subjects will again be educated in study drug 
diary recording and self–administration of study drug. Subjects will be instructed to 
NOT self–administer study drug on the morning of their next scheduled study visit 
(Visit 4, Day 15).  
x Schedule Next Visit Subjects will be scheduled for Visit 4. 
 
 
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8.3.4 Visit 4: Day 15 ± 2  
Pre-CAE® 
x Study Drug Diary/Study Drug Collection Subject study drug diaries and all 
used/unused study drug vials dispensed for Days 8 to 15 should be collected and 
reviewed by a trained study technician. 
x Site staff must confirm subjects have NOT administered their morning study drug 
dose at home 
x Monitor and Query AEs 
x Record all Changes in Concomitant Medications 
x Ora Calibra® Ocular Discomfort Scale  
x Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire  
x VAS discomfort scale 
x OSDI 
x BCVA Utilizing an ETDRS Chart  
x Slit Lamp Biomicroscopy  
x Conjunctival redness  
x TFBUT 
x Fluorescein Staining 
x Lissamine Green Staining 
CAE® 
x During the CAE® exposure, ODS will be collected at 
 
. 
Post-CAE®  
x Ora Calibra® Ocular Discomfort Scale  
x Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score  
x VAS discomfort scale 
x Slit lamp biomicroscopy 
x Conjunctival redness 
x TFBUT 
x Fluorescein Staining 
x Lissamine Green Staining 
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x Schirmer’s test 
x Blood sampling for Immunogenicity testing 
x Study Drug Diary/Study Drug Dispensation Prior to discharge from the study site on 
Visit 4 (Day 15), subjects will be educated in study drug diary recording and self–
administration of study drug. Subjects will receive their assigned study drug kit with 
sufficient supply to last until Visit 5 and will be instructed to NOT self–administer 
study drug on the morning of their next scheduled study visit (Visit 5, Day 29).  
x Schedule Next Visit Subjects will be scheduled for Visit 5. 
8.3.5 Visit 5: Day 29 ± 2  
Pre-CAE® 
x Study Drug Diary/Study Drug Collection Subject study drug diaries and all 
used/unused study drug vials dispensed for Days 15 to 29 should be collected and 
reviewed by a trained study technician. 
x Site staff must confirm subjects have NOT administered their morning study drug 
dose at home 
x Monitoring and Query of AEs 
x Record all Changes in Concomitant Medications 
x Ora Calibra® Ocular Discomfort Scale  
x Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire  
x VAS discomfort scale 
x OSDI 
x BCVA Utilizing an ETDRS Chart  
x Slit Lamp Biomicroscopy  
x Conjunctival redness  
x TFBUT 
x Fluorescein Staining 
x Lissamine Green Staining 
CAE® 
x During the CAE® exposure, ODS will be collected at 
 
. 
Post-CAE®  
x Ora Calibra® Ocular Discomfort Scale  
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x Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score  
x VAS discomfort scale 
x Slit lamp biomicroscopy 
x Conjunctival redness 
x TFBUT 
x Fluorescein Staining 
x Lissamine Green Staining 
x Schirmer’s test 
x Blood sampling for Immunogenicity testing 
x Monitoring and Query of AEs 
x Study Drug Diary/Study Drug Dispensation Prior to discharge from the study site on 
Visit 5 (Day 29), subjects will be educated in study drug diary recording and self–
administration of study drug. Subjects will receive their assigned study drug kit with 
sufficient supply to last until Visit 6 and will be instructed to NOT self–administer 
study drug on the morning of their next scheduled study visit (Visit 6, Day 57).  
x Schedule Next Visit Subjects will be scheduled for Visit 6. 
8.3.6 Visit 6: Day 57 ± 3  
Pre-CAE® 
x Study Drug Diary/Study Drug Collection Subject study drug diaries and all 
used/unused study drug vials dispensed for Days 29 to 57 should be collected and 
reviewed by a trained study technician. 
x Site staff must confirm subjects have NOT administered their morning study drug 
dose at home 
x Monitoring and Query of AEs 
x Record all Changes in Concomitant Medications 
x Urine Pregnancy Test (for females of childbearing potential) 
x Ora Calibra® Ocular Discomfort Scale  
x Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire  
x VAS discomfort scale 
x OSDI 
x BCVA Utilizing an ETDRS Chart  
x Slit Lamp Biomicroscopy  
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x Conjunctival redness  
x Tear sample collection from both eyes 
x TFBUT 
x Fluorescein Staining 
x Lissamine Green Staining 
CAE® 
x During the CAE® exposure, ODS will be collected at 
 
s. 
Post-CAE®  
x Ora Calibra® Ocular Discomfort Scale  
x Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score  
x VAS discomfort scale 
x Slit lamp biomicroscopy 
x Conjunctival redness 
x TFBUT 
x Fluorescein Staining 
x Lissamine Green Staining 
x Schirmer’s test 
x Intraocular Pressure 
x Dilated fundoscopy 
x Blood sampling for Immunogenicity testing 
x Monitoring and Query of AEs 
x Study Exit 
8.4 SCHEDULE OF VISITS, MEASUREMENTS AND DOSING 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
8.4.2 Unscheduled Visits 
These visits may be performed in order to ensure subject safety. All procedures 
performed at an unscheduled visit will be recorded in the source documents and on the 
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Unscheduled Visit eCRF pages. Any procedure indicated in the eCRF that is not 
performed should be indicated as “Not done.” 
Evaluations that may be conducted at an Unscheduled Visit include: 
x Slit-lamp Biomicroscopy; 
x Visual Acuity; 
x Intraocular Pressure; 
x Urine Pregnancy Test; 
x Dilated Fundoscopy; 
x Assessment of Adverse Events; 
x Assessment of concomitant medications and/or treatments; and 
x Any other assessments needed in the judgment of the investigator. 
8.5 COMPLIANCE WITH PROTOCOL 
Subjects will be instructed on proper use of the subject daily diary and proper instillation 
and storage of study drug at the end of Visits 1, 2, 3, 4 and 5, and given written 
instructions. The subject daily diaries and used and unused study drug vials will be 
collected at each visit from Visit 2 up to and including Visit 6 to assess dosing and 
symptom assessment compliance. Dosing compliance will be based off of the used and 
unused vial count. If the subject is less than 80% or more than 125% compliant with 
dosing based on the expected number of used vials, then the subject will be deemed non-
compliant and a deviation should be recorded.  
In the subject daily diary, if more than 20% of Dose Taken boxes are checked “no”, left 
blank, or missing for a diary period, a subject will be deemed non-compliant and a diary 
deviation will be recorded. If more than 20% of the total diary symptom assessments for 
that dosing period are missed, these subjects will be deemed non-compliant and a diary 
symptom assessment deviation will be recorded. These guidelines will be used by the 
Investigator for determining the subject’s necessary compliance for the study and for 
recording deviations from this compliance. 
8.6 SUBJECT DISPOSITION 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
8.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
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x AEs; 
x unmasking when medically necessary; 
x protocol violations; 
x administrative reasons (e.g., inability to continue, lost to follow up); 
x sponsor termination of study; 
x subject choice (e.g. withdrawal of consent); and 
x other 
Note: In addition, any subject may be discontinued for any sound medical reason at the 
discretion of the investigator. 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to Ora and/or study sponsor and will be clearly documented on the eCRF. 
Discontinued subjects will not be replaced. 
8.7 STUDY TERMINATION  
The study may be stopped at any time by the investigator, the sponsor, and/or Ora with 
appropriate notification. 
8.8 STUDY DURATION 
An individual subject’s participation will involve 6 visits over approximately a 10-week 
(~70 days) period (56 days of treatment and 14 days pre-screening). 
8.9 MONITORING AND QUALITY ASSURANCE 
During the course of the study a monitor, or designee, will make routine site visits to 
review protocol compliance, assess study drug/device 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, 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. 
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9 ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence associated with the use of an 
investigational product (IP) in humans, whether or not considered IP-related. An AE can 
be any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an IP, without any judgment about 
causality. An AE can arise from any use of the IP (eg, off-label use, use in combination 
with another drug or medical device) and from any route of administration, formulation, 
or dose, including an overdose. 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. 
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.  
9.1.1 Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an 
AE as determined by the investigator or reported to him/her by the subject.  The 
assessment of severity is made irrespective of relationship to IP or seriousness of the 
event and should be evaluated according to the following scale: 
x Mild:  Event is noticeable to the subject, but is easily tolerated and does not interfere 
with the subject’s daily activities. 
x Moderate:  Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 
x Severe:  Event is intolerable, necessitates additional therapy or alteration of therapy, 
and interferes with the subject’s daily activities. 
9.1.2 Relationship to Investigational Product 
The relationship of each AE to the IP should be determined by the investigator using 
these explanations: 
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x Suspected:  A reasonable possibility exists that the IP caused the AE. A suspected 
AE can be further defined as:  
¾ 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. 
¾ 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. 
¾ 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. 
x Not Suspected:  A reasonable possibility does not exist that the IP caused the AE. A 
not suspected AE cab further be defined as: 
¾ 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. 
9.1.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 
x 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. 
x Expected:  an AE that is listed in the IB or ROPI at the specificity and severity that 
has been observed. 
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x 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 
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. 
9.2 SERIOUS ADVERSE EVENTS 
An AE is considered serious if, in the view of either the investigator or sponsor, it results 
in any of the following outcomes: 
x Death; 
x 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. 
x 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. 
x 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). 
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x 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. 
9.3 PROCEDURES FOR REPORTING ADVERSE EVENTS 
All adverse events and their outcomes must be reported to Ora, the study sponsor, and the 
IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and governing 
health authorities and recorded on the appropriate eCRF. 
9.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All adverse events that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the 
study sponsor and the IRB/IEC as required by the IRB/IEC, federal, state, or local 
regulations and governing health authorities. 
9.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all serious adverse events, regardless of relationship to the study 
drug, must be immediately reported.  All information relevant to the serious adverse 
event 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 serious adverse event must be followed up and the outcome reported. 
In the event of a serious adverse event, the investigator must notify Ora and the sponsor 
immediately; obtain and maintain in his/her files all pertinent medical records, 
information, and medical judgments from colleagues who assisted in the treatment and 
follow-up of the subject; provide Ora and the study sponsor with a complete case history, 
which includes a statement as to whether the event was or was not suspected to be related 
to the use of the study drug; and inform the IRB of the adverse event within their 
guidelines for reporting serious adverse events. 
Contact information for reporting Serious Adverse Events:  
Name: 
Title: 
Company: 
Office Telephone: 
 
Clinical Project Manager, Dry Eye 
Ora, Inc. 
 
Alternative Telephone: 
 
Office Facsimile: 
 
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Name: 
Title: 
Office Telephone: 
Mobile Phone: 
Office Facsimile: 
 
 
Medical Monitor 
 
 
 
9.4 PROCEDURES FOR UNMASKING (IF APPLICABLE) 
All subjects, investigators, and study personnel involved with the conduct of the study 
will be masked with regard to treatment assignments. When medically necessary, the 
investigator may need to determine what treatment arm has been assigned to a subject. 
When possible (i.e., in non-emergent situations), Ora and/or the study sponsor should be 
notified before unmasking study drug. The unmasked subject will be discontinued from 
the study. 
9.5 TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECTS 
AFTER ADVERSE EVENTS 
The investigator will follow unresolved AEs to resolution until the subject is lost to 
follow-up or until the AE is otherwise classified. Resolution means the subject has 
returned to baseline state of health or the Investigator does not expect any further 
improvement or worsening of the AE. If the patient is lost to follow-up, the Investigator 
should make 3 reasonable attempts to contact the patient via telephone, post, or certified 
mail. All follow-up will be documented in the subject’s source document. Non-serious 
AEs identified on the last scheduled contact must be recorded on the AE eCRF with the 
status noted.  
If the Investigator becomes aware of any new information regarding an existing SAE (i.e., 
resolution, change in condition, or new treatment), a new SAE/Unanticipated Report 
Form must be completed and faxed to Ora within 24 hours of the site’s awareness of the 
new information. The original SAE form is not to be altered. The report should describe 
whether the event has resolved or continues and how the event was treated. 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 ANALYSIS POPULATIONS 
The following analysis populations will be considered: 
x Intent-to-Treat Population – The intent-to-treat (ITT) population includes all 
randomized subjects. The primary analysis will be performed on the ITT population 
with the Last Observation Carried Forward (LOCF) imputation method for missing 
values. The ITT population may also be analyzed with observed data only (i.e., 
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without LOCF) and using multiple imputation methods to assess sensitivity. 
Subjects in the ITT population will be analyzed as randomized. 
x Per Protocol Population – The per protocol (PP) population includes subjects in the 
ITT population who do not have significant protocol deviations and who complete 
the study. Protocol deviations will be assessed prior to database lock and 
unmasking. The PP population will be analyzed using observed data only for 
efficacy variables. Subjects in the PP population will be analyzed as treated. 
x Safety Population – The safety population includes all randomized subjects who 
have received at least one dose of the investigational product. The safety population 
will be analyzed for all safety assessments. Subjects in the Safety population will be 
analyzed as treated.  
The statistical analysis of safety data will be performed for the safety population.  The 
analysis of baseline and efficacy data will be performed for the ITT population.  The 
primary efficacy analysis will also be performed on the PP population as sensitivity 
analyses. 
10.2  STATISTICAL HYPOTHESES 
The statistical hypotheses are stated in terms of one-sided hypotheses, although statistical 
testing will be two-sided. 
H01:  There is no difference between HL036 ophthalmic solution (0.25% or 0.10%) 
and placebo in the change from baseline of the pre-CAE® inferior corneal fluorescein 
staining at Day 57 (Visit 6), using the Ora Calibra® scale. 
H11:  The change from baseline of the pre-CAE® inferior corneal fluorescein staining 
at Day 57 (Visit 6) using the Ora Calibra® scale is less with HL036 ophthalmic 
solution (0.25% or 0.10%) than with placebo. 
H02:  There is no difference between HL036 ophthalmic solution (0.25% or 0.10%) 
and placebo in the change from baseline of the pre-CAE® ocular discomfort evaluated 
at Visit 6, using the Ora Calibra® Ocular Discomfort Scale. 
H12:  The change from baseline of the pre-CAE® ocular dryness at Visit 6 using the 
Ora Calibra® Ocular Discomfort Scale is less with HL036 ophthalmic solution 
(0.25% or 0.10%) than with placebo. 
10.3  SAMPLE SIZE 
The primary objective of the study is to demonstrate a statistically significant difference 
between the active treatments and placebo.  
This study is expected to enroll 50 subjects in each of the three treatment arms, for a total 
of 150 randomized subjects.  Assuming a 10% drop out rate, 45 subjects per group are 
expected to complete the study.   
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Assuming a common standard deviation in the change from baseline for the pre-CAE® 
inferior corneal fluorescein staining of 0.72 units, a sample size of 45 subjects per group 
will have 90% power to detect a difference of 0.5 units between each of the active 
treatment groups and the placebo group using a two-sample t-test at a significance level 
of 0.05.  A sample size of 45 subjects per treatment arm will have 90% power to detect a 
mean difference of 0.80 units in the change from baseline for the pre-CAE® ocular 
discomfort as assessed by the Ora Calibra® Ocular Discomfort Scale, assuming a 
standard deviation of 1.15 units.  Using an analysis of covariance model (ANCOVA) for 
each primary endpoint should yield standard deviations no greater than those from a two-
sample t-test.  Therefore, the power for each endpoint for both the sign and the symptom 
is 81%, assuming independence between the endpoints.  The power for both the sign 
and the symptom in both active treatments is 66%, assuming independence of treatments. 
10.4 STATISTICAL ANALYSIS 
10.4.1 General Considerations 
The quantitative variables will be summarized using number of subjects (n), mean, 
median, standard deviation, minimum and maximum. The qualitative variables will be 
summarized using counts and percentages.  
All summaries will be presented by treatment group.  Summaries will be provided for 
demographics, baseline medical history, concurrent therapies, and subject disposition. 
For the purpose of summarization, medical history, concurrent therapies, and adverse 
events will be coded to MedDRA and WHO Drug dictionaries, as appropriate. 
Baseline measures are defined as the last measure prior to the initiation of study 
treatment, usually at Visit 2.  If a measure is taken both pre-CAE® and post-CAE®, the 
baseline will be the time point matched value at Visit 2.  For measures from daily 
subject diaries, baseline is defined as the average of all days during the run-in period.  
For changes from pre-CAE® to post-CAE® post first treatment, the change from pre-
CAE® to post-CAE® at Visit 2 will be considered the baseline value. 
All primary and secondary analyses will be 2-sided at a significance level of 0.05. 
10.4.2 Unit of Analysis 
Safety endpoints will be analyzed for both eyes.  For efficacy endpoints, the unit of 
analysis will be the study eye, or the “worst eye,” as defined by the following: 
Study Eye/Worst Eye: Eyes are eligible for analysis if they meet all of the inclusion 
criteria.  In the case that both eyes are eligible for analysis, the worst eye will be the eye 
with worse (higher) inferior corneal staining pre-CAE® at Visit 2.  If the inferior corneal 
staining is the same in both eyes, then the worst eye will be the eye with the highest 
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ocular discomfort pre-CAE® at Visit 2.  If the ocular discomfort is the same in both eyes, 
then the right eye will be selected as the worst eye. 
10.4.3 Missing Data 
The primary efficacy analyses will be performed using Markov Chain Monte Carlo 
(MCMC) multiple imputation methodology for missing values.  An analysis using 
observed data only will also be performed for the primary efficacy variables.  As 
additional sensitivity analyses, Last Observation Carried Forward (LOCF) methodology 
and imputation via pattern mixture models will also be used to impute missing data for 
the analyses of the primary efficacy variables. 
For the LOCF analyses of the primary efficacy variables at Day 57 (Visit 6), the last 
value from the previous visits will be carried forward, matching pre-CAE® or post-CAE® 
time points.  A pre-CAE® time point will never be imputed for a post-CAE® value, and 
vice versa.     
No secondary efficacy endpoints or safety endpoints will be imputed. 
10.4.4 Multiplicity Consideration 
For success, significance is required for both the primary sign and the primary symptom, 
and for both active treatments, hence no multiplicity adjustment is necessary. 
10.4.5 Primary Efficacy Analyses 
For both coprimary endpoints, pre-CAE® change from baseline will be calculated as visit 
– baseline such that a positive difference indicates a worsening of dry eye signs or 
symptoms.  In addition, treatment comparisons between active and placebo will be 
calculated as active – placebo, such that a negative result indicates a better score for the 
active treatment (i.e., the active treatment had a smaller increase in dry eye signs or 
symptoms than the placebo group).  The coprimary endpoints and changes from 
baseline will be summarized descriptively (n, mean, standard deviation, median, min and 
max) by visit and treatment group. 
ANCOVA models will be used to compare the change from baseline in the pre-CAE® 
inferior corneal fluorescein staining at Day 57 (Visit 6), as measured on the Ora Calibra® 
scale, between each dose of 0.25% and 0.10% HL036 Ophthalmic Solution and Placebo.  
The ANCOVA models will include terms for baseline pre-CAE® inferior corneal 
fluorescein staining and study site.   In addition, the study site by treatment interaction 
will be explored in a separate model to evaluate how the treatment effect may differ 
across study sites.  As supportive analyses, two-sample t-tests and Wilcoxon rank sum 
tests will also be conducted.  The primary analysis will use MCMC multiple imputation 
to have a full accounting of the ITT population at the Day 57 visit, as described in 
Section 10.4.3. 
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Ocular dryness will be analyzed similarly.  ANCOVA models will be used to compare 
the change from baseline in the pre-CAE® ocular discomfort score at Day 57 (Visit 6), as 
measured on the Ora Calibra® Ocular Discomfort Scale, between each dose of 0.25% and 
0.10% HL036 Ophthalmic Solution and Placebo.  The ANCOVA models will include 
terms for baseline (Visit 2) ocular discomfort and study site.   In addition, the study site 
by treatment interaction will be explored in a separate model to evaluate how the 
treatment effect may differ across sites.  As supportive analyses, two-sample t-tests and 
Wilcoxon rank sum tests will also be conducted.   
10.4.6 Secondary Efficacy Analyses 
The continuous and ordinal secondary efficacy variables collected at each visit will be 
summarized descriptively (n, mean, standard deviation, median, min and max) by visit 
and treatment group, and analyzed with two-sample t-tests comparing each of the active 
treatment groups to placebo.  All visit-based data will be analyzed at each visit and 
change from baseline.  Change scores from pre- to post-CAE® will be calculated as 
Post-CAE® score – Pre-CAE® score.  A Wilcoxon rank sum test and an ANCOVA 
model adjusting for baseline and site will also be assessed where appropriate.  No 
imputation will be performed for secondary efficacy variables. 
Fluorescein staining by region and total, lissamine green staining by region, TFBUT, 
conjunctival redness, unanesthetized Schirmer’s test, drop comfort assessment, OSDI, 
ocular discomfort and dry eye symptoms, ocular discomfort during CAE®, pre- to post-
CAE® changes, and changes from baseline in these measures will be analyzed by visit 
using two-sample t-tests and Wilcoxon rank sum tests, as appropriate. 
The worst symptom for each subject will be identified as the symptom with the highest 
average score during the run-in period (Days -14 to -1) as recorded in the subject diary.  
The worst symptom and each individual symptom will be analyzed per day using a two-
sample t-test.  Additionally, the average score for the worst symptom and each 
individual symptom will also be analyzed separately using a Wilcoxon rank sum test.  
10.4.7 Safety Variables 
Adverse events will be coded using the MedDRA dictionary. Frequencies and 
percentages of subjects with treatment-emergent adverse events (TEAEs), serious TEAEs, 
and TEAEs causing premature discontinuation will be provided by treatment group. An 
AE is treatment emergent if it 1) occurs after the first dose of randomized study treatment 
or 2) if it is present prior to receipt of randomized study treatment but worsens in severity 
or increases in frequency after the first dose of randomized study treatment. Furthermore, 
frequencies will be given of subjects with TEAEs by system organ class and preferred 
term; by system organ class, preferred term and maximal severity; by system organ class, 
preferred term for treatment-related AEs; by system organ class and preferred term for 
SAEs; and by system organ class, preferred term, and day of onset. Separate analyses will 
be performed for ocular specific and all AEs (including systemic). 
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Other safety endpoints including visual acuity, slit lamp biomicroscopy, dilated 
fundoscopy, and intraocular pressure, will be summarized by treatment group and visit 
using descriptive statistics.  Changes or shifts from baseline will also be summarized 
where appropriate. For assessments performed by eye, study eye and fellow eye will be 
summarized separately. In addition, shifts from baseline to worst on-treatment value for 
ocular safety assessments will be summarized. 
Immunogenicity will be summarized using discrete summary statistics.  Counts and 
proportions will be presented by visit and treatment group.  Exact 95% Clopper-Pearson 
confidence intervals will be presented.  Treatment groups will be compared using 
Fisher’s Exact Test, and exact 95% confidence intervals for the pairwise proportion 
differences will be constructed. 
10.4.8 Interim Analyses 
No interim analyses are planned for this study. 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonization (ICH) 
Guidelines, and in general, consistent with the Declaration of Helsinki.  In addition, all 
applicable local, state, and federal requirements relevant to the use of investigational 
products in the countries involved will be adhered to. 
11.1 PROTECTION OF HUMAN SUBJECTS 
11.1.1 Subject Informed Consent 
Informed consent must take place before any study specific procedures are initiated.  
Signed and dated written informed consent must be obtained from each subject and/or 
from the subject’s parent or legal guardian prior to enrollment into the study.  If the 
subject is under the legal age of consent, the consent form must be signed by a legal 
guardian or as required by state and/or local laws and regulations. 
All informed consent/assent 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. 
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If informed consent is taken under special circumstances (oral informed consent), then 
the procedures to be followed must be determined by Ora and/or study sponsor and 
provided in writing by Ora and/or study sponsor prior to the consent process. 
11.1.2 Institutional Review Board (IRB) Approval 
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. 
11.2 ETHICAL CONDUCT OF THE STUDY 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
11.3 SUBJECT CONFIDENTIALITY 
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data in accordance with local, state, and federal laws 
and regulations. 
Monitors, auditors and other authorized representatives of Ora, the sponsor, the IRB/IEC 
approving this study, the Food and Drug Administration, the Department of Health and 
Human Services, other domestic government agencies, and other foreign regulatory 
agencies will be granted direct access to the study subject’s original medical and study 
records for verification of the data and/or clinical trial procedures.  Access to this 
information will be permitted to the aforementioned individuals to the extent permitted 
by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the investigational product may ultimately be 
marketed, but the subject’s identity will not be disclosed in these documents. 
11.4 DOCUMENTATION 
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. 
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11.4.1 Retention of Documentation 
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. 
11.5 LABELING, PACKAGING, STORAGE, ACCOUNTABILITY, AND 
RETURN OR DISPOSAL OF INVESTIGATIONAL PRODUCT 
11.5.1 Labeling/Packaging 
Investigational drug will be packaged and labeled into clinical kits. 
For the run-in period, 17 pouches will be packaged in a 2-week clinical kit. Each pouch 
will contain 2 single-use vials to provide a sufficient medication supply for one day.  
For the treatment period, 17 pouches will be packaged in a 2-week clinical kit. Each 
patient will receive 4 kits.  Each pouch will contain 2 vials to provide a sufficient supply 
of randomized study drug for one day. 
11.5.2 Storage of Investigational Product 
The study drugs must be stored in a secure area accessible only to the investigator and 
his/her designees. Study drug(s) must be refrigerated (2-8°C, Do Not Freeze), protected 
from light, and secured at the investigational site in a locked container.  
11.5.3 Accountability of Investigational Product 
The study drugs are 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 study 
drugs must only be distributed to subjects properly qualified under this protocol to 
receive study drug.  The investigator must keep an accurate accounting of the study 
drugs by maintaining a detailed inventory. This includes the amount of study drugs 
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received by the site, amount dispensed to subjects, amount returned to the site by the 
subjects, and the amount returned to the Sponsor upon the completion of the study.  
11.5.4 Return or Disposal of Investigational Product 
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. 
11.6 RECORDING OF DATA ON SOURCE DOCUMENTS AND CASE 
REPORTS FORMS (CRFS) 
All subject data will be captured in the subject source documents which will be 
transcribed in the eCRFs. The investigator is responsible for ensuring that study data are 
completely and accurately recorded on each subject’s eCRF, source documents, and all 
study-related materials. All study data should also be attributable, legible, 
contemporaneous, and original. Recorded datum should only be corrected in a manner 
that does not obliterate, destroy, or render illegible the previous entry (e.g., by drawing a 
single line through the incorrect entry and writing the revision next to the corrected data). 
An individual who has corrected a data entry should make clear who made the correction 
and when, by adding to the correction his/her initials as well as the date of the correction.  
Data entry of all enrolled and randomized subjects will use software that conforms to 21 
CFR Part 11 requirements, and will be performed only by staff who have been trained on 
the system and have access to the system. Data will not be entered for screen failure 
subjects. An audit trail will be maintained within the electronic system to capture all 
changes made within the eCRF database. After the end of the study and database lock, 
compact discs (CDs) containing copies of all applicable subjects’ eCRFs will be provided 
to each Investigator Site to be maintained on file by the Investigator. 
11.7 HANDLING OF BIOLOGICAL SPECIMENS 
Tear samples will be submitted to one or more central laboratories and / or analytical 
laboratories for processing, storage and analysis. All laboratories meet Good Laboratory 
Practice requirements. 
11.8 PUBLICATIONS 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study.  Authorship will be established before writing the manuscript.  
Ora and the study sponsor will have the final decision regarding the manuscript and 
publication. 
 
 
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12 REFERENCES 
1. 
Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease 
among US men: estimates from the Physicians' Health Studies. Archives of 
ophthalmology 2009;127:763-8. 
2. 
Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye 
syndrome among US women. American journal of ophthalmology 2003;136:318-26. 
3. 
Schaumberg DA, Sullivan DA, Dana MR. Epidemiology of dry eye syndrome. 
Advances in experimental medicine and biology 2002;506:989-98. 
4. 
Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Survey of 
ophthalmology 2001;45 Suppl 2:S199-202. 
 
 
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13 APPENDICES 
APPENDIX 1:  SCHEDULE OF VISITS AND MEASUREMENTS 
Procedure 
Visit 1 
Day -14±1 
Visit 2 
Day 1 
Visit 3 
Day 
8±1 
Visit 4 
Day 15 ± 2 
Visit 5 
Day 29 ± 2 
Visit 6 
Day 57 ± 3 
 
Pre  
CAE® 
Post  
CAE® 
Pre 
CAE® 
Post 
CAE® 
Non 
CAE® 
Pre 
CAE® 
Post 
CAE® 
Pre 
CAE® 
Post  
CAE® 
Pre 
CAE® 
Post  
CAE® 
Informed Consent / HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
Medical / Medication History and 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical / Medication Update 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Placebo Run-In Dispensation 
 
X 
 
 
 
 
 
 
 
 
 
Placebo Run-in Collection 
 
 
X 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
Study Drug Dispensation 
 
 
 
X 
X2 
 
X 
 
X 
 
 
Study Drug Instillation 
 
 
 
X 
X 
 
 
 
 
 
 
Study Drug Collection 
 
 
 
 
X 
X 
 
X 
 
X 
 
Diary Dispensation 
 
X 
 
X 
X 
 
X 
 
X 
 
 
Diary Collection 
 
 
X 
 
X 
X 
 
X 
 
X 
 
Review of Qualification Criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
Adverse Event Query 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X1 
 
 
 
 
 
 
 
 
X1 
 
Drop Comfort Assessment 
 
 
 
X 
 
 
 
 
 
 
 
Ora Calibra® Ocular Discomfort 
Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ora Calibra® Ocular Discomfort & 
4-Symptom Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VAS Discomfort Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OSDI© Questionnaire 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Visual Acuity (ETDRS) 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
Slit-lamp Biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conjunctival Redness 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tear Collection 
 
 
X 
 
 
 
 
 
 
X 
 
Blood sampling for 
Immunogenicity testing 
 
 
 
X 
 
 
X 
 
X 
 
X 
TFBUT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fluorescein Staining 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lissamine Green Staining 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CAE® Exposure 
X 
X 
 
X 
X 
X 
Discomfort Grading during CAE® 
Exposure 
X 
X 
 
X 
X 
X 
Schirmer’s Test 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Intraocular Pressure 
 
X 
 
 
 
 
 
 
 
 
X 
Dilated Fundus Exam 
 
X 
 
 
 
 
 
 
 
 
X 
Exit Subject from Study 
 
 
 
 
 
 
 
 
 
 
X 
1: To women of child-bearing potential, as defined.  2The Visit 2 study drug kit is redispensed at Visit 3.  
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APPENDIX 2: EXAMINATION PROCEDURES, TESTS, 
EQUIPMENT, AND TECHNIQUES 
Visual Acuity Procedures (ETDRS Chart) 
LogMAR visual acuity (VA) must be assessed using an Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart. The procedure used will be consistent with the 
recommendations provided for using the ETDRS eye chart. VA should be evaluated at 
the beginning of each visit in the study (ie, prior to slit-lamp examination). VA testing 
should be done with most recent correction. 
Equipment 
The VA chart to be used is the ETDRS chart. If smaller reproduction (18" by 18", eg, 
from Prevent Blindness) wall charts are used, the subject viewing distance should be 
exactly 10 feet (or as specified by the manufacturer). In ALL cases, for purposes of 
standardizing the testing conditions during the study, all sites must use only the 'R' charts, 
and the right eye should be tested first. For reflectance (wall) charts, the chart should be 
placed frontally and well-illuminated. 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. 
The subject should attempt to read each letter, line-by-line, left to right, beginning with 
line 1 at the top of the chart. The subject should be told that the chart has letters only, no 
numbers. If the subject reads a number, he or she should be reminded that the chart 
contains no numbers, and the examiner should then request a letter in lieu of the number. 
The subject should be asked to read slowly, so as to achieve the best identification of 
each letter. He/she is not to proceed to the next letter until he/she has given a definite 
response. 
If the subject changes a response (eg, 'that was a "C" not an "O"') before he has read 
aloud the next letter, then the change must be accepted. If the subject changes a response 
having read the next letter, then the change is not to be accepted. The examiner should 
never point to the chart or to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the subject 
says he or she cannot read a letter, he or she should be encouraged to guess. If the subject 
identifies a letter as 1 of 2 letters, he or she should be asked to choose 1 letter and, if 
necessary, to guess. When it becomes evident that no further meaningful readings can be 
made, despite encouragement to read or guess, the examiner should stop the test for that 
eye. However, all letters on the last line should be attempted as letter difficulties vary and 
the last may be the only one read correctly. The number of letters missed or read 
incorrectly should be noted. 
 
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LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. 
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 
logMAR VA for that eye. 
For Example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 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=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of VA during the study, 
all VA assessments at a single site must be consistently done using the same lighting 
conditions and same correction if possible during the entire study. If the same correction 
cannot be used (ie, a subject forgets his glasses), the reason for the change in correction 
should be documented. 
Slit Lamp Biomicroscopy Procedures 
Slit lamp biomicroscopic observations will be graded as Normal or Abnormal. Abnormal 
findings will be categorized as clinically significant (findings that may interfere with 
study parameters or otherwise confound the data as determined by the investigator) or not 
clinically significant (NCS). The following will be examined:  
x Cornea  
x Conjunctiva 
x Anterior Chamber 
x Iris 
x Lens 
x Eyelid 
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External magnification and biomicroscopy will be performed using a slit-lamp. 
Magnification will be consistent with standard clinical practice. The subject will be 
seated. 
Dilated Fundoscopy 
Dilated fundoscopy will be performed using indirect ophthalmoscopy.  The investigator 
will make observations of the vitreous, retina, macula, choroid and optic nerve.   
Observations will be graded as Normal or Abnormal.  Abnormal findings that are 
clinically significant (as determined by the investigator that may interfere with study 
parameters or otherwise confound the data) and those that are not clinically significant 
will be described. A dilated fundoscopy examination should be performed if retinal 
disease is detected.  
x Vitreous:  Examination should emphasize the visual axis.  
x Retina, Macula, Choroid:  Include an observation of the retina and its blood 
vessels. Eyes should be excluded from the study if active inflammation is present.  
x Optic Nerve:  Significant damage or cupping to the optic nerve should be noted. 
It is recommended that tropicamide 1% ophthalmic solution be used to dilate subjects. 
The use of cyclopentolate 1% ophthalmic solution is recommended as secondary dilating 
medication, should the need arise.   
Intraocular Pressure 
Intraocular pressure (IOP) will be measured in each eye by contact tonometry by the 
examiner and the results will be recorded in mmHg.  A single measurement is made to 
obtain a determination of IOP.  The same tonometer employing the Investigator’s 
standard technique will be used throughout the study.  In addition, all reasonable efforts 
will be made to have the same examiner obtain all IOP measurements for a given subject. 
Tear Collection 
Subjects will be seated at a reclined position. The investigator will collect tears for up to 
5 min from each eye. The right eye will be collected, followed by the left eye. Once tears 
are collected, they will be pipetted into a separate tube for storage. Further details on tear 
collection process and storage will be found in a separate manual. 
 
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Blood Sampling for Immunogenicity Testing 
Serum blood draws will be collected at Visits 2, 4, 5 and 6 for immunogenicity testing.  
Instructions for the collection, handling and shipping blood for immunogenicity testing 
are given in a separate laboratory manual. 
 
 
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Ora proprietary scales – Not for distribution without 
permission 
Ora Calibra®  Ocular Discomfort Scale for Dry Eye 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
Ora Calibra®  Ocular Discomfort & 4-Symptom Questionnaire for Dry 
Eye 
 
 
 
 
  
 
 
 
 
 
 
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Visual Analogue Scale (VAS) 
Subjects will be asked the following questions regarding ocular discomfort (unrelated to 
study drug instillation) at all visits.  
The subject will be asked to rate each ocular symptom due to ocular dryness by placing a 
vertical mark on the horizontal line to indicate the level of discomfort. 0% corresponds to 
“no discomfort” and 100% corresponds to “maximal discomfort.”  
 
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Ocular Surface and Disease Index (OSDI)© for Dry Eye 
 
 
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HL036 Ophthalmic Solution 
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Ora Calibra® Conjunctival Redness Scale for Dry Eye 
 
 
  
 
  
 
  
 
  
 
  
 
 
Tear Film Break-Up Time (TFBUT)© 
The examiner will instill 
 solution into 
the inferior conjunctival cul-de-sac of each eye.  To thoroughly mix the fluorescein with 
the tear film, the subject will be instructed to blink several times.  In order to achieve 
maximum fluorescence, the examiner should wait approximately 30 seconds after 
instillation before evaluating TFBUT.    
With the aid of a slit-lamp, the examiner will monitor the integrity of the tear film, noting 
the time it takes to form micelles from the time that the eye is opened.  TFBUT will be 
measured in seconds using a stopwatch and a digital image recording system for the right 
eye followed by the left eye.  A Wratten #12 yellow filter will be used to enhance the 
ability to grade TFBUT.   
For each eye, 2 measurements will be taken and averaged unless the 2 measurements are 
> 2 seconds apart and are each < 10 seconds, in which case, a third measurement would 
be taken and the2 closest of the 3 would be averaged. 
 
 
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Fluorescein Staining  
The examiner will instill
 solution into 
the inferior conjunctival cul-de-sac of each eye. In order to achieve maximum 
fluorescence, the examiner should wait approximately 3-5 minutes after instillation 
before evaluating fluorescein staining. A Wratten #12 yellow filter will be used to 
enhance the ability to grade fluorescein staining. The staining will be graded with the Ora 
CalibraTM Corneal and Conjunctival Staining Scale.  
Ora Calibra®  Corneal and Conjunctival Staining Scale for Grading of 
Fluorescein Staining 
 
 
 
  
  
 
  
 
  
 
  
 
  
 
Staining areas: 
 
 
 
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Lissamine Green Staining  
The Investigator will instill 
 
 into the inferior conjunctival cul-de-sac and wait approximately 30 seconds before 
evaluating staining. The subject will be instructed to blink several times to distribute the 
lissamine green. The staining will be graded with the Ora CalibraTM Corneal and 
Conjunctival Staining Scale.  
Ora Calibra®  Corneal and Conjunctival Staining Scale for Grading of 
Lissamine Green Staining 
 
 
 
 
  
 
  
 
  
 
  
 
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Staining areas: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unanesthetized Schirmer’s Test 
Schirmer’s Tear Test will be performed according to the following procedure: 
x Using a sterile Tear Flo Schirmer test strip (Rose Enterprises), a bend in the strip 
will be made in line with the notch in the strip 
x The subject will be instructed to gaze up and in 
x The Schirmer test strip will be placed in the lower temporal lid margin of each 
eye such that the strip fits tightly. Subjects will be instructed to close their eyes 
x After 5 minutes have elapsed, the Schirmer strip will be removed. The length of 
the moistened area will be recorded (mm) for each eye 
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Drop Comfort Assessments 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
Subject-Reported Drop Comfort Scale 
 
 
 
Ora Calibra®  Drop Comfort Scale 
Subject-Reported Drop Comfort Questionnaire 
 
 
Ora Calibra®  Drop Comfort Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 3:  INVESTIGATIONAL PRODUCT COMPOSITION/ 
DESIGN 
 
 
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APPENDIX 4:  PROTOCOL AMENDMENT SUMMARY 
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31 OCTOBER 2017
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8NOV2017
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8NOV2017
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Appendix 6:  Investigator’s Signature 
Protocol Title: 
A Phase 2, Multicenter, Randomized, Double–Masked and 
Placebo–Controlled Study Evaluating the Efficacy of Two 
Concentrations (0.10%, 0.25%) of HL036 Ophthalmic Solution 
Compared to Placebo in Subjects with Dry Eye 
Protocol Number: 
HL036-DED-US-P201 
Final Date: 
31 OCT 2017 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations.  I agree to 
maintain all information supplied by Ora and the sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Ethical Review 
Committee (ERC) or another group, it will be submitted with a designation that the 
material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
 
 
Date:  
 
 
Name:  
 
 
 
Title:  
 
 
 
Site:  
 
 
 
Address:  
 
 
 
Phone Number:  
 
 
 
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