A Phase 2, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Efficacy and Safety of HBM9036 Ophthalmic Solution Versus Placebo in Subjects With Moderate to Severe Dry Eye
Phase: PHASE2
Conditions: Dry Eye
Sponsor: Harbour BioMed (Guangzhou) Co. Ltd.

 
 
Study Protocol 
 
 
Official title： 
 
 
 A Phase 2, Multicenter, Randomized, 
Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of 
HBM9036 Ophthalmic Solution 0.25% versus 
Placebo in Subjects with Moderate to Severe 
Dry Eye  
NCT number: 
 
NCT04092907 
Document date 
 
9 January 2019 
 
 

 
Confidential and proprietary 
Page 1 of 79 
Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.1 
 
 
Clinical Trial Protocol 
Study Title 
A 
Phase 
2, 
Multicenter, 
Randomized, 
Double-Blind, 
Placebo-Controlled Study Evaluating the Efficacy and Safety of 
HBM9036 Ophthalmic Solution 0.25% versus Placebo in 
Subjects with Moderate to Severe Dry Eye 
Study Number 
9036.1 
Study Phase 
II 
Investigational Product HBM9036 Ophthalmic Solution 
Indications 
Dry eye 
Investigators 
Multi-center 
Sponsor 
Harbour BioMed (Guangzhou) Co., Ltd 
Sponsor Contact 
Xiaoxiang Chen 
Harbour BioMed (Guangzhou) Co., Ltd 
 
 
 
Version No. 
Date 
Original Protocol 
Version 1.0 
7 November 2018 
Revised Protocol 
Version 1.1 
15 November 2018 
Revised Protocol 
Version 1.2 
9 January 2019 
 
 
 
Confidentiality Statement 
 
Property of Harbour BioMed (HBM). 
This document is confidential and may not be used, divulged, published or otherwise 
disclosed without consent of HBM. 
 

HBM9036 Ophthalmic Solution 
Sponsor: Harbour Biomed (Guangzhou) Co., Ltd 
Clinical Trial Protocol 9036.1, V1.2 
9 Jan 2019 
 
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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.1 
SYNOPSIS 
Sponsor: Harbour BioMed (Guangzhou) Co., Ltd 
Investigational Product: HBM9036 Ophthalmic Solution 
Name of Active Ingredient: HBM9036 
Study Title: A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study 
Evaluating the Efficacy and Safety of HBM9036 Ophthalmic Solution 0.25% versus Placebo 
in Subjects with moderate to Severe Dry Eye 
Study Number: 9036.1 
Study Phase: II 
Primary Objective: 
To compare the efficacy and safety of HBM9036 Ophthalmic Solution (0.25%) versus 
placebo in the treatment of dry eye 
Study Design: A multicenter, randomized, double-blind, placebo-controlled, and 
parallel-group study. 
Selection of Subjects: 
Subjects who are≥ 18 years of age; have a history of dry eye for ≥ 6 months; have a best 
corrected visual acuity of 0.7 logMAR or better in each eye; have in the study eye a 
Schirmer’s test score of ≤10 mm and ≥1 mm; have at least in the study eye a corneal 
fluorescein staining score of ≥2 according to the Ora Calibra® Corneal and Conjunctival 
Fluorescein Staining Scale; have at least in the study eye a score of ≥2 according to the Ora 
Calibra® Ocular Discomfort and 4-Symptom Questionnaire in at least one of the dry eye 
symptoms; have in the study eye a conjunctival redness score≥ 1 according to the Ora 
Calibra® Conjunctival Redness for Dry Eye Scale; and demonstrate in the study eye a 
response to the CAE® as defined by: 
a) 
Having at least a ≥1 point increase in fluorescein staining in the inferior region in 
at least one eye following CAE® exposure; 
b) 
Reporting an Ocular Discomfort score ≥3 at 2 or more consecutive time points in 
at least one eye during CAE® exposure (if a subject has an Ocular Discomfort 
rating of 3 at time = 0 for an eye, he/she must report an Ocular Discomfort rating 
of 4 for two consecutive measurements for that eye). Note: a subject cannot have 
an Ocular Discomfort score of 4 at time = 0). 
Drug, Dose and Mode of Administration: 
Investigational Product: HBM9036 Ophthalmic Solution 
Dose: 0.25% 
Mode of Administration: eye drop 

HBM9036 Ophthalmic Solution 
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Clinical Trial Protocol 9036.1, V1.2 
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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
Dose Regimen: one drop per eye, twice a day in the morning and evening 
Reference Therapy: placebo 
Dose: not applicable 
Mode of Administration: eye drop 
Dose Regimen: one drop per eye, twice a day in the morning and evening 
Duration of Treatment: Eight weeks 
Primary Efficacy Endpoint: 
• Changes from baseline in change from pre- to post-CAE inferior corneal staining (ICS) 
score of the study eye evaluated at Visit 6 (Day 57, Week 8) according to Ora Calibra® 
Corneal and Conjunctival Fluorescein Staining Scale 
Secondary Efficacy Endpoints: 
• Changes from baseline in change from pre- to post-CAE ICS score of the study eye 
evaluated at Visit 5 using Ora Calibra® Corneal and Conjunctival Fluorescein Staining 
Scale 
• Changes from baseline in pre-CAE ocular discomfort of the study eye evaluated at Visit 6 
according to Ora Calibra® Ocular Discomfort Scale 
• Changes from baseline in pre-CAE ocular discomfort of the study eye evaluated at Visit 5 
according to Ora Calibra® Ocular Discomfort Scale 
• Changes from baseline in pre-CAE symptom score evaluated at Visit 6 according to Ora 
Calibra® Ocular Discomfort and 4-Symptom Questionnaire 
• Changes from baseline in pre-CAE symptom score evaluated at Visit 5 according to Ora 
Calibra® Ocular Discomfort and 4-Symptom Questionnaire 
• Changes from baseline in post-CAE TFBUT of the study eye evaluated at Visit 6 
• Changes from baseline in post-CAE conjunctival redness score of the study eye evaluated 
at Visit 6 according to Ora Calibra® Conjunctival Redness Scale 
• Changes from baseline in Schirmer’s test (nonanesthetized) results at Visit 6 
• Change from baseline in OSDI© scores at Visit 6 
• Changes from baseline in pre-CAE burning sensation score evaluated at Visit 6 according 
to Visual Analogue Scale (VAS) 
• Changes from baseline in average weekly burning sensation score in subject diary at 
Week 8 
Safety Evaluation: 
• Incidence and severity of ocular AEs 
• Incidence and severity of non-ocular AEs 
• BCVA at each visit 
• Slit-lamp bio-microscopic results at each visit 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
• Evaluation of tolerance (at Visit 2) 
• Intraocular pressure (at Visits 1 and 6) 
• Fundus photography (at Visits 1 and 6) 
Statistical Methods: 
Primary Efficacy Analysis 
ANCOVA models will be used to compare the change from baseline in the pre- to 
post-CAE® ICS staining at Day 57 (Visit 6), as measured on the Ora Calibra® scale, between 
0.25% HBM9036 Ophthalmic Solution and placebo groups. The ANCOVA model will 
include the change from pre- to post-CAE inferior corneal fluorescein staining at baseline as 
a covariant. 
Secondary Efficacy Analysis 
The continuous and ordinal secondary efficacy variables collected at each visit will be 
summarized descriptively (n, mean, standard deviation, median, min and max). All 
visit-based data will be analyzed at each visit and based on the change from baseline. T test, 
Wilcoxon rank sum test and ANCOVA adjusting for baseline will also be performed as 
appropriate and no imputation of missing values will be performed. 
Safety Analysis 
The frequency and percentage of subjects who report treatment-emergent adverse events 
(TEAEs), serious TEAEs, and TEAEs leading to premature discontinuation of study will be 
summarized. An AE is treatment emergent if 1) it occurs after the first dose of study 
treatment; or 2) exists before the first dose of study treatment and its severity worsens or 
frequency increases after first dose. The AEs will be coded using the MedDRA preferred 
term and system organ class and listed by severity and the causal relationship with the study 
drug. The AEs leading to discontinuation of the study will be listed. No hypothesis test will 
be performed. Separate analyses will be performed for ocular specific and all AEs (including 
systemic). Other safety endpoints including visual acuity, slit-lamp biomicroscopy, fundus 
color photography, 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 on eyes, the data for 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. 
Data Monitoring and Clinical Endpoint Committee  
Not applicable 

HBM9036 Ophthalmic Solution 
Sponsor: Harbour Biomed (Guangzhou) Co., Ltd 
Clinical Trial Protocol 9036.1, V1.2 
9 Jan 2019 
 
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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.1 
Table of Contents 
LIST OF TABLES .................................................................................................................... 8 
LIST OF FIGURES .................................................................................................................. 8 
LIST OF APPENDICES ........................................................................................................... 8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................... 9 
1 
INTRODUCTION .......................................................................................................... 11 
1.1 
Medical Background ............................................................................................. 11 
1.2 
Overview of Drug ................................................................................................. 11 
1.3 
Non-clinical Studies .............................................................................................. 12 
1.4 
Previous Clinical Studies ...................................................................................... 12 
1.4.1 
Phase I Study ............................................................................................. 12 
1.4.2 
Phase II Study ........................................................................................... 13 
1.5 
Rationale ............................................................................................................... 14 
1.6 
Clinical Risk/Benefits Assessment ....................................................................... 15 
2 
OBJECTIVE ................................................................................................................... 17 
2.1 
Primary Objective ................................................................................................. 17 
2.2 
Secondary Objective ............................................................................................. 17 
3 
STUDY ENDPOINTS .................................................................................................... 18 
3.1 
Primary Efficacy Endpoint ................................................................................... 18 
3.2 
Secondary Efficacy Endpoints .............................................................................. 18 
3.3 
Safety Evaluation .................................................................................................. 18 
4 
INVESTIGATIONAL PLAN ......................................................................................... 20 
4.1 
Overall Study Design and Plan ............................................................................. 20 
4.2 
Rationale of Study Design .................................................................................... 22 
4.3 
Rationale of Dose/Regimen and Duration of Treatment ...................................... 22 
5 
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .......... 23 
5.1 
Inclusion Criteria .................................................................................................. 23 
5.2 
Exclusion Criteria ................................................................................................. 24 
5.3 
Subject Identification ............................................................................................ 26 
5.4 
Previous, Concomitant and Prohibited Medications ............................................. 26 
5.4.1 
Other Medications for the Treatment of Dry Eye ................................. 26 
5.4.2 
Prohibited Medications ............................................................................ 26 
5.4.3 
Other Prohibited Medications ................................................................. 26 
5.5 
Other Restrictions, Illicit Drugs or Drug Abuse ................................................... 26 
5.5.1 
Illicit Drugs ................................................................................................ 26 
5.5.2 
Dietary Restriction .................................................................................... 26 
5.6 
Reasons for Discontinuation of Treatment or Study Withdrawal ......................... 27 
5.7 
Removal of Subjects from Treatment or Assessment ........................................... 28 
5.7.1 
Removal of Individual Subjects ............................................................... 28 
5.7.2 
Termination of the Trial by the Sponsor ................................................ 28 

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6 
LABELING, PACKAGING, STORAGE, DISPENSE AND RETURN OF STUDY 
DRUGS ........................................................................................................................... 30 
6.1 
Subject Information .............................................................................................. 30 
6.2 
Product Description .............................................................................................. 30 
6.3 
Packaging and Labeling Information .................................................................... 30 
6.4 
Emergent Unblinding of Treatment Assignment .................................................. 30 
6.5 
Storage Requirements ........................................................................................... 31 
6.6 
Preparation and Dispensing of Study Treatments ................................................. 31 
6.7 
Treatment Compliance .......................................................................................... 31 
6.8 
Drug Accountability/Return of Study Drugs ........................................................ 31 
7 
SAFETY ......................................................................................................................... 33 
7.1 
Safety Assessments ............................................................................................... 33 
7.1.1 
Medical/Surgical History and Ophthalmologic Examination ............... 33 
7.1.2 
Pregnancy Test .......................................................................................... 33 
7.1.3 
Drop Tolerance Assessed Using Ora Calibra® Drop Tolerance Scale 
and Ora Calibra® Drop Tolerance Questionnaire ................................. 33 
7.2 
Adverse events ...................................................................................................... 33 
7.2.1 
Definition of AEs ....................................................................................... 33 
7.2.2 
Collection of Adverse Events ................................................................... 34 
7.2.3 
Assessment of Adverse Events ................................................................. 34 
7.2.4 
Causality .................................................................................................... 34 
7.2.5 
Recording of Symptoms, Signs and Scale/Questionnaire Evaluation 
Results ........................................................................................................ 35 
7.2.6 
Clinical Laboratory Abnormalities Reported as Adverse Events ........ 35 
7.2.7 
Serious Adverse Events ............................................................................ 36 
7.2.7.1 
Reporting Serious Adverse Events .......................................................... 36 
7.2.7.2 
Post-Study Follow-Up of Adverse Events ............................................... 37 
7.2.7.3 
Reporting Serious Adverse Events to Ethics Committees ..................... 37 
7.2.7.4 
Safety Reports to the Health Authority .................................................. 37 
7.2.8 
Overdose .................................................................................................... 37 
7.2.9 
Pregnancy .................................................................................................. 38 
7.2.10 
Clinical Endpoint Committee .................................................................. 38 
7.2.11 
Data Monitoring Committee .................................................................... 38 
8 
STUDY PLAN ................................................................................................................ 38 
8.1 
Schedule of Study ................................................................................................. 38 
8.1.1 
Visit 1: Day -13±2 to Subject Scr eening (CAE) ...................................... 41 
8.1.2 
Day -13 to Day 0 ........................................................................................ 43 
8.1.3 
Visit 2：Day 1- Subject Confirmation (CAE) and Baseline ................. 43 
8.1.4 
Day 1 to Day 7±1  ....................................................................................... 45 
8.1.5 
Visit 3 (Day 8±1)  ........................................................................................ 46 
8.1.6 
From Day 8 to Day 14±2  ........................................................................... 47 
8.1.7 
Visit 4: Day 15±2  ....................................................................................... 47 
8.1.8 
From Day 15 to Day 28±2  ......................................................................... 48 
8.1.9 
Visit 5: Day 29±2  ....................................................................................... 48 

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8.1.10 
From Day 29 to Day 56±3  ......................................................................... 49 
8.1.11 
Visit 6: Day 57±3  ....................................................................................... 49 
8.2 
Discontinuation of Treatment and Premature Withdrawal from Study ................ 51 
8.3 
Unscheduled Visits and End of Treatment/Study Exit Visit ................................ 51 
8.4 
End of Study ......................................................................................................... 52 
8.5 
Termination of Study ............................................................................................ 53 
8.6 
Completion of Study ............................................................................................. 53 
9 
STATISTICAL METHODS ........................................................................................... 54 
9.1 
Analysis Populations ............................................................................................. 54 
9.2 
Determination of Sample Size .............................................................................. 54 
9.3 
Blinding and Randomization ................................................................................ 55 
9.4 
General Considerations for Statistical Analysis ................................................... 55 
9.5 
Efficacy and Safety Analysis ................................................................................ 56 
9.5.1 
Efficacy Analysis ....................................................................................... 56 
9.5.2 
Safety Analysis .......................................................................................... 57 
9.6 
Subgroup Analyses ............................................................................................... 57 
9.7 
Handling of Missing Data ..................................................................................... 58 
9.8 
Interim analysis ..................................................................................................... 58 
9.9 
Multiplicity Adjustment ........................................................................................ 58 
9.10 
Statistical Analysis Plan and Analysis Software .................................................. 58 
10 STUDY MANAGEMENT ............................................................................................. 59 
10.1 
Regulatory Authority Approval ............................................................................ 59 
10.2 
Ethical Conduct of the Study and Institutional Review Board/Independent 
Ethics Committee Approval .................................................................................. 59 
10.3 
Subject Information and Informed Consent .......................................................... 59 
10.4 
Laboratory Accreditation ...................................................................................... 60 
10.5 
Confidentiality ...................................................................................................... 60 
10.5.1 
Data Confidentiality .................................................................................. 60 
10.5.2 
Confidentiality of Subject / Patient Records .......................................... 60 
10.6 
Quality Control and Assurance ............................................................................. 60 
10.7 
Data Management ................................................................................................. 60 
10.8 
Study Monitoring .................................................................................................. 61 
10.9 
Data Retention ...................................................................................................... 62 
10.10 Financial Disclosure .............................................................................................. 62 
10.11 Publication Policy ................................................................................................. 62 
11 LIST OF REFERENCES ................................................................................................ 63 
12 APPENDICES ................................................................................................................ 65 
12.1 
APPENDIX 1：EXAMINATION PROCEDURE, TESTS, EQUIPMENTS 
AND TECHNIQUES ............................................................................................ 65 
 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
 
 
LIST OF TABLES 
Table 1. 
Schedule of Study .......................................................................................... 39 
 
 
LIST OF FIGURES 
No table of contents entries found. 
 
LIST OF APPENDICES 
No table of contents entries found. 
 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ANOVA 
analysis of variance 
APC 
antigen presenting cell 
API 
active pharmaceutical ingredient 
BCVA 
best corrected visual acuity 
BID 
twice daily 
CAE 
controlled adverse environment 
CD 
optical disk 
CDA 
clinical data analyst 
CDM 
clinical data manager 
CRA 
clinical research associate 
CRO 
contract research organization 
CTR 
clinical trial report 
DCF 
data clarification form 
DVM 
data verification manual 
EC 
ethics committee 
e-CRF 
electric case report form 
EDC 
electronic data acquisition system 
EDTA 
ethylenediaminetetraacetic acid 
ET 
early termination 
ETDRS 
early treatment diabetic retinopathy study 
FAS 
full analysis set 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
international conference of harmonization 
ICS 
inferior corneal staining 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IND 
investigational new drug 
IOP 
intraocular pressure 
IP 
investigational product 
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 
logarithm of the minimum angular resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MW 
molecular weight 
N 
number 
ODS 
ocular discomfort score 
OPI 
ocular protection index 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
OSDI 
ocular surface disease index 
OTC 
over-the-counter drugs 
OU 
oculus uterque (each eye or two eyes) 
PI 
principal investigator 
PK 
pharmacokinetic 
PP 
per protocol 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SDC 
Statistics and Data Corporation, Inc. 
SEC 
self-evident correction 
STT 
Schirmer tear test 
TFBUT 
break up time of tear film 
TM 
trademark 
VA 
visual acuity 
VAS 
Visual Analogue Scale 
 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
1 
INTRODUCTION 
1.1 
Medical Background 
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. In the US, 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. In China, the prevalence of dry eye is up to 
13.55%4. With the dramatic increase of aging population in our country and the increase of 
computer use, dry eye is expected to become more prevalent and finding a treatment is 
becoming even more important5. 
Dry eye can be related to external factors, such as the low humidity of air-conditioned offices, 
winter heating, a dusty or windy outdoor environment, prolonged use of computers, or 
wearing of contact lenses, as well as to internal factors, such as hormonal imbalance, 
autoimmune disease, the use of many widely prescribed systemic medications, anatomical 
changes or trauma, and aging. Symptoms result in mildly decreased quality of life at a 
minimum, and with increasing severity, loss of function and productivity, pain, light 
sensitivity, and the misery that accompanies significantly impaired vision and decreased 
quality of life6-8. 
Dry eye is a multifactorial disorder that is directly linked to a disturbance in the production or 
properties of the tear film that protects and lubricates the ocular surface9, and can be roughly 
categorized into two major subgroups, respectively aqueous-deficient dry eye and 
evaporative dry eye. Inflammation is primary in dry eye disease associated with Sjögren’s 
Syndrome, sarcoidosis and chronic graft versus host disease, but is a secondary consequence 
of cell damage due to dessicating stress and hyperosmolarity in non-autoimmune dry eye10-11. 
The secreted inflammatory cytokines, especially TNF-α, interleukin (IL)-1, and IL-6, 
facilitate the activation and migration of antigen presenting cells (APCs) toward the draining 
lymph nodes12. In the lymph nodes, these APCs stimulate naïve T cells (Th0),  leading to the 
expansion of Th1/Th17 cells, and antagonize the regulatory T cell (Treg) function. 
Once these effectors are generated in the lymph nodes, they migrate to the ocular surface. 
Interaction of IL-17 with its receptors on the ocular surface leads to epithelial damage 
through increased secretion of matrix metalloproteinases and inflammatory cytokines13. 
These events lead to tear film instability which exacerbates ocular surface hyperosmolarity 
and completes the vicious circle. 
1.2 
Overview of Drug 
HBM9036 is a molecularly engineered TNF receptor 1 (TNFR1) fragment. Molecule 
fragmentation and engineering techniques are applied for enhanced tissue distribution, 
increased stability and potency. 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
HBM9036 is composed of 171 amino acids, from 41-211 residues of TNFR1 outside domain 
and a methionine residue added at the N-terminal. HBM9036 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. 
1.3 
Non-clinical Studies 
HBM9036 was found to significantly decrease the signs of dry eye disease induced in two 
studies implementing an established murine model of the disease, and in one study of 
spontaneous dry eye disease in dogs. In the murine dry eye models, keratitis scores and 
goblet cell number significantly improved in each study. In the dog study, Schirmer’s scores 
showed significantly increased tear production, and scoring of signs demonstrated 
significantly decreased total signs, ocular discharge and hyperemia. 
Pharmacokinetic profiles in blood and ocular tissues (cornea, aqueous humor, and vitreous 
humor) were evaluated with repeat ocular instillation of HBM9036 in male New Zealand 
white rabbits. HBM9036 1, 5, and 25 mg/mL was administered into both eyes three times per 
day in 3-hour intervals for 14 days. Results showed that systemic and ocular drug 
concentrations after ocular administration of 1 and 5 mg/mL HBM9036 were low or 
undetectable (<Lower level of Quantitation [LLOQ]). Drug was identified in the cornea and 
vitreous humor only at the high dose of 25 mg/mL. After topical administration of 25 mg/mL 
HBM9036, the concentration quickly decreased (α-phase) within two hours, and then 
remained at a constant level (β-phase) in the cornea. In the vitreous humor, the maximum 
concentration was found within one to two hours after the last administration of 25 mg/mL 
HBM9036. A gradual decrease until six hours and steady state after were then observed. 
The toxicity of HBM9036 has been investigated in seven repeat-dose studies. Six of these 
studies involved ocular dosing: two ocular repeat-dose studies in mice for durations of 
2 weeks and 28 days (with a 14-day recovery period in the latter study); two studies in 
rabbits with durations of 1-day and 8 weeks (with a 4-week recovery period in the latter 
study), and two in dogs with durations of 2 and 8 weeks (with a 2-week recovery period in 
the latter study). One 28-day study assessed the systemic toxicity and toxicokinetics of 
HBM9036 with repeat intravenous (IV) dosing in dogs. The results of these studies 
demonstrated no significant toxicity across all species. The results indicated that HBM9036 
Ophthalmic Solution was well tolerated and caused no alterations in ocular tissues or other 
tissues examined. 
1.4 
Previous Clinical Studies 
1.4.1 Phase I Study 
A first-in-human study was completed in Korea in August 2016 aiming to assess the safety, 
local tolerance, and PK properties of HBM9036. A total of 77 subjects were screened and 
20 subjects were randomized to Group A and Group B to receive topical ophthalmic 
instillation of HBM9036 0.5 mg/mL and 5 mg/mL twice in one day into left eyes, while right 
eyes received vehicle placebo. 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
Of the 20 subjects who received study drugs, 11 subjects reported 27 AEs. Twenty AEs were 
mild in severity and the subjects recovered without sequela. The remaining 7 AEs were 
moderate in severity, and all events were reported by one subject. Among the 7 moderate 
AEs, all symptoms except for corneal opacity resolved completely. The assessment of causal 
relationship between the study drug and the 7 AEs was determined to be “unlikely” for all 
events. The most frequently reported AE after administration of the study drug was 
conjunctival hyperemia, with 18 events reported. There were 5 AEs reported by 2 subjects 
from the HBM9036 0.5 mg/mL group and 6 AEs reported by 3 subjects from the HBM9036 
5 mg/mL group. The remaining 7 AEs were reported by 3 subjects in the placebo group. 
There were 24 AEs reported by 9 subjects (45%) that may have been caused by the study 
drug (the causal relationship was possible, probable, or certain). Among the AEs thought to 
be caused by the study drug in each group, conjunctival hyperemia was the most frequently 
reported (17 AEs reported by 7 [35.0%] subjects). All conjunctival hyperemia events were 
mild, and the subjects recovered without sequelae. 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 and 
there were no moderate or severe ophthalmologic symptoms observed. 
1.4.2 Phase II Study 
The Phase II, dose range, and proof-of-concept study of HBM 9036 was completed in the US. 
This was a multicenter, randomized, double-blinded, placebo-controlled study. Subjects were 
randomly assigned to one of three treatment groups (HBM9036 Ophthalmic Solution 0.10%, 
0.25% or placebo) to receive topical ophthalmic drops administered bilaterally BID. The 
study lasted for 8 weeks and included 6 visits. Although the primary sign of fluorescein 
staining at Visit 6 pre-CAE was not met with an ANCOVA analysis, analysis of the change 
in fluorescein staining score pre-CAE to post-CAE as well as post-CAE showed significant 
treatment differences from baseline starting as early as Visit 4 (Day 15) in total corneal and 
superior staining, and these significant treatment differences became consistent at Visit 5 
(Day 29) and Visit 6 (Day 57). Significant improvements in burning and itching as assessed 
by the VAS were seen in favor of the HBM9036 0.25% group as early as Visit 4 (Day 15) 
and continued to Visit 6 (Day 57). Significant improvement was observed in total OSDI 
score in the HBM9036 0.25% treatment group compared with placebo group. 
In the safety population, 44 (29.3%) subjects reported 64 AEs. Of them, 37 (24.7%) subjects 
reported 51 treatment-emergent adverse events (TEAEs), including 26 ocular TEAEs and 25 
non-ocular TEAEs. All TEAEs were of mild or moderate severity. A total of 16 (10.7%) 
subjects reported at least one ocular TEAE related to the study drug. Of them 7 subjects were 
treated with HBM9036 (HL036) 0.10%, 8 subjects were treated with HBM9036 0.25%, and 
1 subject was treated with placebo. The most common unexpected ocular TEAEs related to 
the study drug were installation site pain and allergic conjunctivitis. No deaths or SAEs were 
reported in the study. A total of 8 subjects withdrew from the study due to allergic 
conjunctivitis: 3 subjects were from HBM9036 (HL036) 0.10% group and 5 subjects were 
from HBM9036 (HL036) 0.25% group. No change of clinical significance was reported for 
other safety endpoints. 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
1.5 
Rationale 
Currently, mild dry eye is treated with artificial tears, which only provide temporary relief of 
symptoms. For moderate to severe cases, cyclosporine ophthalmic emulsion 0.05% 
(Restasis®, Allergan, Inc) is administered. Recently, lifitegrast ophthalmic solution 5% 
(Xiidra®, Shire US, Inc) has been approved for targeting the inflammatory aspects of dry 
eye.14-16 In China, the treatments for dry eye are very limited. The most common treatment is 
artificial tears. However, it can only alleviate symptoms and may induce drug dependency. 
No clinical trials on the two new drugs, Xiidra® and Restasis®, have been conducted in China 
and the approval for marketing in China for them has not been obtained. Therefore, a more 
effective and safe treatment for dry eye is urgently needed in China. 
TNF is a cytokine that mediates various inflammatory diseases. It is secreted chiefly by 
activated macrophages, although it can be produced by many other cell types such as T 
helper cells, NK cells and neurons. 
The primary role of TNF is the regulation of immune cells. TNF acts as an endogenous 
pyrogen, which induces fever, apoptotic cell death, sepsis via IL-1 and IL-6 producing cells, 
carchexia by stimulation of fat accumulation in liver, and inflammation, and inhibits 
tumorigenesis and viral replication. 
TNF exists in soluble form (sTNF) or in transmembrane form (tmTNF). Transmembrane 
TNF elicits cytotoxicity and inflammation through cell-to-cell contact. From the 
transmembrane TNF form, soluble TNF is released by the TNF alpha-converting enzyme 
(TACE). TNF strongly binds two receptors, TNFR1 (p55) and TNFR2 (p75), and this 
induces pathologic activities including inflammation and disease promotion.17 
TNF inhibitors (anti-TNF molecules), which block TNF-TNFR binding, are in development, 
and antibody-based therapeutics have proven the most effective. 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.18-20 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, 
there is a need for topical eyedrop forms of TNF-inhibitors with increased penetration and 
distribution and minimal systemic side effects.  
HBM9036 (HL036) ophthalmic solution is a TNFR1 fragment developed as an eye drop 
formulation. HBM9036 (HL036) is molecularly engineered for enhanced stability, and 
TNF-neutralizing activity. Previous results showed that HBM9036 (HL036) significantly 
improved signs of dry eye in mouse and dog models. Toxicological studies showed that 
HBM9036 (HL036) exhibited no significant toxicity and was well tolerated (see Section 1.3). 
In the Phase I clinical trial, HBM 9036 (HL036) also showed good tolerance and neither 
SAEs nor unexpected adverse drug reactions were reported (see Section 1.4). 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
This study is a proof-of-concept study in Chinese population to explore whether the optimal 
dose (HMB9036 0.25%) in the US population is consistently effective and safe in Chinese 
population. 
1.6 
Clinical Risk/Benefits Assessment 
The toxicity of HBM9036 (HL036) has been investigated in 7 repeat-dose studies. Six of 
these studies involved ocular dosing: 2 ocular repeat-dose studies in mice, 2 studies in rabbits, 
and 2 in dogs. One 28-day study assessed the systemic toxicity and toxicokinetics of 
HBM9036 (HL036) with repeat intravenous (IV) dosing in dogs. The results of these studies 
demonstrated no significant toxicity across all experimental species and HBM9036 (HL036) 
caused no alterations in ocular tissues or other tissues examined. 
In the murine dry eye models, keratitis scores and goblet cell number significantly improved 
in each study. In the dog study, Schirmer’s scores showed significantly increased tear 
production, and scoring of signs demonstrated significantly decreased total signs, ocular 
discharge and hyperemia. These results confirmed the effectiveness of HBM9036 (HL036) in 
animal models. 
The Phase I study completed in Korea assessed the safety, local tolerance, and PK properties 
of HBM9036 (HL036). Healthy subjects received topical ophthalmic instillation of 
HBM9036 (HL036) (twice a day at 12-hour interval) into left eyes, while right eyes received 
vehicle placebo. Of the 20 subjects who received study drugs, 11 subjects reported 27 AEs. 
Twenty AEs were mild in severity and the subjects recovered without sequela. The remaining 
seven AEs were moderate in severity, and all events were reported by one subject. All 
symptoms except for corneal opacity resolved completely. The assessment of causal 
relationship between the study drug and the seven AEs was determined to be “unlikely” for 
all events. 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 and there were no moderate or severe 
ophthalmologic symptoms observed. 
The Phase II, dose range, and proof-of-concept study of HBM9036 (HL036) completed in 
the US also showed that, after administration of HBM9036 (HL036) 0.25% BID, the change 
in fluorescein staining score (baseline correction value) pre-CAE to post-CAE as well as 
post-CAE showed significant differences compared with placebo group. Significant 
improvements in burning and itching were seen in favor of the HBM9036 (HL036) 0.25% 
group. Significant improvement was observed in total OSDI score in the HBM9036 (HL036) 
0.25% treatment group compared with placebo group. A total of 44 (29.3%) subjects reported 
64 AEs. Of them, 37 (24.7%) subjects reported 51 treatment-emergent adverse events 
(TEAEs). All TEAEs were of mild or moderate severity. No deaths or SAEs were reported in 
the study. A total of 16 (10.7%) subjects reported at least one ocular TEAE related to the 
study drug. Of them 7 subjects were treated with HBM 9036 0.10%, 8 subjects were treated 
with HBM9036 (HL036) 0.25%, and 1 subject was treated with placebo. No change of 
clinical significance was reported for other safety endpoints. 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
All data above indicate that HBM9036 (HL036) 0.25% (BID) was safe and well tolerated in 
previous clinical studies and could improve dry eye symptoms. The overall benefit-to-risk 
ratio is good. 

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2 
OBJECTIVE 
2.1 
Primary Objective 
The objective of this study is to compare the safety and efficacy of HBM9036 (HL036) 
0.25% ophthalmic solutions with placebo for the treatment of the signs and symptoms of dry 
eye. 
The primary objective is to evaluate the efficacy of 8-week continuous treatment with 
HBM9036 (HL036) ophthalmic solution (BID) in Chinese patients with dry eye and provide 
evidences for the Phase III trial. 
2.2 
Secondary Objective 
The secondary objective is to evaluate the safety of 8-week continuous treatment with 
HBM9036 (HL036) ophthalmic solution (BID) in Chinese patients with dry eye. 

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3 
STUDY ENDPOINTS 
3.1 
Primary Efficacy Endpoint 
• Changes from baseline in change from pre- to post-CAE ICS score of the study eye 
evaluated at Visit 6 (Day 57, Week 8) according to Ora Calibra® Corneal and 
Conjunctival Fluorescein Staining Scale 
3.2 
Secondary Efficacy Endpoints 
• Changes from baseline in change from pre- to post-CAE ICS score of the study eye 
evaluated at Visit 5 using Ora Calibra® Corneal and Conjunctival Fluorescein Staining 
Scale 
• Changes from baseline in pre-CAE ocular discomfort of the study eye evaluated at Visit 6 
according to Ora Calibra® Ocular Discomfort Scale 
• Changes from baseline in pre-CAE ocular discomfort of the study eye evaluated at Visit 5 
according to Ora Calibra® Ocular Discomfort Scale 
• Changes from baseline in pre-CAE symptom score evaluated at Visit 6 according to Ora 
Calibra® Ocular Discomfort and 4-Symptom Questionnaire 
• Changes from baseline in pre-CAE symptom score evaluated at Visit 5 according to Ora 
Calibra® Ocular Discomfort and 4-Symptom Questionnaire 
• Changes from baseline in post-CAE TFBUT© of the study eye evaluated at Visit 6 
• Changes from baseline in post-CAE conjunctival redness score of the study eye evaluated 
at Visit 6 according to Ora Calibra® Conjunctival Redness Scale 
• Changes from baseline in Schirmer’s test (nonanesthetized) results at Visit 6 
• Change from baseline in OSDI© scores at Visit 6 
• Changes from baseline in pre-CAE burning sensation score evaluated at Visit 6 according 
to Visual Analogue Scale (VAS) 
• Changes from baseline in average weekly burning sensation score in subject diary at 
Week 8 
3.3 
Safety Evaluation 
• Incidence and severity of ocular AEs 
• Incidence and severity of non-ocular AEs 

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• BCVA at each visit 
• Slit-lamp bio-microscopic results at each visit 
• Evaluation of tolerance (at Visit 2) by Ora Calibra® Drop Comfort Scale and Ora 
Calibra® Drop Comfort Questionnaire 
• Intraocular pressure (at Visits 1 and 6) 
• Fundus photography (at Visits 1 and 6) 

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4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This study is a multicenter, randomized, double-blinded placebo-controlled, parallel-group 
Phase II study. Subjects will be randomized at Visit 2 to one of following treatment groups: 
• HBM9036 (HL036) 0.25% Ophthalmic Solution 
• Placebo 
Subjects will receive either HBM9036 (HL036) Ophthalmic Solution (0.25%) or placebo 
solution as topical ophthalmic drops administered bilaterally BID. Subjects, Sponsor, and site 
personnel will be masked to treatment assignment. 
Controlled adverse environment (CAE) is an environmental chamber used to improve the 
accuracy for measuring signs and symptoms (such as corneal staining and ocular discomfort) 
of dry eye by regulating indoor humidity, temperature, air flow and visual tasks. The 
introduction of CAE® can improve the accuracy of predicting the efficacy of the 
investigational product by fewer patients, fewer study sites and less time. This environmental 
chamber has a reliable record of use under conditions of standard test design. 
During the screening period, 90-minute exposures to the CAE® (at Visits 1 and 2, two times) 
will be conducted to ascertain eligibility to enter the study by assessing the change of signs 
and symptoms during the 90-minute period and post-CAE exposure. Those who qualify will 
be randomized to receive study drug in a double-blinded manner for 56 days. Subjects will 
self-administer drops twice daily and will complete daily diary assessments. 
At Visits 1, 2, 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 Visits 3 and 4, no CAE® exposure will occur but signs and symptoms will be assessed. 
The total number of expected participants, including screen failures, is approximately 
200 subjects. A total of 100 subjects are expected to be randomized. 
A study flow chart appears below: 
 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.1 
 
Visit 1 
(Day -13 ± 2): 
Subject screening 
(CAE®) 
Informed Consent 
Demographics, Medical/Medication & Ocular History 
Urine Pregnancy Testing (as needed) 
Symptom Questionnaire, Visual Acuity 
Eye evaluations before entering the CAE® 
CAE® Exposure 
Eye evaluations after leaving the CAE® 
Safety Assessments (IOP and Fundus Color 
Photography) 
Run-in & Subject Daily Diary Dispensed 
↓ 
Placebo Run-in Period (Day 14/7±2) 
↓ 
Visit 2 
(Day 1): 
Subject Confirmation 
(CAE®)/Baseline 
Collection of Run-in Placebo/Diary 
Medical/Medication Update: AE Query 
Symptom Questionnaire, Visual Acuity 
Eye evaluations before entering the CAE® 
CAE® Exposure 
Eye evaluations after leaving the CAE® 
Randomization 
On-Site 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 Questionnaire, Visual Acuity 
Eye Evaluations 
On-Site Dose 
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 Questionnaire, Visual Acuity 
Eye Evaluations 
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 Questionnaire, Visual Acuity 
Eye evaluations before entering the CAE® 
CAE® Exposure 
Eye evaluations after leaving the CAE® 
Study Drug & Subject Daily Diary Dispensed 
↓ 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
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 Questionnaire, Visual Acuity 
Eye evaluations before entering the CAE® 
CAE® Exposure 
Post-CAE® Eye Evaluations 
Safety Assessments (IOP and Fundus Color 
Photography) 
Study Exit 
Subjects who terminate early during the treatment period will be asked to complete safety 
assessments prior to commencement of any alternative dry eye therapy. 
4.2 
Rationale of Study Design 
The expectation of this study is to observe that compared with the placebo, HBM9036 
(HL036) 0.25% Ophthalmic Solution can significantly improve the tolerance of dry eye 
patients to environment, which is consistent with the results from the Phase II clinical trial 
conducted in the US. The primary endpoint of this study is: 
• Changes from baseline in change from pre- to post-CAE® ICS score evaluated at 
Visit 6 according to Ora Calibra® Corneal and Conjunctival Fluorescein Staining 
Scale 
Considering the mechanism of action, a randomized, double-blinded, parallel-group study 
design will be used. Details are provided in Section 9.2. 
4.3 
Rationale of Dose/Regimen and Duration of Treatment 
Ocular topical administration is the best route of administration for dry eye treatment. The 
proposed 8-week treatment period is also based on the results from non-clinical studies, 
current clinical study data and the anti-inflammatory mechanism of action. 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
5 
SELECTION OF STUDY POPULATION AND WITHDRAWAL 
CRITERIA 
5.1 
Inclusion Criteria 
Individuals eligible to participate in this study must meet all of the following criteria: 
1. Provide written informed consent; 
2. Be at least 18 years of age at Visit 1; 
3. Have a patient-reported history of dry eye for≥ 6 months prior to enrollment; 
4. Have a history of use eye drops for dry eye symptoms within 6 months of Visit 1 or 
desire to use eye drops; 
5. Have a best corrected visual acuity of 0.7 logMAR or better (Snellen equivalent score 
of 20/100 or better) in each eye at Visit 1; 
6. Report in the study eye a score of ≥ 2 according to the Ora Calibra® Ocular 
Discomfort and 4-Symptom Questionnaire in at least one of the dry eye symptoms at 
Visits 1 and 2; 
7. Have in the study eye a Schirmer’s Test score of ≤ 10 mm and ≥ 1 mm at Visits 1 and 
2; 
8. Have at least in the study eye a corneal fluorescein staining score of≥ 2 for at least 
one subregion (inferior cornea, superior cornea or central cornea) according to the 
Ora Calibra® Corneal and Conjunctival Fluorescein Staining Scale at Visits 1 and 2; 
9. Have at least in the study eye a conjunctival redness score ≥ 1 according to the Ora 
Calibra® Conjunctival Redness for Dry Eye Scale at Visits 1 and 2; 
10. Demonstrate in the study eye a response to the CAE® at Visits 1 and 2 as defined by: 
a) Having at least a ≥1 point increase in fluorescein staining in the inferior region 
in at least the study eye following CAE® exposure; 
b) Reporting an Ocular Discomfort score ≥3 at 2 or more consecutive time points 
in at least the study eye during CAE® exposure (if a subject has an Ocular 
Discomfort rating of 3 at time = 0 for an eye, he/she must report an Ocular 
Discomfort rating of 4 for two consecutive measurements for that eye). Note: 
a subject cannot have an Ocular Discomfort score of 4 at time = 0); 
11. Be willing and can adjust current treatment for dry eye according to the protocol, 
judged by the Investigator; 
12. Must be willing to complete all study assessments required by the protocol. 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
5.2 
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, lid margin inflammation or active ocular allergies that require therapeutic 
treatment, and/or in the opinion of the investigator may interfere with study 
parameters; have meibomian gland dysfunction requiring local or systemic treatment 
with antibiotics; 
2. Be diagnosed with an ongoing ocular infection (bacterial, viral, or fungal), or active 
ocular inflammation at Visit 1; 
3. Be diagnosed with Sjogren's syndrome, Steven-Johnson syndrome, or dry eye 
secondary to chronic graft-versus-host disease; 
4. Have worn contact lenses within 7 days of Visit 1 or anticipate using contact lenses 
during the study; 
5. Have previously had laser-assisted in situ keratomileusis (LASIK) surgery within the 
last 12 months, or had femtosecond small incision lenticule extraction (SMILE) 
within the last 12 months, or had phacoemulsification within the last 3 months, or had 
dry eye or aggravation of dry eye caused by other ocular operations has not been 
stable; 
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, or anticipate 
having permanent punctal occlusion, or have used permanent punctal occlusion and 
had complications such as extrusion or shifting; 
8. Have used ophthalmic cyclosporine A, tacrolimus or Xiidra® within 60 days prior to 
Visit 1; 
9. 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 study (excluding 
medications allowed during the study); the respective wash-out periods are required 
for the following medications, otherwise the subjects will be excluded: 
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 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
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 
10. Be a woman who is pregnant, nursing or planning to be pregnant, or be a woman of 
childbearing potential who is not using an acceptable means of birth control; 
11. Be a man who does not take one or more acceptable contraceptive methods; 
12. Have severe cardiovascular diseases, liver diseases, nervous system diseases and 
malignant tumors, or other diseases that the Investigator believes may interfere 
significantly with the subject’s participation in the study and follow-up, or may cause 
diseases leading to hospitalization during the study; 
13. Drug allergy: patients who are allergic to drugs similar to study drugs or allergic to 
excipients of study drugs; 
14. Drug abuse: subjects who have obvious alcohol and drug abuse judged by the 
Investigator; 
15. Have other remarkable diseases, traumas, or other conditions except for dry eye, 
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; 
16. Have connection with the study sites: investigators, sub-investigators, study 
coordinators or employers of investigators, or direct relatives of those listed above 
cannot participate in the study; 
17. Cannot provide valid informed consent: have mental disorders, mental retardation, 
bad intentions or a history of other illnesses that limit the validity of informed consent 
in this study; 
18. Study drugs or devices: have used an investigational drug or device within 30 days of 
Visit 1 (screening) or 5 half-lives, whichever longest. 
Note: subjects who participate in an observational study (i.e. no change in treatment 
or no other interventions is required) are not excluded. 

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5.3 
Subject Identification 
At screening visit (Visit 1), each subject will be assigned a unique 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 criteria are met and no exclusion criteria are met at 
Visits 1 and 2, each subject will then be assigned a randomization number at the end of 
Visit 2 and block randomization will be conducted by IWRS system. 
All the subjects, the Sponsor, and investigators will not know the treatment assigned to each 
subject and will be masked throughout the study. 
5.4 
Previous, Concomitant and Prohibited Medications 
The use of any prescription or over-the-counter medications within 30 days before Visit 1 is 
to be recorded on the previous/concomitant page in electronic case report form (eCRF). Any 
increase or decrease in drugs or dosage change during the study should also be recorded on 
eCRF. Any drugs currently in use, including OTC medications and Chinese herbal medicines, 
are permitted if they are not prohibited in the protocol and are approved by investigators. 
Subjects will be told that they should contact investigators in case of any disease occurring. 
All concomitant medications used during the study and their indications, doses, route of 
administration and dates of administration will be recorded on the concomitant page in eCRF. 
5.4.1 
Other Medications for the Treatment of Dry Eye 
Other medications for the treatment of dry eye other than the study drugs are not permitted 
during the study. 
5.4.2 
Prohibited Medications 
Prohibited medications/treatments during the study are outlined in the exclusion criteria 
(Section 5.2). 
5.4.3 
Other Prohibited Medications 
Not applicable. 
5.5 
Other Restrictions, Illicit Drugs or Drug Abuse 
5.5.1 
Illicit Drugs 
See the exclusion criteria for details (Section 5.2). 
5.5.2 
Dietary Restriction 
There is no dietary restriction in this study. 

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5.6 
Reasons for Discontinuation of Treatment or Study Withdrawal 
Subjects may withdraw their consent to participate in the study at any time. 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. When possible, the tests 
and evaluations listed for the termination visit should be carried out. 
The Investigator must notify the Sponsor of all subject withdrawals as soon as possible. The 
Sponsor also reserves the right to terminate the study at any time for either clinical or 
administrative reasons and to discontinue participation of the individual Investigator or study 
site for slow enrollment or noncompliance. 
Reasons for which the Investigator may withdraw a subject from the study include, but are 
not limited to, the following: 
• Subject experiences a serious or intolerable AE; 
• Subject requires medication prohibited by the protocol; 
• Subject does not adhere to study requirements specified in the protocol; 
• Subject was erroneously admitted into the study or does not meet entry criteria; 
• Subject is lost to follow–up; 
• Subject becomes pregnant; 
• Death; 
• Investigator’s decision; 
• Termination of the study by the sponsor; 
• Subject’s willingness. 
If a subject fails to return for scheduled visits, efforts must be made to determine the reason. 
If the subject cannot be reached by telephone after two attempts, he will be discontinued 
from the study. The date of last visit will be recorded in the study records and CRF. For 
subjects who are reached again after lost to follow-up and have missed the visit, 
supplementary medications should be provided as soon as possible for them to continue the 
study. 
If a female subject is pregnant during the study, she should withdraw from the study and be 
followed up until childbirth or pregnancy outcome. 

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5.7 
Removal of Subjects from Treatment or Assessment 
5.7.1 
Removal of Individual Subjects 
Subjects who meet any of the following criteria will withdraw from the trial: 
• Withdraw the ICF for any reason; 
• No longer able to continue to participate in the study for medical reasons (e.g. 
pregnancy, surgery, AEs or other diseases); 
• Administrative reasons (protocol violation, lack of compliance); 
• Harbour BioMed decides to terminate the trial early for one or all subjects (previous 
positive benefit-risk assessment is not supported by new toxicological findings or 
SAEs). 
Subjects should not be discontinued from the trial due to protocol violations before 
discussion with the clinical research associate. 
The data of the subjects who discontinue from the study before enrollment will be recorded 
in the study database and listed. The data of the subjects who discontinue from the study after 
enrollment must be recorded, and the reasons must be recorded in the source documents as 
well as in eCRF. These data must be included in the study database and be reported. 
The procedures after early withdrawal from the trial are presented in Section 8.2. 
Pregnancy 
If a subject is pregnant during the study, the study drug needs to be discontinued, and the 
subject should be followed up until childbirth or termination of pregnancy. The data of the 
subject until completion of the last visit will be collected and reported in the clinical trial 
report (CTR); and any subsequent events will be reported in the Drug Safety Database of 
Harbour BioMed. Detailed information about reporting of the pregnancy events is presented 
in Section 7.2.9. 
5.7.2 
Termination of the Trial by the Sponsor 
Harbour BioMed reserves the right to terminate the trial or a study site for any reason listed 
below at any time: 
• The overall enrollment or enrollment at a study site does not meet the target; 
• Any efficacy/safety information that can significantly affect the implementation of 
this trial and does not support the initial positive benefit-risk assessment; 
• Violations against GCP, CTP or the contract and interfere with normal 
implementation of the trial. 

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If the trial is terminated, investigators/study sites will be compensated reasonably (except in 
the third case listed above). 

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6 
LABELING, PACKAGING, STORAGE, DISPENSE AND RETURN 
OF STUDY DRUGS 
6.1 
Subject Information 
The packaging for the study drugs needs to meet the study requirements. Study staffs will use 
IWRS to assign subjects to treatment groups, dispense study drugs, and manage the drug 
dispense. The study drugs need to be packaged according to the drug package plan made by 
the Sponsor. A unique personal identification number (PIN) must be assigned to the persons 
who access the IWRS system. These personnel must use the PIN allocated to them to enter 
the system and not share their PIN with anyone else. 
6.2 
Product Description 
Study drug will be supplied as a sterile, clear, colorless liquid solution containing 0.25% API 
(HBM9036) in 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. In 
addition to HBM9036, the components of the drug solution are: sodium chloride (tonicity 
adjusting agent), citric acid monohydrate (buffering solution), sodium hydroxide solution and 
hydrochloric acid 1% (both for pH adjustments), and sterile water for injection as a solvent. 
The placebo solution consists of all components of the drug product solution except for 
HBM9036. 
6.3 
Packaging and Labeling Information 
Batch #(ID for tracing packaging ID) 
Drug # 
Composition ID # 
Specification and Formulation 
Storage Conditions 
Protocol # 
Regulatory Requirements 
Sponsor’s Contact Information 
ID= identification number; #=number 
6.4 
Emergent Unblinding of Treatment Assignment 
The IWRS should be used to unblind subjects and to unmask drug identity. When the 
Investigator contacts the system to unblind a subject, he/she must provide the requested 
subject identifying information and confirm the necessity to unblind the subject. Harbour 
BioMed will not provide a disclosure envelope with the clinical supplies. 
The Investigator or treating physician may unblind a subject’s treatment assignment only in 
the case of an emergency, when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject. 
Whenever possible, the Investigator must first discuss options with the clinical research 
associate (CRA) or appropriate study personnel before unblinding the subject’s treatment 
assignment. If this is impractical, the Investigator must notify the Sponsor as soon as possible, 

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but without revealing the treatment assignment of the unblinded subject, unless that 
information is important for the safety of subjects currently in the study. The date and reason 
for the unblinding must be recorded in the appropriate data collection tool. 
6.5 
Storage Requirements 
HBM9036 and placebo solution must be refrigerated (2-8°C). Subjects will be told to store 
HBM9036 and placebo solution in the fridge (at 2-8℃). 
6.6 
Preparation and Dispensing of Study Treatments 
Study drugs will be packaged and labeled into study kits. Both sterile drug and placebo 
solutions are packaged in disposable 0.5 mL LDPE vials with a dose of about 50 μL per drop. 
Each two vials are placed in a nitrogen-filled aluminum foil bag, providing the dose for one 
day. Each study kit contains enough medications until the next study visit.  
For the screening visit (Visit 1), drugs will be dispensed according to the schedule of 
assessments and visit window. 
For the treatment period, drugs are distributed according to requirements of each study visit 
considering visit window. 
Subjects will be suggested to put 1 vial of HBM9036 or placebo solution at room 
temperature 1±0.5 hours before drug administration. 
At study sites, all IPs must be stored safely under the storage conditions specified in the 
protocol and only accessed by qualified personnel designated by the study site. All IPs must 
be stored and managed in accordance with local regulations, ICH GCP and study procedures, 
and inventory must be carefully and accurately recorded. 
6.7 
Treatment Compliance 
Subjects will be required to record the use of study drugs in their diaries every day which 
will be used for evaluation of subject’s treatment compliance. Drug usage of 80% to 125% 
will be evaluated as good compliance. 
Treatment compliance will be calculated as: (actual drug use/ planned drug use) × 100%. The 
actual drug use is the amount of drug used by subjects between the drug dispensing and next 
study visit (based on the records of drug use reviewed by the Investigator); and the planned 
drug use is calculated as (daily drug use specified in the protocol) × (the optimum interval 
between two study visits). The decrease in drug dose caused by the treatment interruption or 
dose decrease because of AEs is not considered as poor compliance. 
6.8 
Drug Accountability/Return of Study Drugs 
The study drug is not allowed to be used by investigators in any case, unless specified in the 
protocol. 

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A staff will be authorized by the study site to receive, safely and appropriately manage and 
preserve and store study drug in a safe place. The study drug can be inspected only by 
authorized staff. The storage conditions of the study drugs should be observed, monitored 
and recorded carefully, and study drugs should be distributed according to the protocol. 
Investigators or other authorized personnel will be responsible for accurately recording the 
amount of drugs received from Harbour BioMed, delivered to subjects, returned by subjects, 
and the amount of drugs remaining at the end of study. The study drug should be disposed 
according to Good Supply Practice for Pharmaceutical Products. In case of any problems 
requiring special or protective handling, the clinical research associate should be contacted. 
All study drugs, including partially used or empty containers, must be returned at the end of 
the study as required by Harbour BioMed. 
Staff at study sites will check the records for drug accountability together and the records 
will be monitored by the Sponsor’s CRA regularly. 
Before the completion of all pre-dose evaluations and confirmation of subjects’ eligibility for 
randomization/participation in the study, authorized staff will not be allowed to open the 
package of study drug. Any action that violates the requirements listed above must be 
discussed with the CRA. 
All used drug package used by subjects and unused study drugs will be collected. The study 
drugs used by subjects will be stored in safety locker at room temperature before being 
returned to Harbour BioMed or its authorized personnel. 
Note: the used drug package and unused study drugs should be stored separated from the 
study drugs not dispensed. 
All complaints related to product quality (including package problems) must be reported to 
Harbour BioMed using the Product Complaint Form in the folders of each site. Harbour 
BioMed will contact study sites to assess the nature of the complaints and decide the further 
measures that need to be taken. 

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7 
SAFETY 
7.1 
Safety Assessments 
The safety of the investigational product will be evaluated according to adverse reactions and 
all ophthalmologic findings (see details in Section 3.3). 
7.1.1 Medical/Surgical History and Ophthalmologic Examination 
See Section 8 Study Plan and Section 3.3 Safety Endpoints for detailed information. 
7.1.2 Pregnancy Test 
Urine pregnancy tests will be conducted for premenopausal women without surgical 
contraception in the laboratories of all study sites at Visit 1 (screening visit) and Visit 6 
(Week 8) or at study discontinuation/withdrawal. 
7.1.3 Drop Tolerance Assessed Using Ora Calibra® Drop Tolerance Scale and Ora 
Calibra® Drop Tolerance Questionnaire 
Drop tolerance will be assessed using the Ora Calibra® Drop Tolerance Scale and Ora 
Calibra® Drop Tolerance Questionnaire at each study site at Visit 2. 
7.2 
Adverse events 
7.2.1 Definition of AEs 
An AE refers to all untoward medical occurrence after the use of an IP. An AE can be any 
sign, symptom or abnormal clinical laboratory results, but may not necessarily have a causal 
relationship with the IP. 
An AE includes, but are not limited to: 
• Any symptom or condition (medical history) not reported previously by subjects; 
• An aggravation of existing symptoms or conditions; 
• Significantly increased frequency or intensity of existing events or conditions; 
• Conditions discovered or diagnosed for first time after the administration of the 
investigational product, even if they may already exist prior to initiation of the study. 
An AE does not include: 
• Routine medical or surgical procedures caused by non-disease factors (e.g., plastic 
surgery, endoscopy, biopsy); 
• Planned surgical procedures before enrollment (e.g., cataract surgery) or 
hospitalization due to social factors (e.g., medical insurance); 

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• Overdose of either study drug or concurrent medication without any clinical signs or 
symptoms; 
• Non-clinically significant abnormal laboratory values. (If accompanied by 
signs/symptoms, the signs or symptoms are considered an AE.). 
7.2.2 Collection of Adverse Events 
Adverse events that occur between the time subject signs the ICF for the study and the time 
when that subject is randomized will be summarized as medical history and not as a 
treatment-emergent adverse event unless the event meets the definition of an SAE or AE 
related to protocol specific procedures. 
Adverse events that occur between the time when subject is randomized and last visit should 
be reported through CRF. All SAEs should be reported to Harbour BioMed within 24 hours 
of awareness. 
Any SAE between last visit and study completion that has a causal relationship with 
investigational product should be immediately reported to Harbour BioMed and recorded in 
CRF. 
Post-study AE/SAE that investigators judge its occurrence related to investigational product 
should be reported to Harbour BioMed PV through spontaneous reporting. 
7.2.3 Assessment of Adverse Events 
The Investigator should immediately record and report all AEs via CRF and AE report forms 
during the study. All SAEs (see Section 7.2.7) must be reported to Harbour BioMed or 
designee within 24 hours after the Investigator recognizes/classifies the event as an SAE. 
When a SAE occurs, the subject may be discontinued from the treatment after investigators 
have thorough discussion with medical monitors. 
The Investigator will categorize the severity of each AE according to the following criteria: 
Mild: Associated with no limitation of daily activities or only slight discomfort; generally not 
requiring change or interruption of study drugs; and/or not needing therapeutic intervention; 
Moderate: Associated with limitation of daily activities or obvious discomfort; generally 
requiring change or interruption of study drugs; and/or requiring therapeutic intervention; 
Severe: Associated with inability of subject to carry out daily activities or obvious discomfort; 
considered to be life-threatening; resulting in significant disability or incapacity; and 
requiring therapeutic intervention. 
7.2.4 Causality 
The relationship of each AE to the administration of study drug will be assessed by the 
Investigator after careful consideration, and according to the following guidelines: 

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Definitely: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug; it disappears 
or decreases on cessation or reduction in study drug dose; and/or it reappears or worsens 
when the study drug is administered; 
Probably: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug; but it could 
also be reasonably explained by other factors such as underlying disease, complications, 
concomitant medications or treatments; 
Possibly unrelated: A reaction that does not follow a reasonable temporal sequence from 
administration of study drug; that does not follow a known or expected response pattern to 
the study drug; it could be reasonably explained by other factors such as underlying disease, 
complications, concomitant medications or treatments; 
Unrelated: A reaction that follows a reasonable temporal sequence from administration of 
study drug; that follows a known or expected response pattern to the study drug; it disappears 
or decreases on cessation or reduction in study drug dose; and/or it reappears or worsens 
when the study drug is administered; 
Inaccessible: A reaction for which current data is too insufficient to assess its relationship 
with the study drug. 
7.2.5 Recording of Symptoms, Signs and Scale/Questionnaire Evaluation Results 
During the study period, not all symptoms, signs, and scale/questionnaire assessment will be 
recorded as AEs, and the following conditions will not be recorded as AEs: 
• Symptoms and signs due to fluctuation in dry eye disease. Symptoms and signs of dry 
eye disease will be analyzed as the efficacy endpoint and will not be recorded as AEs; 
• The assessment of tolerance to eye drops will be analyzed as a safety endpoint, and 
will not be recorded as AEs; 
• The CAE simulates daily adverse environment and triggers the symptoms and signs 
which will be evaluated as the efficacy endpoint. Therefore, dry eye symptoms and 
signs triggered by CAE will not be recorded as AEs unless the dry eye symptoms and 
signs triggered by CAE exceed the expected range of dry eye. 
7.2.6 Clinical Laboratory Abnormalities Reported as Adverse Events 
Clinical laboratory tests will not be required during the study. However, some subjects may 
be asked to take clinical laboratory tests. 
Not all laboratory abnormalities observed during the study will be reported as AEs unless one 
of the following criteria is met: 

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• A laboratory abnormality that leads to a dose adjustment (e.g., an abnormality that 
results in dose decrease, treatment interruption, or discontinuation of study); 
• A laboratory abnormality that results in any therapeutic intervention (i.e., 
concomitant medication or non-drug therapy is needed); 
• Other laboratory abnormality judged by the Investigator to be of any clinical 
significance (e.g., significant decrease in hemoglobin not requiring transfusion); 
For laboratory abnormalities that do not meet the above criteria but are outside of normal 
range (e.g., < or > normal reference range), the Investigator should indicate whether the value 
is clinically significant or not for the subject. 
7.2.7 Serious Adverse Events 
A SAE refers to the event meeting one of the following criteria: 
• Results in death; 
• Is life-threatening (i.e., in the view of the Investigator, 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.); 
• Results in hospitalization or prolongation of hospitalization; 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
• Results in congenital anomaly/birth defect; 
• Important medical events that may require intervention to prevent one of the 
outcomes listed above (e.g. allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, dyscrasias or convulsions that do not result in 
hospitalization, or drug dependency or drug abuse.). 
When a SAE occurs, the Investigator should immediately provide appropriate treatments to 
the subject for their safety and benefit. 
7.2.7.1 Reporting Serious Adverse Events 
In agreeing to the provisions of this protocol, the Investigator accepts all legal responsibilities 
for AE identification, documentation, grading, assignment of causality, and prompt 
notification of SAEs to Harbour BioMed. All SAEs must be reported to Harbour BioMed 
within 24 hours after the Investigator recognizes/classifies the event as an SAE. At a 
minimum, the term of the event and the causality determined by the Investigator must be 
provided at the time of the initial report. The Investigator should follow up the event and 
report to Harbour BioMed within 24 hours after he/she receives the follow-up information. 

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7.2.7.2 Post-Study Follow-Up of Adverse Events 
Any AEs that are unresolved at the subject’s last study visit need to be followed up by the 
Investigator until clinical signs/symptoms disappear or return to baseline level, or become 
stable at the Investigator’s discretion, or refusal to follow-up by subjects, or lost to follow-up. 
Harbour BioMed reserves the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
7.2.7.3 Reporting Serious Adverse Events to Ethics Committees 
The Investigator is responsible for notifying the Ethics Committee of all SAEs, including any 
follow-up information. Documentation of the safety report submitted to the EC must be 
retained. The Investigator is also responsible for notifying Harbour BioMed if the EC 
requires revisions to the ICF or other measures based on its review of the SAE report. 
7.2.7.4 Safety Reports to the Health Authority 
The Investigator must report the SAE to National Medical Products Administration (NMPA) 
and its local affiliates, and National Health Commission (NHC) within 24 hours after he 
receives the SAE information. The report also needs to be sent to the pharmacovigilance 
team at Harbour BioMed. The follow-up report should be reported within the same time 
frame as the initial SAE report. 
Harbour BioMed or its representatives will submit a safety report to NMPA and NHC, for 
any suspected adverse reaction that is both serious and unexpected (SUSAR) within the 
appropriate time frame (initial report: 7 days for death or life-threating case, 15 days for other 
SUSAR; follow-up report: 8 days for death or life-threating case, 15 days for other SUSAR). 
Other SAEs will be reported in annual report. 
Harbour BioMed or its representatives will send the investigators who are participating in the 
clinical studies sponsored by Harbour BioMed the copies of each safety report submitted to 
NMPA. Safety reports must be submitted to the appropriate EC as soon as possible.  
Documentation of the safety report submitted to the EC must be retained. 
7.2.8 Overdose 
An overdose is defined as a dose greater than the dose specified in this study protocol. In the 
event of an overdose of study drug, the Investigator should treat the overdose based on 
clinical judgement and contact the medical monitor. The overdose information needs to be 
recorded in the drug overdose form. Any overdose which results in AE should be reported on 
AE page in CRF. Any case which meets the definition of SAE should be reported per SAE 
reporting procedures. The Investigator should refer to Investigator’s Brochure for detailed 
information of study drug(s) being used in this study. Investigator should take appropriate 
actions to treat the event to ensure the safety and benefit of subject. 

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7.2.9 Pregnancy 
To ensure subject safety, pregnancy occurring in female subjects from Visit 1 to study 
completion must be reported to Harbour BioMed within 24 hours of awareness of the event. 
The pregnancy should be followed up to determine outcome. Outcomes include spontaneous 
or voluntary termination of pregnancy, details of the birth, and the presence or absence of 
any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded on a Pregnancy Report Form and reported to Harbour BioMed 
by the Investigator. Any AE occurring during pregnancy must be reported on the AE page in 
CRF; any event meeting the criteria of SAE should be reported per SAE reporting procedures. 
The pregnancy occurring in female partner of male subjects during the study should be 
collected and reported following the pregnancy reporting procedures. 
7.2.10 Clinical Endpoint Committee 
No Clinical Endpoint Committee will be used for this study. 
7.2.11 Data Monitoring Committee 
No Data Monitoring Committee will be used for this study. 
8 
STUDY PLAN 
8.1 
Schedule of Study 
See Table 1. 

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Table 1. 
Schedule of Study 
Procedure 
Visit 1 
Day -13 ± 2 
Visit 2 
Day 1 
Visit 3 
Day 8 ± 1 
Visit 4 
Day 15 ± 
2 
Visit 5 
Day 29 ± 2  
Visit 6 
Day 57 ± 3  
EOT4 FU2 
 
Before 
CAE 
After 
CAE 
Before 
CAE 
After 
CAE 
No 
CAE 
No 
CAE 
Before 
CAE 
After 
CAE 
Before 
CAE 
After 
CAE 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/medication history and 
demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical/Medication 
history 
update 
 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Placebo run-in dispensation 
 
X 
 
 
 
 
 
 
 
 
 
 
Placebo run-in collection 
 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
 
 
Study drug dispensation 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Study drug instillation 
 
 
 
X 
X 
 
 
 
 
 
 
 
Study drug collection 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
Diary dispensation 
 
X 
 
X 
X 
X 
 
X 
 
 
 
 
Diary collection 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
Review 
of 
inclusion/exclusion 
criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Adverse event Query 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test 
X1 
 
 
 
 
 
 
 
X1 
 
X1 
 
Drop tolerance assessment 
 
 
 
X 
 
 
 
 
 
 
 
 
Ora Calibra® Ocular Discomfort 
Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Ora Calibra® Ocular Discomfort 
and 4-Symptom Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
VAS Discomfort Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

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Procedure 
Visit 1 
Day -13 ± 2 
Visit 2 
Day 1 
Visit 3 
Day 8 ± 1 
Visit 4 
Day 15 ± 
2 
Visit 5 
Day 29 ± 2  
Visit 6 
Day 57 ± 3  
EOT4 FU2 
 
Before 
CAE 
After 
CAE 
Before 
CAE 
After 
CAE 
No 
CAE 
No 
CAE 
Before 
CAE 
After 
CAE 
Before 
CAE 
After 
CAE 
 
 
OSDI© Questionnaire 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
 
Visual acuity (ETDRS) 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
Slit-lamp bio-microscopy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Conjunctival redness 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
TFBUT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Fluorescein staining 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
CAE exposure 
X 
X 
 
 
X 
X 
 
 
Discomfort grading during CAE 
exposure 
X 
X 
 
 
X 
X 
 
 
Schirmer’s test 
 
X 
 
X 
 
X  
 
X 
 
X 
 
 
Intraocular pressure 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Fundus color photography 3 
 
X 
 
 
 
 
 
 
 
X 
X 
 
Subject withdrawal from the 
study 
 
 
 
 
 
 
 
 
 
X 
 
 
EOT: End of Treatment 
1. 
Applies to females of child bearing potential. See the definition for details. 
2. 
A telephone follow-up will be made 7 days after the last dose of study drugs to collect safety information. See Section 8.4 for details. 
3. 
If retinopathy is detected, or if it is impossible to take clear photos of both optic dics and mucula lutea simultaneously, the indirect ophthalmoscope or preset lens should 
be inspected under the pupil dilation conditions. 
4. 
The examination that a subject who withdraws the study must receive. See Section 8.3 for details. 
 

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Before any study-related procedure is performed, subjects, investigators or specified persons 
and witnesses (if necessary) must sign and date the ICF. 
The following procedure should be performed in sequence. For detailed information about 
the related methods and grading system, see Annex 1. 
8.1.1 Visit 1: Day -13±2 to Subject Screening (CAE) 
All subjects will be screened and assessed as follows. 
Before entering the CAE 
• Informed consent. Before change of drug treatment and/or invasive procedures (such 
as CAE), this study will be discussed with each subject, and those subjects who are 
willing to join this study must provide written informed consent. 
• Demographics, medical/medication/ophthalmological history. All the demographic 
data, medical history, use of medications and underlying diseases will be collected 
and recorded. Only the serious non-ophthalmological medical history in the past one 
year and the medication history in the past 30 days are collected. The medications 
that subjects are receiving and have used but stopped within 30 days before screening 
will be recorded. 
• Review of inclusion/exclusion criteria 
• Urine pregnancy test (for females of childbearing potential). The result of urine 
pregnancy test for females of childbearing potential must be negative before 
participation in the study. 
• Ora Calibra® Ocular Discomfort Scale 
• Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score 
• Ocular discomforts assessed by Visual Analog Scale (VAS) 
• OSDI© 
• BCVA assessed by the ETDRS Charts. At Visit 1, the score for each eye of a subject 
must be 0.7 logMAR or better (Snellen equivalent score is 20/100 or better) 
• Slit-lamp bio-microscopy. Slit-lamp bio-microscopy will be performed at the start of 
visit and be re-performed after CAE exposure to exclude any subjects with 
undesirable eye diseases. 
• Conjunctival redness score. It is an objective index that assesses conjunctival redness 
through the Ora Calibra® Dry Eye Conjunctival Redness Scale. For an increment, half 
a point may be used (0.5 points). 

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• TFBUT 
• Corneal staining (fluorescein), assessed by the Ora Calibra® Fluorescein Staining 
Rating Scale for cornea and conjunctiva 
• AE query. All the AEs that occur after signing of ICF will be reported. 
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 90 ± 5  minutes. 
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 time 0 and every 5 minutes thereafter throughout the 90 ± 5 minutes.  
After leaving the CAE 
• Ora Calibra® Ocular Discomfort Scale 
• Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score 
• VAS discomfort scale 
• Slit-lamp biomicroscopy 
• Conjunctival redness 
• TFBUT 
• Corneal staining (fluorescein) 
• Schirmer’s test 
• IOP 
• Fundus color photography 
• Review of inclusion/exclusion criteria 
• 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: 
▪ Having at least a ≥1 point increase in fluorescein staining in the 
inferior region in at least one eye following CAE® exposure; 
▪ Reporting an Ocular Discomfort score ≥3 at 2 or more consecutive 
time points in at least one eye during CAE® exposure (if a subject has 

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an Ocular Discomfort rating of 3 at time = 0 for an eye, he must report 
an Ocular Discomfort rating of 4 for two consecutive measurements 
for that eye). Note: a subject cannot have an Ocular Discomfort score 
of 4 at time = 0); 
▪ If both eyes are equal, the right eye (OD) will be designated as the 
study eye. 
• 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 –13. 
• Placebo and diary dispensation and administration. Prior to discharge from the study 
site on Day –13, 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). 
• Monitoring and query of AEs. Report any AEs that occur after signing the ICF. 
• Schedule next visit. Subjects will be scheduled for Visit 2. 
8.1.2 Day -13 to Day 0 
• From Day -13 to Day 0, subjects will self-administer one drop of placebo eye drop 
into both eyes in open-label status every morning and evening (BID). The placebo 
eye drop will be provided in disposable vials. Subjects need to report any AEs and 
record drug administration information in subject diary. 
8.1.3 Visit 2：Day 1- Subject Confirmation (CAE) and Baseline 
Before entering the CAE 
• Study diary/placebo collection. Subject study diaries and all used/unused placebo 
vials dispensed for Days –13 to 1 should be collected and reviewed by a trained study 
technician. 
• Site staff must confirm subjects have not administered their morning placebo dose at 
home. 
• Review of inclusion/exclusion criteria 
• Monitoring and query of AEs 

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• Record all changes in concomitant medications 
• Ora Calibra® Ocular Discomfort Scale 
• Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score 
• VAS discomfort scale 
• OSDI 
• BCVA Utilizing an ETDRS Chart 
• Slit-lamp biomicroscopy 
• Conjunctival redness 
• TFBUT 
• Corneal staining (fluorescein) 
Re-confirmation of Screening Challenge (CAE # 2) 
Subjects will be exposed to the CAE® for 90 ± 5 minutes. Ocular discomfort se lf–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 time 0 and every 5 minutes thereafter 
throughout the 90 ± 5 minutes.  
After leaving the CAE 
• Inclusion/exclusion evaluation 
• Ora Calibra® Ocular Discomfort Scale 
• Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score 
• VAS discomfort scale 
• Slit-lamp biomicroscopy 
• Conjunctival redness 
• TFBUT 
• Corneal staining (fluorescein) 
• Schirmer’s test 

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• Review of inclusion/exclusion criteria 
• 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: 
▪ Having at least a ≥1 point increase in fluorescein staining in the 
inferior region in at least one eye following CAE® exposure; 
▪ Reporting an Ocular Discomfort score ≥3 at 2 or more consecutive 
time points in at least one eye during CAE® exposure (if a subject has 
an Ocular Discomfort rating of 3 at time = 0 for an eye, he must report 
an Ocular Discomfort rating of 4 for two consecutive measurements 
for that eye). Note: a subject cannot have an Ocular Discomfort score 
of 4 at time = 0); 
▪ If both eyes are equal, the right eye (OD) will be designated as the 
study eye. 
Randomization 
• 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 two treatment arms. Randomized subjects will self-administer 
their initial study drug dose bilaterally at the study site. 
• Drop comfort assessment. A drop tolerance evaluation will be performed by using the 
Ora Calibra® drop tolerance scale immediately and then at 1 and 2 minutes following 
initial dosing. A drop tolerance evaluation will be performed by using the Ora 
Calibra® drop tolerance questionnaire at 3 minutes following initial dosing. 
• Monitoring and query of AEs 
• Subject 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 4 (Day 15) and will be instructed not to 
self-administer study drug on the morning of their next scheduled study visit (Visit 3, 
Day 8). 
• Schedule next visit. Subjects will be scheduled for Visit 3. 
8.1.4 Day 1 to Day 7±1  
Subjects will self-administer the study drug (BID) in the morning and evening of Day 1 and 
continue to take the study drug till Day 7. The study drugs are provided in disposable vials. 
Subjects must instill a drop of the study drug to each eye when they are awake in the morning 

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and evening. Subjects need to report any AEs and record drug administration information in 
subject diary. 
8.1.5 Visit 3 (Day 8±1)  
There is no CAE® evaluation at Day 8, Visit 3. 
• Subject diary/study drug collection. Subject diaries and all used study drug vials 
dispensed for Days 1 to 7 should be collected and reviewed by a trained study 
technician. 
• Site staff must confirm subjects have not administered their morning placebo dose at 
home. 
• Monitoring and query AEs 
• Recording of all changes in concomitant medications 
• Ora Calibra® Ocular Discomfort Scale 
• Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire 
• VAS discomfort scale 
• OSDI 
• BCVA Utilizing an ETDRS Chart 
• Slit lamp biomicroscopy 
• Conjunctival redness 
• TFBUT 
• Study drug instillation at the study site. Subjects will self-administer study drug dose 
bilaterally at the study site following the last study assessment. The evening dose will 
be administered at home by the subject. 
• Monitoring and query AEs 
• Subject diary. 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. 
Subjects will be instructed not to self-administer study drug on the morning of their 
next scheduled study visit (Visit 4, Day 15). 
• Schedule next visit. Subjects will be scheduled for Visit 4 and will be instructed not 
to self-administer study drug on the morning of their next scheduled study visit 
(Visit 4, Day 15). 

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8.1.6 From Day 8 to Day 14±2  
Subjects will self-administer the study drug (BID) in the morning and evening of Day 8 and 
continue to take the study drug till Day 14±2 . The study drugs are provided in disposable 
vials. 
Subjects need to report any AEs and record drug administration information in subject diary. 
8.1.7 Visit 4: Day 15±2  
There is no CAE® evaluation at Day 15, Visit 4. 
• Subject diary/study drug collection. Subject diaries and all used study drug vials 
dispensed for Days 8 to 15 should be collected and reviewed by a trained study 
technician. 
• Site staff must confirm subjects have not administered their morning placebo dose at 
home. 
• Monitoring and query AEs 
• Recording of all changes in concomitant medications 
• Ora Calibra® Ocular Discomfort Scale 
• Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire 
• VAS discomfort scale 
• OSDI 
• BCVA Utilizing an ETDRS Chart 
• Slit-lamp biomicroscopy 
• Conjunctival redness 
• TFBUT 
• Corneal staining (fluorescein) 
• Schirmer’s test 
• Subject diary. 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 not to self-administer study drug on the morning of their 
next scheduled study visit (Visit 5, Day 29). 

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• Schedule next visit. Subjects will be scheduled for Visit 5. 
8.1.8 From Day 15 to Day 28±2   
Subjects will self-administer the study drug (BID) in the morning and evening of Day 15 and 
continue to take the study drug till Day 28±2. The study drugs are provided in disposable 
vials. Subjects must instill a drop of the study drug to each eye when they are awake in the 
morning and evening. Subjects need to report any AEs and record drug administration 
information in subject diary. 
8.1.9 Visit 5: Day 29±2  
Before entering the CAE 
• Subject diary/study drug collection. Subject diaries and all used study drug vials 
dispensed for Days 15 to 29 should be collected and reviewed by a trained study 
technician. 
• Site staff must confirm subjects have not administered their morning study drug dose 
at home. 
• Monitoring and query of AEs 
• Record all changes in concomitant medications 
• Ora Calibra® Ocular Discomfort Scale 
• Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire 
• VAS discomfort scale 
• OSDI 
• BCVA Utilizing an ETDRS Chart 
• Slit lamp biomicroscopy 
• Conjunctival redness 
• TFBUT 
• Corneal staining (fluorescein) 
CAE 
• During the CAE® exposure, ODS will be collected at time 0 and every 5 minutes 
thereafter throughout the 90 ± 5  minutes. 

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After leaving the CAE 
• Ora Calibra® Ocular Discomfort Scale 
• Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score 
• VAS discomfort scale 
• Slit lamp biomicroscopy 
• Conjunctival redness 
• TFBUT 
• Corneal staining (fluorescein); 
• Schirmer’s test; 
• Monitoring and query of AEs 
• 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). 
• Schedule next visit. Subjects will be scheduled for Visit 6. 
8.1.10 From Day 29 to Day 56±3  
Subjects will self-administer the study drug (BID) in the morning and evening of Day 29 and 
continue to take the study drug till Day 56±3. The study drugs are provided in disposable 
vials. Subjects must instill a drop of the study drug to each eye when they are awake in the 
morning and evening. Subjects need to report any AEs and record drug administration 
information in subject diary. 
8.1.11 Visit 6: Day 57±3  
Before entering the CAE 
• Subject diary/study drug collection. Subject diaries and all used/unused study drug 
vials dispensed for Days 29 to 57 should be collected and reviewed by a trained study 
technician. 
• Site staff must confirm subjects have not administered their morning study drug dose 
at home. 

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• Monitoring and query of AEs 
• Record all changes in concomitant medications 
• Urine pregnancy test (for females of childbearing potential) 
• Ora Calibra® Ocular Discomfort Scale 
• Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire 
• VAS discomfort scale 
• OSDI 
• BCVA Utilizing an ETDRS Chart 
• Slit lamp biomicroscopy 
• Conjunctival redness 
• TFBUT 
• Corneal staining (fluorescein) 
CAE 
• During the CAE® exposure, ODS will be collected at time 0 and every 5 minutes 
thereafter throughout the 90 ± 5 minutes.  
After leaving the CAE 
• Ora Calibra® Ocular Discomfort Scale 
• Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire Ocular Discomfort 
Score 
• VAS discomfort scale 
• Slit lamp biomicroscopy 
• Conjunctival redness 
• TFBUT 
• Corneal Staining (fluorescein) 
• Schirmer’s test 

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• Intraocular Pressure 
• Fundus color photography 
• Monitoring and query of AEs, and a telephone follow-up will be made 7 days later 
• Study Exit 
8.2 
Discontinuation of Treatment and Premature Withdrawal from Study 
Subjects may be discontinued before their completion of the study due to: 
• Adverse events; 
• Unblinding when medically necessary; 
• Protocol violations; 
• Administrative reasons (e.g., inability to continue, lost to follow up); 
• Termination of study by sponsor; 
• Subject choice (e.g. Withdrawal of consent); and 
• 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 
the Sponsor and will be clearly documented on the eCRF. 
Subjects who discontinue treatment should switch to proper maintenance treatment at the 
discretion of the Investigator. For subjects who discontinue treatment and do not finish at 
least one post-treatment data collection, a telephone follow-up should be made at least 7 days 
after the last dose of study drug. 
Discontinued subjects will not be replaced. 
8.3 
Unscheduled Visits and End of Treatment/Study Exit Visit 
Repeat assessments, if needed, will be captured in unscheduled visits. 
End of treatment/study exit visits will be captured as unscheduled visits. At least the 
following procedures will be completed at these visits: 
• Record AEs and SAEs (if any); 

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• Review concomitant medications; 
• Urine samples will be collected from women of childbearing potential for pregnancy 
tests； 
• All the study drugs/subject diaries will be collected； 
• Subjects will resume pre-study treatment or receive appropriate medication treatment; 
• Subjects will be told to report all the SAEs that occur within 7 days after the last dose 
of study drug； 
• Collect the reasons for discontinuation of study. These visits may be made to ensure 
safety of subjects. All the procedures performed at unscheduled visits must be 
recorded in the source documents and the eCRF page for unscheduled visits. For any 
procedure indicated in the eCRF, "unperformed" should be indicated if they have not 
been performed； 
• Assessment that may be performed at unscheduled visits： 
1. Slit-lamp biomicroscopy; 
2. Visual acuity; 
3. Intraocular pressure; 
4. Urine pregnancy test; 
5. Fundus color photography or mydriasis fundus examination； 
6. Any other assessment needed in the judgement of the Investigator. 
8.4 
End of Study 
All subjects will be followed up by telephone call 7 days after last dose of study drug. The 
following procedures will be completed: 
• Review ongoing AEs and SAEs (if any)； 
• Collection of new SAEs (if any)； 
• Review of concomitant medications. 
Note: For the subjects who withdraw the informed consent, a telephone follow-up will be 
made at least 7 days after last dose of study drug. 

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8.5 
Termination of Study 
According to the contract signed with Harbour BioMed, investigators may choose to 
discontinue the study for any reason on a fully-informed basis. 
Harbour BioMed reserves the right to terminate the study at any time due to clinical or 
administrative reasons. If Harbour BioMed decides to terminate the study, the termination 
process must be implemented by investigators within a time frame that is favorable to 
subjects' health conditions. 
8.6 
Completion of Study 
Investigators will record the reasons for study completion or early withdrawal on the eCRF. 
The events will be classified as follows on the eCRF： 
• Subjects’ decision (record the reasons); 
• For subjects’ best benefit in the judgement of the Investigator; 
• Adverse events; 
• Administrative reasons (e.g. premature termination of the study); 
• Lost to follow-up; 
• Lack of efficacy; 
• Major protocol deviations; 
• Death; 
• Study completion; 
• Specific criteria specified in protocol (see Section 5). 

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9 
STATISTICAL METHODS 
9.1 
Analysis Populations 
The analysis populations in this study are defined as follows: 
• Full Analysis Set (FAS) includes all the randomized subjects who have received at 
least one dose of study drug according to the principle of intention-to-treat (ITT). 
Subjects will be analyzed as randomized. 
• Per Protocol Set (PPS) is a subset of the FAS population including all the subjects 
who do not have major protocol deviations and who complete the study. Subjects in 
the PP population will be analyzed as treated. Protocol deviations will be assessed 
before database lock and unblinding. For the subjects who have major protocol 
deviations (protocol violations), all their data should be eliminated from the PPS data, 
or the data of specific time points and/or subsequent time points should be eliminated. 
• Safety Set (SS) includes all randomized subjects who have received at least one dose 
of the investigational product. The SS will be analyzed for all safety assessments. 
Subjects in the SS will be analyzed as treated. 
In this study, the baseline data analysis will be based on the FAS. The efficacy analysis will 
be based on both FAS and PPS. The PPS will be used for main analysis. For the FAS, the 
missing data after dropout will be imputed using the Last Observation Carried Forward 
(LOCF) method. The observed and imputed data will be used for the analysis of FAS to 
assess the robustness of study results. The SS will be used for analysis of laboratory 
examination data, adverse events, and adverse reactions. 
9.2 
Determination of Sample Size 
This study is expected to enroll 50 subjects in each treatment group so a total of 100 subjects 
will be randomized. Assuming a 20% drop out rate, 40 subjects per group are expected to 
complete the study. 
According to the results from the US Phase II study, assuming the standard deviation is 0.7 
unit for the change from baseline in the pre- to post-CAE® inferior corneal fluorescein 
staining (ICSS) score and the mean of the change from baseline in the pre- to post-CAE ICSS 
score is about 0.65, the efficacy results will be very promising if the difference in the mean 
of ICSS change for the placebo and treatment groups are greater than 0.3. If the difference< 
0.1, the efficacy may not be promising. 
If 40 subjects in each group will complete the study, the probability for observing the 
efficacy< 0.1 in this study will be about 74% if the study drug is not effective in the 
treatment group. If the difference in the efficacy between the treatment and placebo groups 
is >0.4, the probability for observing the efficacy> 0.3 in this study will be at least 75%. 
Other possibilities are summarized in the table below. 

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ICSS 
Actual Mean 
Difference 
Ideal Region 
Mean difference >=0.3 
Consideration Region 
Mean Difference [0.1, 
0.3) 
Unsatisfactory Region 
Mean difference <0.1 
0.0 
3.0% 
23.3% 
73.8% 
0.1 
9.9% 
40.1% 
50.0% 
0.2 
26.2% 
48.6% 
25.2% 
0.3 
50.0% 
40.2% 
9.8% 
0.4 
74.8% 
22.7% 
2.6% 
9.3 
Blinding and Randomization 
Random numbers will be generated at a ratio of 1:1 (treatment group to control group) using 
the randomized block method by independent biostatisticians responsible for the data 
management and statistical analysis of this study. The selected block size and random seeds 
will be kept confidential. Statisticians unrelated to this study will label study drugs with the 
random number. Each study site will use the assigned code according to the sequence of 
enrollment. 
This study will use the centralized randomization method and each study site will enroll 
subjects competitively. For each eligible subject, the study staff at study sites will log into the 
IWRS system, complete screening information, and obtain the random number and 
corresponding drug number. Investigators will dispense study drugs according to the random 
number and drug number. 
9.4 
General Considerations for Statistical Analysis 
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. 
Medical history, concurrent therapies, and AEs will be coded to MedDRA and WHO Drug 
dictionaries. 
Baseline measures are defined as the last measure before 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 analyses for primary and secondary efficacy outcomes will be tested 2-sided at a 
significance level of 0.05. 

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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: 
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 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. 
9.5 
Efficacy and Safety Analysis 
9.5.1 
Efficacy Analysis 
9.5.1.1 Primary Efficacy Analyses 
For primary efficacy endpoints, the pre- to post-CAE ICSS change will be calculated as post-
CAE ICSS score-pre-CAE ICSS score. The change from baseline will be calculated as visit 
(post-CAE-pre-CAE)-baseline (post-CAE-pre-CAE) such that a positive difference indicates 
the change at study visit is larger than that at baseline. In addition, treatment comparisons 
between treatment and placebo groups will be calculated as treatment – placebo, such that a 
negative result indicates a better score for the treatment group (i.e., the treatment group have 
a smaller increase in dry eye signs or symptoms than the placebo group). 
ANCOVA models will be used to compare the change from baseline in the pre- to 
post-CAE® inferior corneal fluorescein staining at Day 57 (Visit 6) (measured by the Ora 
Calibra® scale), between 0.25% HBM9036 Ophthalmic Solution and Placebo. The 
ANCOVA models will include the change in pre- to post-CAE ICSS at baseline as a 
covariate. The primary analysis will use LOCF imputation to have a full accounting of the 
FAS at the Day 57 visit, as described in Section 9.7. 
9.5.1.2 Secondary Efficacy Analysis 
The continuous and ordinal secondary efficacy variables collected at each visit will be 
summarized descriptively (n, mean, standard deviation, median, min and max), and analyzed 
with two-sample t-tests comparing the treatment group with 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 will also be assessed where appropriate. No 
imputation will be performed for secondary efficacy variables. 
Two-sample t-tests and Wilcoxon rank sum tests will be used for ANCOVA model adjusting 
for baseline: the change from baseline in the pre- to post-CAE® change of the ICS 
fluorescein staining at Visit 5; the change from baseline in post-CAE® TFBUT and 
conjunctival redness; the change from baseline in unanesthetized Schirmer’s test results and 
OSDI scores at Visit 6; the change from baseline in pre--CAE® ocular discomfort (including 

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the Ora Calibra Dry Eye Ocular Discomfort Scale, Ora Calibra Ocular Discomfort and Dry 
Eye 4-Symptom Questionnaire) at Visits 5 and 6; the change from baseline in pre--CAE® 
burning sensation score assessed by VAS scale at Visit 6; and the change from baseline in the 
mean score of burning sensation by week assessed according to subject diaries. 
The worst symptom for each subject will be identified as the symptom with the highest 
average score during the run-in period (Days -13 to 0) 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. 
9.5.2 
Safety Analysis 
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. 
Frequencies and percentages of subjects with AEs, SAEs, and AEs causing premature 
discontinuation will be provided by treatment group. The AEs will be listed by MedDRA 
SOCs and PTs and the AE listings will be categorized by severity, the causal relationship 
with study drug, and whether the AEs leading to discontinuation of study. No hypothesis test 
will be performed. Separate analyses will be performed for ocular specific and all AEs 
(including systemic). 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, fundus color 
photography, drop tolerance, and intraocular pressure, will be summarized by treatment 
group and visit using descriptive statistics. Changes 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 will be 
summarized. 
The exposure time (number of days) and drug administration times will be summarized by 
treatment group. The number and percentage of subjects with compliance will be calculated. 
The total exposure of the safety population will be summarized based on actual treatment 
received. 
9.6 
Subgroup Analyses 
The four subgroups below are considered for subgroup analyses of primary efficacy 
outcome： 
• Baseline subcorneal fluorescent staining score <2, ≥2； 
• Baseline conjunctival redness score <2, ≥2； 
• The course of disease is longer than average level, shorter than average level； 

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• The baseline CAE screening <20 minutes, ≥20 minutes. 
The subgroup analyses above will be performed for secondary efficacy outcomes as 
appropriate. 
9.7 
Handling of Missing Data 
The primary efficacy analyses will be performed using the Last Observation Carried Forward 
(LOCF) imputation method for missing values. For the analysis of ICSS 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. 
For the primary efficacy variables, the measured data will be used to assess the robustness of 
the study results. 
No secondary efficacy endpoints or safety endpoints will be imputed. 
9.8 
Interim analysis 
No interim analysis will be conducted in this study. 
9.9 
Multiplicity Adjustment 
No multiplicity adjustment is considered in this study. 
9.10 Statistical Analysis Plan and Analysis Software 
All the analyses will be described in detail in the Statistical Analysis Plan (SAP), and the 
shells of tables, data listings and figures will be attached. The SAP will be signed for 
approval before database locking and unblinding. 
The SAS9.4 will be used for data processing, statistical screening, descriptive reporting and 
efficacy and safety analyses. The R3.5.1 software may also be used for plotting. 

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10 STUDY MANAGEMENT 
10.1 Regulatory Authority Approval 
Harbour BioMed will obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country-specific regulatory requirements before a 
study site initiates the study. 
10.2 Ethical Conduct of the Study and Institutional Review Board/Independent 
Ethics Committee Approval 
The study will be conducted in accordance with Good Clinical Practice (GCP). These 
standards respect the following guidelines: 
• Guideline for Good Clinical Practice E6 (R1); 
• Good Clinical Practice in China in current use;  
• Declaration of Helsinki, concerning medical research in humans (Ethical Principles 
for Medical Research Involving Human Subjects); 
• Any additional regulatory requirements. 
The Investigator (or Harbour BioMed, where applicable) will be responsible for ensuring that 
this protocol, the site’s ICF, and any other information that will be presented to potential 
subjects (e.g., advertisements or information that supports or supplements the ICF) will be 
reviewed and approved by the appropriate EC. The Investigator agrees to allow the EC direct 
access to all relevant documents. The EC must be constituted in accordance with all 
applicable regulatory requirements. 
Harbour BioMed will provide the Investigator with relevant document(s)/data that are needed 
for EC review and approval of the study. If the protocol, the ICF, or any other information 
approved by EC and provided to potential subjects is amended during the study, the 
Investigator will be responsible for ensuring the EC reviews and approves, where applicable, 
these amended documents. The Investigator must follow all applicable regulatory 
requirements pertaining to the use of an amended ICF including obtaining EC approval of the 
amended form before new subjects consent to take part in the study using this version of the 
form. The EC approval of the amended ICF/other information and the approved amended 
ICF/other information must be forwarded to Harbour BioMed promptly. 
10.3 Subject Information and Informed Consent 
The study will be conducted in accordance with applicable subject privacy requirements.  
The proposed ICF, which must be in compliance with applicable regulations, must be 
reviewed and approved by the EC and Harbour BioMed prior to initiation of the study. 

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The Investigator will be responsible for obtaining written informed consent from potential 
subjects prior to any study-specific screening and enrollment. A copy of the signed ICF will 
be provided to the subject. The original will be retained by the Investigator. 
10.4 Laboratory Accreditation 
Any laboratory facility intended to be used for analysis of clinical laboratory samples 
required by this protocol must provide evidence of adequate licensure or accreditation 
according to the prevailing regulations. Reference values and/or normal ranges for the test 
results must be provided to Harbour BioMed. Sponsor must be notified promptly in writing 
of any changes occurring in reference values during the course of the study. 
10.5 Confidentiality 
10.5.1 
Data Confidentiality 
By signing this protocol, the Investigator affirms to Harbour BioMed that information 
provided to the Investigator by Harbour BioMed will be maintained in confidence and such 
information will be disclosed to the EC, or similar organizations or expert committee; 
affiliated institution and employees only after confirming the confidentiality of such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential except those included in a publication. 
10.5.2 
Confidentiality of Subject / Patient Records 
By signing this protocol, the Investigator agrees that Harbour BioMed (or representative), EC, 
or Regulatory Agency representatives may review and/or copy study documents to verify 
worksheet/case report form data. By signing the consent form, the subject/patient agrees to 
this process. If study documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject/patient will be identified by unique code 
only; full names/initials will be masked before sending the document to Harbour BioMed. In 
addition, the Investigator agrees to treat all subject data used and disclosed in connection 
with this study in accordance with all applicable laws (such as the Health Insurance 
Portability and Accountability Act), rules and regulations. 
10.6 Quality Control and Assurance 
Harbour BioMed will be responsible for implementing and maintaining quality control and 
quality assurance systems with written SOPs to ensure that the study will be conducted and 
data will be generated, documented, and reported in compliance with the protocol, accepted 
standards of GCP, and all applicable local laws relating to the conduct of the clinical study. 
10.7 Data Management 
Data management procedures and information for this protocol will be provided by Harbour 
BioMed or its designee. 

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10.8 Study Monitoring 
In accordance with applicable regulations, GCP, and Harbour BioMed procedures, clinical 
research associates (CRAs) will contact the site prior to subject enrollment to review the 
protocol and data collection procedures with site staff. In addition, the CRA will periodically 
contact the site, including conducting on-site visits. The extent, nature, and frequency of 
on-site visits will be based on the study objective and/or endpoints, the purpose of the study, 
study design complexity, and enrollment rate. 
During these procedures, the CRA will: 
• Check the progress of the study; 
• Review study data collected; 
• Conduct source document verification; 
• Identify and address any issues. 
The work above is to verify that: 
• The data are authentic, accurate, and complete; 
• Safety and rights of subjects are being protected. 
• Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
The Investigator agrees to allow the CRA direct access to all relevant documents and to 
allocate his/her time to the CRA to discuss findings and any relevant issues. 
Upon completion of the study, the CRA will conduct the following activities in conjunction 
with the Investigator or site staff, as appropriate: 
• Return of all study data to Harbour BioMed;  
• Data queries; 
• Accountability, reconciliation, and arrangements for unused study drugs; 
• Review of site study records for completeness. 
After the final review of the study files, the files should be secured for the appropriate time 
period. The Investigator will also permit inspection of the study files by Quality Assurance 
auditors from Harbour BioMed, and authorized representatives of the NMPA or other 
applicable regulatory agencies. 

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10.9 Data Retention 
Documents that individually and collectively being evaluable for the conduct of the study 
and the quality of the data must be maintained for review by quality assurance auditors from 
Harbour BioMed and by all applicable regulatory authorities. The period of time for which 
these documents must be maintained is determined by applicable regulations. Harbour 
BioMed or its designee will inform the Investigator when these documents may be destroyed. 
Harbour BioMed or its designee must be notified in writing prior to the intended date of 
disposal of any study record related to this protocol for making alternate storage 
arrangements. 
10.10 Financial Disclosure 
The Principal Investigator or sub-Investigators will need to complete a financial disclosure 
form prior to study initiation, at any time during the study execution if new information 
needs to be disclosed. 
10.11 Publication Policy 
All the clinical study results will be published according to the Declaration of Helsinki. The 
drafts, publications or reports related to this study must be submitted to Harbour BioMed for 
review and approval before submission for publication or being reported, so as to ensure 
consistency with the policy of this protocol. All the communications between the 
investigators and Harbour BioMed and any third party should be carried out according to the 
confidentiality agreement. 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
11 List of 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. Peige Song, Wei Xia, Manli Wang, Xinlei Chang.Variations of dry eye disease 
prevalence by age,sex and geographic characteristics in China:a systematic review 
and meta-analysis.J Glob Health.2018 Dec;8(2):020503.doi:10.7189/jogh.08.020503 
5. Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Survey of 
ophthalmology 2001;45 Suppl 2:S199-202. 
6. Pflugfelder ,S.C., A .Solomon and M .E .Sten(2000).”The diagnosis and management 
of  dry eye :a twenty-five-year review .”Cornea 19(5):644-649. 
7. Pflugfelder,S .C.(2008).”Prevalence ,burden ,and pharmacoeconomics of dry eye 
disease.” Am J Manag Care 14(3 Suppl): S102-106. 
8. Friedman,N.J (2010).”Impact of dry eye disease and treatment on quality of life.” 
Curr Opin Ophthalmol 21(4):310-316. 
9. Lemp. M.A. and G. N. Foulks (2007).” The definition and classification of dry eye 
disease:Report of the Definition and Classification Subcommittee of the International 
Dry Eye Workshop(2007).”Ocul Surf 5(2):75-92. 
10. Wilson.  S. E. (2003).” Inflammation: a unifying theory for the origin of dry eye 
syndrome.” Manag Care 12(12 Suppl):14-19. 
11. De Paiva, C.S. and S.C. Pflugfelder (2008).” Rationale for anti-inflammatory therary 
in dry eye syndrome.”Arq Bras Oftalmol 71(6 Suppl):89-95. 
12. Lam, 
H., 
L.Bleiden, 
C.S. 
de 
Paiva, 
W 
.Farley, 
M 
.E 
.Stem 
and 
S.C.Pflugfelder(2009).”Tear cytokine profiles in dysfunctional tear syndrome.” Am J   
Ophthalmol 147(2):198-205 e191. 
13. Black, R. A., C. T. Rauch, C. J. Kozlosky,J. J. Peschon, J. L. Slack, M. F. Wolfson, B. 
J. Castner, K. L. Stocking, P. Reddy, S. Srinivasan, N. Nelson, N. Bioani, K. A. 
Schooley, M. Gerhart, R. Davis, J. N. Fitzner, R. S. Johnson, R. J. Paxton, C. J. 
March and D. P. Cerretti(1997).”A metalloproteinase disintegrin that releases tumour-
necrosis factor-alpha from cells.”Nature 385(6618):729-733. 
14. Semba, C.P., D. Swearingen, V.L. Smith, M.S. Newman, C.A. O’Neil, J.P. Burnier, 
D.B. Haughey and T.R. Gadek (2011). “Safety and pharmacokinetics of a novel 
lymphocyte function-associated antigen-1 antagonist ophthalmic solution (SAR 1118) 
in healthy adults.” J Ocul Pharmacol Ther 27(1): 99-104. 
15. Semba, C.P., G.L. Torkildsen, J.D. Lonsdale, E.B. McLaurin, J.A. Geffin, T.K. 
Mundorf, K.S. Kennedy and G.W.Ousler(2012). “A phase 2 randomized, double-
masked, placebo-controlled study of a novel integrin antagonist (SAR 1118) for the 
treatment of dry eye.” Am J Ophthalmol 153(6): 1050-1060 e1051. 
16. Holland, E.J., J. Luchs, P.M. Karpecki, K.K. Nichols, M.A. Jackson, K.Sall, J.Tauber, 
M.Roy, A. Raychaudhuri and A. Shojaei(2017). “Lifitegrast for the Treatment of Dry 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
Eye Disease: Result of a Phase Ⅲ, Randomized, Double-Masked, Placebo-Controlled  
Trial(OPUS-3).” Ophthalmology 124(1): 53-60. 
17. Chen, G. and D.V.Goeddel(2002). “TNF-R1 signaling: a beautiful pathway.” Science 
296(5573): 1634-1635. 
18. Zoukhri, D., R.R. Hodges, D. Byon and C.L.Kublin(2002). “Role of proinflammatory 
cytokines in the impaired lacrimation associated with autoimmune xerophthalmia.” 
Invest Ophthalmol Vis Sci 43(5):1429-1436. 
19. Massingale, M.L., X.Li, M.Vallabhajosyula, D.Chen, Y.Wei and P.A. Asbell(2009). 
“Analysis of inflammatory cytokines in the tears of dry eye patients.” Cornea 28(9): 
1023-1027. 
20. Albertsmeyer, A.C., V. Kakkassery, S. Spurr-Michaud, O. Beeks and I.K. 
Gipson(2010). “Effect of proinflammatory mediators on membrane-associated 
mucins expressed by human ocular surface epithelial cells.” Exp Eye Res 90(3):444-
451. 

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12 APPENDICES 
12.1 APPENDIX 1：EXAMINATION PROCEDURE, TESTS, EQUIPMENTS 
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 form used is the ETDRS Charts. If a small wall chart (18 "x 18", such as blindness 
prevention) is used, the measuring distance for subjects should be as accurate as 10 feet (or 
as per manufacturer instructions). In all cases, all the study sites can only use the same target 
form and should first test the right eye in order to standardize the test conditions during the 
study. For reflection-type wall charts, they should be placed right ahead, good lighting should 
be provided. 
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 number target, 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 numbers only, no 
letters. If the subject reads a letter, he or she should be reminded that the chart contains no 
letters, and the examiner should then request a number in lieu of the letter. The subject 
should be asked to read slowly, so as to achieve the best identification of each number. 
He/she is not to proceed to the next number until he/she has given a definite response. 
If the subject changes a response (e.g., 'that was a "9" not an "3"') before he has read aloud 
the next number, then the change must be accepted. If the subject changes a response having 
read the next number, then the change is not to be accepted. The examiner should never point 
to the chart or to specific numbers on the chart during the test. 
A maximum effort should be made to identify each number on the chart. When the subject 
says he or she cannot read a number, he or she should be encouraged to guess. If the subject 
identifies a number as 1 of 2 numbers, he or she should be asked to choose 1 number 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 number difficulties vary and the 
last may be the only one read correctly. The targets missed or read incorrectly should be 
noted. 
LogMAR Visual Acuity Calculations 

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The last line in which a number 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 
number targets 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 numbers on the 0.2 line, and 2 of 5 numbers on 
the 0.1 line. 
Base logMAR 
= 0.1 
N (total number of targets incorrect on line 0.2 as 
well as 0.1) 
= 4 
N×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: 
• Cornea 
• Conjunctiva 
• Anterior Chamber 
• Iris 
• Lens 
• Eyelid 
External magnification and biomicroscopy will be performed using a slit-lamp. 
Magnification will be consistent with standard clinical practice. The subject will be seated. 
Fundus Color Photography 

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The fundus color camera will be used to take photos of the patients' fundus, and the photos 
will be kept. Pupil dilation is not a must, but the photos must be clear and include optic dics 
and macula lutea. The Investigator will examine the vitreous body, retina, macula lutea, 
choroid, and optic nerves. 
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. 
An indirect ophthalmoscope or preset lens examination should be performed if retinal disease 
is detected or optic dics and macula lutea can’t be photographed simultaneously. 
● Vitreous: Examination should emphasize the visual axis. 
● 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. 
● 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 non-contact tonometry by the 
examiner and the results will be recorded in mmHg. The measurement of intraocular pressure 
will be repeated three times to calculate the mean value. If the variation is large, the 
measurement will be repeated as appropriate to calculate the mean value. 
Ora proprietary scales – Not for distribution without permission 
Ora Calibra® Ocular Discomfort Scale for Dry Eye 
Ocular discomfort scores will be subjectively graded by the subjects according to the 
following scale, rating each eye separately. 
0 
No discomfort 
1 
Intermittent awareness 
2 
Constant awareness 
3 
Intermittent discomfort 
4 
Constant discomfort 
Ora Calibra® Eye Discomfort and 4-Symptom Dry Eye Questionnaire 
At each day during the at-home dosing period, subjects will grade the severity of their dry 
eye syndrome symptoms in their diary in the morning and in the evening, before instilling the 
study drug. 

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Subjects will rate the severity of each of the following symptoms, with regards to how both 
their eyes feel, in general – overall ocular discomfort, burning, dryness, grittiness and 
stinging according to the following 6-point (0 to 5) scale where 0 = none and 5 =worst. 
 
(None) 
(Most) 
 

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Visual Analog Scale (VAS) 
 
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.” 
Burning/Stin
ging 
 
0% 
100% 
 
 
 
Pruritus 
 
0% 
100% 
 
 
 
Foreign body 
sensation 
 
0% 
100% 
 
 
 
Blurred 
vision 
 
0% 
100% 
 
 
 
Eye dryness 
 
0% 
100% 
 
 
 
Photophobia 
 
0% 
100% 
 
 
 
Pain 
 
0% 
100% 
 
 
 
 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
Ocular Surface and Disease Index (OSDI)© for Dry Eye 
Ocular Surface Disease Index® (OSDI®)2 
Ask the patients the following 12 questions, and circle the number that best represents the 
answer of each question. Then fill in the boxes A, B, C, D and E according to the instructions 
beside each. 
Have your experienced any of 
the following during the last 
week? 
All of 
the time 
Most 
of the 
time 
Half 
of the 
time 
Some 
of the 
time 
None of 
the time 
1.Eyes that are sensitive to 
light? ........................................... 
4 
3 
2 
1 
0 
2. Eyes that feel gritty? ............... 
4 
3 
2 
1 
0 
3.Painful or score eyes? .............. 
4 
3 
2 
1 
0 
4. Blurred vision? ........................ 
4 
3 
2 
1 
0 
5. Poor vision? ............................ 
4 
3 
2 
1 
0 
 
 
 
 
 
 
 
Subtotal score for answers 1 to 5 
(A) 
 
Have problems with your eyes 
limited you in performing any 
of the following during the last 
week? 
All of 
the 
time 
Most 
of the 
time 
Half of 
the 
time 
Some 
of the 
time 
None of 
the time 
N/A 
6. Reading? ...................................
4 
3 
2 
1 
0 
N/A 
7.Driving at night? ........................
4 
3 
2 
1 
0 
N/A 
8.Working with a computer or 
bank machine (ATM)? ..................
4 
3 
2 
1 
0 
N/A 
9. Watching TV? ...........................
4 
3 
2 
1 
0 
N/A 
 
 
 
 
 
 
 
 
Subtotal score of answers 6 to 9 
(B) 
 
 
Have your eyes felt 
uncomfortable in any of the 
following situations during 
the last week? 
All of 
the time 
Most 
of the 
time 
Half 
of the 
time 
Some of 
the time 
None of 
the 
time 
N/A 
10.Windy conditions? ................ 
4 
3 
2 
1 
0 
N/A 
11.Places or areas with low 
humidity (very dry)? .................. 
4 
3 
2 
1 
0 
N/A 
12.Areas that are air 
conditioned? ............................... 
4 
3 
2 
1 
0 
N/A 
 
 
 
 
 
 
 
 
Subtotal score of answers 10 to 12 
(C) 
 

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Add the subtotals A, B and C to obtain D (D = sum of scores for 
all questions answered) 
(D) 
 
 
 
 
 
 
 
 
 
Total number of questions answered (do not include questions 
answered N/A) 
(E) 
 
 
 
 
Please turn over the questionnaire to calculate the patient’s final OSDI score. 

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Evaluating the OSDI© score1 
The OSDI© is assessed on a scale of 0 to 100, with higher scores representing greater 
disability. The index demonstrates sensitivity and specificity in distinguishing between 
normal subjects and patients with dye eye disease. The OSDI© is a valid and reliable 
instrument for measuring dry eye disease (normal, mild to moderate, and severe) and effect 
on vision-related function. 
Assessing Your Patient’s Dry Eye Disease1,2 
Use your answers D and E from side 1 to compare the sum of scores for all questions 
answered (D) and the number of questions answered (E) with the chart below.* Find where 
your patient’s score would fall. Match the corresponding shade of red to the key below to 
determine whether your patient’s score indicates normal, mild, moderate, or severe dry eye 
disease. 
 
 
 
 

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Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
Ora Calibra® Conjunctival Redness Scale for Dry Eye 
None 
0 = Normal, no vascular dilation 
Trace 
1 = Trace ciliary or conjunctival vasodilation 
Mild 
2 = Broad ciliary vasodilation; 
Moderate 
3 = Broad ciliary and slight, horizontal conjunctival vasodilation 
Severe 
4 = Broad ciliary and prominent, horizontal conjunctival vasodilation 
Half (0.5) unit increments are allowed. 
Tear Film Break-Up Time (TFBUT) 
The examiner will instill 5 μL of 2% preservative-free sodium fluorescein solution into the 
inferior conjunctival cul-de-sac of each eye or use the sodium fluorescein test strips for 
staining (moisturized in saline). 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 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. 

HBM9036 Ophthalmic Solution 
Sponsor: Harbour Biomed (Guangzhou) Co., Ltd 
Clinical Trial Protocol 9036.1, V1.2 
9 Jan 2019 
Confidential and proprietary 
Page 74 of 79 
Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
Fluorescein Staining 
The examiner drips 5μL of 2% preservative-free sodium fluorescein solution or use the 
sodium fluorescein test strip for staining (moisturized in saline).to the subconjunctival 
posterior fornix of each eye. In order to maximize fluorescent staining, the examiner should 
wait for about 3-5 minutes after dripping the dyes, and then assess fluorescein staining. Use 
the Wratten #12 yellow optical filter to enhance rating of fluorescein staining, and the Ora 
Calibra® corneal and corneal fluorescein staining scale to rate staining (the NEI scale may be 
used for re-assessment after assessment with this scale). 
Ora Calibra® Corneal and Conjunctival Staining Scale for Grading of Fluorescein 
Staining 
The following scale will be used to grade staining of the ocular surface (areas A, B, C, D, and 
E). Half (0.5) grade increments may be used. 
 
None 
0 = No staining 
Slight 
1 = Occasional 
Mild 
2 = Countable 
Moderate 
3 = Uncountable, but unfused 
Severe 
4 = Fusion 
Staining areas: 
 

HBM9036 Ophthalmic Solution 
Sponsor: Harbour Biomed (Guangzhou) Co., Ltd 
Clinical Trial Protocol 9036.1, V1.2 
9 Jan 2019 
Confidential and proprietary 
Page 75 of 79 
Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
 
Staining Areas 
Ocular Structure 
Position 
A – Inferior 
Cornea 
4-8 o’clock, extending 2 mm onto the 
conjunctiva 
Limbus/conjunctiva 
4-8 o’clock, extending 2 mm towards the 
center 
B – Superior 
Cornea 
8-4 o’clock, extending 3 mm onto the 
conjunctiva 
Limbus/Conjunctiva 
8-10 o’clock and 2-4 o’clock, extending 1 
mm onto the conjunctiva; 
10-2 o’clock, extending 2 mm onto the 
conjunctiva 
C - Central 
Cornea 
Central cornea 
D – Temporal 
Conjunctiva 
Triangular wedge of temporal conjunctiva 
E = Nasal 
Conjunctiva 
Triangular wedge of nasal conjunctiva 

HBM9036 Ophthalmic Solution 
Sponsor: Harbour Biomed (Guangzhou) Co., Ltd 
Clinical Trial Protocol 9036.1, V1.2 
9 Jan 2019 
Confidential and proprietary 
Page 76 of 79 
Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
Unanesthetized Schirmer’s Test 
Schirmer Tear Test will be performed according to the following procedure: 
• Using a sterile Schirmer test strip, a bend in the strip will be made in line with the 
notch in the strip 
• The subject will be instructed to gaze up and in 
• 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 
• After 5 minutes have elapsed, the Schirmer strip will be removed. The length of the 
moistened area will be recorded (mm) for each eye 

HBM9036 Ophthalmic Solution 
Sponsor: Harbour Biomed (Guangzhou) Co., Ltd 
Clinical Trial Protocol 9036.1, V1.2 
9 Jan 2019 
Confidential and proprietary 
Page 77 of 79 
Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
Drop Comfort Assessments 
 
Subject-Reported Drop Comfort Scale 
Drop comfort will be assessed for each eye immediately upon instillation, and at 1 and 2 
minutes following initial dosing at Visits 2, 3, 4, 5 and 6 using the Ora Calibra™ Drop 
Comfort Scale. 
Ora Calibra® Drop Comfort Scale 
 
Very comfortable                                                                                      Very   Uncomfortable 
Subject-Reported Drop Comfort Questionnaire 
Description of drop comfort will be assessed at 3 minutes following initial dosing at Visits 
2-6 using the Ora Calibra™ Drop Comfort Questionnaire: 
Ora Calibra® Drop Comfort Questionnaire 
The subjects will be asked to choose 3 words that best describe how each eye drop feels in 
both of his/her eyes: 
 
Burning 
Refreshing 
Comfortable 
Smooth 
Cool 
Soothing 
Filmy 
Sticky 
Gritty 
Stinging 
Irritating 
Thick 
Others: 
 

HBM9036 Ophthalmic Solution 
Sponsor: Harbour Biomed (Guangzhou) Co., Ltd 
Clinical Trial Protocol 9036.1, V1.2 
9 Jan 2019 
Confidential and proprietary 
Page 78 of 79 
Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
 
Appendix 
Sponsor's Signature Page 
 
Study Title: 
 
Study Number: 
 
Version Date: 
 
 
 
This clinical protocol is reviewed and approved by the sponsor. The following personnel are 
involved in writing and approving this protocol. 
 
 
Signature:  
 
Date:  
 
 
Name/title: 
 
 
 
 
 
Signature:  
 
Date:  
 
 
Name/title: 
 
 
 

HBM9036 Ophthalmic Solution 
Sponsor: Harbour Biomed (Guangzhou) Co., Ltd 
Clinical Trial Protocol 9036.1, V1.2 
9 Jan 2019 
Confidential and proprietary 
Page 79 of 79 
Translated from the Chinese version clinical study protocol 9 January 2019, Version 1.2 
 
Appendix 
Investigator's Signature Page 
Title of Study: 
 
Study Number: 
 
Version Date: 
 
I agree: 
• To assume responsibility for the proper conduct of the study at this site. 
• To conduct the study in compliance with the protocol and with any other study conduct 
procedures provided by Harbour BioMed. (hereafter referred to as Sponsor). 
• Not to implement any changes to the protocol without agreement from Sponsor and prior 
review and written approval from the Ethics Committee, except where necessary to 
eliminate an immediate hazard to the subjects, or for administrative aspects of the study 
(where permitted by all applicable regulatory requirements). 
• That I am aware of, and will comply with Good Clinical Practices and all applicable 
regulatory requirements. 
• That I am thoroughly familiar with the appropriate use of the investigational product(s), 
and other information provided by Sponsor including, but not limited to, the following: 
the protocol and the current Investigators Brochure (IB). 
• To ensure that all persons assisting me with the study are qualified, adequately informed 
about the investigational product(s) and of their study-related duties and functions. 
• To supply Sponsor with any necessary information regarding ownership interest and 
financial ties; to promptly update this information if any relevant changes occur during 
the course of the study and for 1 year following completion of the study; and agree that 
Sponsor may disclose any information it has about such ownership interests and financial 
ties to regulatory authorities. 
• I agree to report all information or data in accordance with the protocol and any other 
study conduct procedures provided by Sponsor. 
• That since the information in this protocol and IB is confidential, I understand that its 
disclosure to any third parties. 
• To accurately transfer all required data from each subject’s source document to the 
electronic case report forms (eCRFs). 
• To allow authorized representatives of Sponsor or regulatory authority representatives to 
conduct on-site visits to review, audit, and copy study documents.  I will personally meet 
with these representatives to answer any study-related questions. 
 
Signature:  
 
Date:  
 
Name:  
 
 
 
 
 
 
 
 
 
 
 
 
Study Site: