Clinical trial NCT04222725
Conditions: Post Surgical Ocular Inflammation
Keywords: postoperative postsurgical ocular inflammation pain
Sponsor: Tarsier Pharma
Start date: 2020-02-01; Completion date: 2020-07-17
Enrollment: 37 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this study is to evaluate the safety and preliminary efficacy of TRS01 eye drops as compared to placebo on participants with ocular inflammation after cataract surgery.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: TRS01 eye drops intervention 2: TRS01 eye drops intervention 3: TRS01 eye drops intervention 4: Placebo eye drops
Intervention descriptions: intervention 1: Dosed 4 times a day (QID) intervention 2: Dosed QID intervention 3: Dosed QID intervention 4: Dosed QID

Protocol documents:
Prot_SAP_000.pdf: 


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Project: 
 
 
 
 
TRS01 
 
Compound Number / Name: 
 
TRS01 
 
Protocol Number: 
 
 
 
Tarsius 2020  
 
Protocol Title: 
A Phase I/IIa Multicenter, Double-Masked, 
Randomized, Vehicle-controlled, Dose-ranging 
Study to Evaluate the Safety of TRS01 Eye Drops 
in Subjects with Post-surgical Inflammation. 
 
Sponsor: 
 
 
 
 
Tarsius Pharma, Ltd. 
 
 
 
 
 
 
19 Yahalom St. 
 
 
 
 
 
 
Zichron Yaacov 
 
 
 
 
 
 
30900 Israel 
 
Issue Date: 
 
 
 
 
Original: 12November2019 
Amendment 01:  06March2020 
   
Contact for Serious   
 
 
 
Adverse Events: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator Name: 
 
___________________________________________ 
 
Investigator’s Signature: 
 
___________________________________________                                 ________________ 
 
 
 
 
 
 
 
 
 
 
Date  
 
 
Tarsius Pharma, Ltd. 
Clinical Protocol Tarsius 2020 Trial 
Investigator Signature Page 


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SYNOPSIS 
Sponsor 
Tarsius Pharma Ltd. 
Study Title 
A Phase I/IIa Multicenter, Double-Masked, Randomized, Vehicle-
controlled, Dose-ranging Study to Evaluate the Safety of TRS01 Eye 
Drops in Subjects with Post-surgical Inflammation. 
Study Objective 
The primary objective of the study is to investigate the safety of TRS01 
 (w/v) eye drops compared to vehicle in subjects who 
have undergone cataract surgery. 
Study 
Population 
The study population will consist of male and female subjects, aged 18 
or older, who have undergone routine uncomplicated cataract surgery 
and experience ≥ grade 2 threshold level of ocular inflammation 1 day 
post-operatively. 
Number of 
Subjects 
Approximately 60 subjects that meet the selection criteria will be 
randomized for treatment following cataract surgery (one study eye). 
The number of subjects that will be screened to obtain 60 randomized 
subjects is estimated at approximately 100 subjects. 
Investigational 
Product 
TRS01-
, TRS01-
, and TRS01-
 eye drops, or vehicle, will 
be supplied as investigational product.  
Route and 
duration of 
administration 
Study subjects will administer the randomly assigned treatment, as eye 
drops, four times a day (QID) for 2 weeks. 
Study Design 
A Phase I/IIa multicenter, double-masked, randomized, vehicle-
controlled, dose-ranging study designed to evaluate the safety and 
preliminary efficacy of TRS01 eye drops (
 compared 
to vehicle in subjects with post-surgical inflammation. Potential study 
participants will be asked to sign an informed consent document before 
the surgery and have to meet all preoperative inclusion/exclusion 
criteria. Following cataract surgery, subjects who are observed to have 
anterior chamber cells ≥ grade 2 in the study eye on the Day 1 post-
operative visit following a routine, uncomplicated cataract surgery will 
be eligible to be randomized to treatment (subjects who have < grade 2 
anterior chamber cells must be screen failed). Once it is determined that 
all eligibility criteria have been met, subjects will be enrolled and 
treated with one of three concentrations of TRS01 or vehicle in a 
1:1:1:1 ratio. Approximately 60 eligible subjects will be enrolled in 
approximately five centers located in the United States (US) and 
France. 
Study subjects will administer the randomly assigned treatment four times 
a day (QID) for 14 (±1) days. All study subjects will return for 
examination on day 3, day 8 and day 15 post surgery. Day 15 visit will be 


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one day after the last day of treatment.  
Clinical assessments will include subject-rated ocular pain assessment, slit 
lamp biomicroscopy, dilated ophthalmoscopy, intraocular pressure (IOP) 
measurement, snellen distance visual acuity (VA) by Pinhole Method. 
 
The study visits schedule and assessments to be performed are described in 
Appendix 1. 
Primary Safety 
Endpoints 
Assessment of ocular AEs: Changes that are expected due to 
uncomplicated cataract surgery will not be classified as AEs but will be 
recorded. AEs will be captured by verbatim term and coded using 
MedDRA. 
Relevant clinical findings will also be recorded in the electronic case report 
form (eCRF) related to the following: 
1. Snellen distance VA by pinhole method   
2. Slit lamp biomicroscopy 
3. IOP measurement 
4. Dilated ophthalmoscopy 
5. Safety parameters include a change from baseline (1-day post-
surgery) to each post-surgery visit in ocular signs such as: 
o Conjunctival hyperemia 
o Corneal edema 
Exploratory 
Efficacy 
Measurements 
• Anterior chamber cell count on slit lamp biomicroscopy. At 
select sites,
 
 
• Anterior chamber flare assessed on slit lamp biomicroscopy  
• PROs-Subject-rated ocular pain assessment  
Eligibility 
Criteria 
Inclusion Criteria 
Pre-operatively, individuals of either gender or any race will be eligible 
for study participation if they are: 
1. 18 years of age or older. 
2. Able to provide informed consent, follow instructions and 
complete all required study visits for the duration of the study. 
3. Scheduled for routine cataract surgery (phacoemulsification or 
extracapsular extraction) with posterior chamber intraocular lens 
(IOL) implantation, and not combined with any other surgery. 


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4. Have vision ≥ 20/200 in the non-study eye. 
5. Able to self-administer eye drops (tested during screening by 
self-administration of “artificial tears”), or have a care provider 
that can administer the drops. 
6. Have no known sensitivity /allergy to the TRS01 or formulation 
excipients as detailed in TABLE 2 and TABLE 3. 
7. Using adequate birth control by men and women, if of 
reproductive potential and sexually active. Adequate birth control 
is defined as agreement to consistently practice an effective and 
accepted method of contraception throughout the duration of the 
study and for 2 weeks after the last dose of investigational 
product. 
a. For females, adequate birth control methods will be defined 
as hormonal contraceptives, intrauterine device or double 
barrier contraception, i.e., condom + diaphragm, condom or 
diaphragm + spermicidal gel or foam. 
b. For males, adequate birth control methods will be defined as 
double barrier contraception, i.e., condom + diaphragm, 
condom or diaphragm + spermicidal gel or foam. 
c. For females, menopause is defined as one year without 
menses; if in question, a follicle-stimulating hormone of >40 
IU/L must be documented. Hysterectomy, bilateral 
oophorectomy, or bilateral tubal ligation must be 
documented, as applicable. 
Exclusion Criteria 
In order for subject to be eligible at Visit 1 they may not:  
1. Be scheduled to undergo cataract surgery in the non-study eye for 2 
months prior to Visit 1 and during the study. 
2. Require use of any topical ophthalmic medications (either eye) other 
than study required medications for 14 days prior to surgery and for 
the duration of the trial.  Note: Use of PRN artificial tears up to 
twice a day is allowed and should not be dosed within 10 minutes of 
investigational product dosing. 
3. Require topical ocular therapy (either eye) with antibiotics for 30 
days prior to surgery except antibiotic eye drops used as part of the 
Investigator’s routine pre-op, intra-op, and post-op routine care.  
4. Require treatment with systemic NSAIDs, within 14 days prior to 
the surgery and for the duration of the trial. Occasional use (≤ 2 
times per week) of NSAIDs or over the counter (OTC) painkillers 


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to treat minor non-ocular conditions is acceptable. Low-dose 
aspirin (81 mg) for cardiovascular prophylaxis is allowed. 
Acetaminophen is the preferred treatment for post-op pain on the 
day of surgery. 
5. Require treatment with systemic or ocular immunosuppressants or 
immunomodulators including systemic steroids (oral, inhaled, 
injectable, nasal, topical dermal) or alpha-1 antagonists for 30 
days prior to surgery and for the duration of the trial.   
6. Use any ocular, topical or systemic medication that could interfere 
with wound healing, the test agent, or the interpretation of study 
results, within 30 days prior to the day of surgery and for the 
duration of the trial.  
7. Use of contact lenses in the study eye are prohibited for the duration 
of the study. 
8. Have history of glaucoma surgery or any incisional ocular surgery in 
the study eye. History of uncomplicated refractive surgery 3 years 
prior to the cataract surgery is acceptable.   
9. Have any significant ocular disease in the study eye in addition to 
the cataract that may confound the trial results per the Investigator’s 
judgement. 
10. Have proliferative diabetic retinopathy (PDR), not stable for at least 
one year in the study eye. 
11. Currently being treated for wet macular degeneration. 
12. Have current or history of herpes keratitis in the study eye. 
13. Be diagnosed with Fuchs Corneal Dystrophy (FCD). 
14. Have current or history of prior ocular inflammation in the 
study eye not related to prior allowed surgical procedure. 
15.  In the opinion of the Investigator, have current clinically 
significant dry eye requiring therapy of greater than twice a 
day (BID) eye drops in the study eye. Use of PRN artificial 
tears up to twice a day is allowed and should not be dosed 
within 10 minutes of investigational product dosing. 
16. Use any Cannabidiol products during the trial. 
17. Have history of glaucoma or uncontrolled IOP >22mmHg in the 
study eye on the day of screening. 
18. Have floppy iris syndrome noted for the contralateral eye prior to 
surgery in the study eye. 
19. Have any clinically significant systemic disease or condition (e.g. 


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hematological diseases) that, in the Investigator's opinion, may 
confound the trial results, pose a safety risk to the subject or 
preclude the subject from adhering to the protocol or completing the 
trial per protocol and instilling eye drops. 
20. Have a known history of alcohol and/or drug abuse. 
21. Be an employee of the site that is directly involved in the 
management, administration, or support of this study or be an 
immediate family member of the same.  
22. Have been exposed to an investigational drug or investigational 
medical device within 60 days prior to Visit 1. 
23. Be pregnant or lactating. 
 
Randomization Inclusion Criteria (Visit 3/Day 1) 
To qualify for randomization at the Day 1 (Visit 3), a subject must: 
1. Have undergone routine, uncomplicated cataract surgery 
(phacoemulsification or extracapsular extraction) with posterior 
chamber IOL implantation, not combined with any other surgery  
(including but not limited to use of iris retractors, capsular 
fixation ring or anterior capsule staining with dye). Specifically, 
have NOT had any cataract surgery complication such as a 
posterior capsular rupture, vitreous loss or significant iris 
damage. 
2. Have an IOP of ≤ 30 mmHg.  Notes:  Fluid release from the 
anterior chamber through the surgical incision is allowed 
(manual burping). The final IOP post release of fluid must be   
≤ 30 mmHg and will be recorded as the visit IOP value.  Use of 
IOP lowering medications are allowed beginning on Day 0, with 
the exception of prostaglandins.  IOP lowering eye drops should 
be dosed at least 30 minutes before investigational product 
dosing. 
3. Have anterior chamber cells ≥ grade 2. 
4. Continue to meet inclusion/exclusion criteria with respect to 
current ocular and medical conditions and must not be taking 
prohibited medications (section 6.4). 


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TABLE OF CONTENTS 
1 
Introduction ......................................................................................................................... 13 
1.1 
Description of Investigational Product ........................................................................... 14 
1.2 
GCP Compliance ............................................................................................................ 17 
1.3 
Study Population ............................................................................................................ 17 
2 
Study Objectives.................................................................................................................. 18 
3 
Study Design ........................................................................................................................ 19 
3.1 
Safety Endpoints ............................................................................................................ 19 
3.2 
Exploratory Efficacy Endpoints ..................................................................................... 19 
3.3 
Description of the Study Design .................................................................................... 19 
3.3.1 
Investigational product kit ...................................................................................... 21 
3.3.2 
Treatments administered ......................................................................................... 21 
3.3.3 
Method to minimize bias ........................................................................................ 22 
4 
Selection of Study Population ............................................................................................ 23 
4.1 
Subject Inclusion Criteria ............................................................................................... 23 
4.2 
Subject Exclusion Criteria .............................................................................................. 23 
4.3 
Randomization Inclusion Criteria .................................................................................. 25 
4.3.1 
Masking and Randomization Methodology ............................................................ 26 
4.4 
Informed Consent ........................................................................................................... 26 
5 
Study Assessments .............................................................................................................. 27 
5.1 
Timing of Study Assessments ........................................................................................ 27 
5.1.1 
Visit 1: Screening (Day (-30) to Day (-1)). ............................................................. 27 
5.1.2 
Visit 2: Day 0 – Surgery ......................................................................................... 27 
5.1.3 
Visit 3: Day 1 (1-day post-surgery) ........................................................................ 27 
5.1.4 
Visit 4: Day 3 (± 1 day) post surgery ...................................................................... 28 
5.1.5 
Visit 5: Day 8 (± 1 day) post surgery ...................................................................... 29 
5.1.6 
Visit 6/Early Termination: Day 15 (± 1 day) post surgery ..................................... 29 
5.1.7 
Unscheduled Visits ................................................................................................. 30 
5.2 
Withdrawal Criteria / Early Termination ....................................................................... 30 
6 
Treatment of Subjects......................................................................................................... 31 
6.1 
Prior and Concomitant Therapy ..................................................................................... 31 
6.2 
Permitted Medications.................................................................................................... 31 


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6.3 
Rescue medication use ................................................................................................... 31 
6.4 
Medications Not Permitted............................................................................................. 32 
6.5 
Treatment Compliance ................................................................................................... 32 
7 
Safety and Efficacy Variables ............................................................................................ 33 
7.1 
Safety Variable ............................................................................................................... 33 
7.2 
Safety Variables ............................................................................................................. 33 
7.2.1 
Adverse Events ....................................................................................................... 34 
7.2.2 
Criteria for Rescue Therapy  ................................................................................... 34 
7.2.3 
Other Safety Variables ............................................................................................ 35 
7.3 
Adverse Event Definitions ............................................................................................. 35 
7.4 
Procedures for AE Reporting by the Investigator .......................................................... 36 
7.5 
Serious Adverse Event Reporting by the Investigator ................................................... 37 
8 
Exploratory Efficacy ........................................................................................................... 39 
8.1 
Efficacy Variables .......................................................................................................... 39 
8.1.1 
Anterior Chamber Cells .......................................................................................... 39 
8.1.2 
Flare ........................................................................................................................ 39 
8.1.3 
Subject-Rated Ocular Pain Assessment .................................................................. 40 
9 
Statistics ............................................................................................................................... 41 
9.1 
Statistical Methods ......................................................................................................... 41 
9.1.1 
Subject Disposition, Demographic and Background Characteristics ..................... 41 
9.1.2 
Analysis of Safety ................................................................................................... 41 
9.1.3 
Analysis of Efficacy ................................................................................................ 41 
9.2 
Sample Size Estimation .................................................................................................. 42 
9.3 
Level of Significance ..................................................................................................... 42 
9.4 
Procedure for Accounting for Missing, Unused, or Spurious Data ............................... 42 
9.5 
Procedure for Reporting Deviations from the Statistical Plan ....................................... 42 
9.6 
Subjects to be Included in the Analysis ......................................................................... 42 
10 Direct Access to Source Data/Documents ......................................................................... 43 
11 Quality control .................................................................................................................... 44 
12 Ethics .................................................................................................................................... 45 
12.1 
Independent Ethics Committee or Institutional Review Board .................................. 45 
13 Amendments to the Protocol .............................................................................................. 46 


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14 Data handling and recordkeeping ..................................................................................... 47 
14.1 
Data Quality Control and Reporting ........................................................................... 47 
14.2 
Records Retention....................................................................................................... 47 
15 Publication Policy................................................................................................................ 48 
16 Appendices ........................................................................................................................... 49 
17 References ............................................................................................................................ 51 
 
 
 
 


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LIST OF TABLES 
TABLE 1: TRS01 AND VEHICLE DOSING VOLUME AND DOSE DELIVERY ................................. 14 
TABLE 2: COMPOSITION OF TRS01 
 INVESTIGATIONAL PRODUCT ................ 16 
TABLE 3: COMPOSITION OF  VEHICLE ......................................................................................... 17 
TABLE 4: OCULAR SAFETY MEASURES ....................................................................................... 33 
 
 
LIST OF FIGURES 
FIGURE 1: STUDY VISITS ................................................................................................................ 21 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation/Term 
Definition 
ACC 
Anterior Chamber Cells 
AE 
Adverse Event 
C 
Degrees Celsius 
CRO 
Contract Research Organization 
eCRF 
Electronic Case Report Form 
F 
Degrees Fahrenheit  
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee  
IOL 
Intraocular lens 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
ITT 
Intent-to-Treat 
LDPE 
Low-density polyethylene 
NSAIDs 
Non-steroidal Anti-inflammatory Drugs 
OD 
Oculus Dexter (right eye) 
OS 
Oculus Sinister (left eye) 
OTC 
Over the counter 
OU 
Oculus Uterque (both eyes) 
PP 
Polypropylene 
PP 
Per Protocol 
QID 
Four times daily 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
 
 
US 
United States of America 
VA 
Visual Acuity 
w/v 
Weight to Volume 
 
 


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1 
INTRODUCTION 
Intraocular inflammation is a typical undesirable consequence of intraocular surgery such as 
cataract surgery. It is manifested principally as conjunctival injection, corneal edema, ciliary 
flush and aqueous cells and flare. Surgical trauma and phacoemulsification energy activate an 
inflammatory cascade that ultimately leads to formation of prostaglandins, which results in local 
vasodilation and increased vascular permeability.  
Inflammation may resolve with no treatment in 15-28% of patients. However, inadequately 
treated inflammation after cataract surgery frequently causes pain, photophobia, increased risk 
for elevated intraocular pressure (IOP), corneal edema, corneal scarring and cystoid macular 
edema [Aptel et al., 2017]. Thus, managing and treating postoperative inflammation is an 
important goal following cataract surgery.  
Other ocular inflammatory diseases include, for example, non-infectious uveitis, a potentially 
blinding condition that is the fifth leading cause of visual loss in the developed world (third 
leading cause of preventable blindness), has been estimated to account for 10% of all visual 
impairment in the western world and 10–15% of cases of total blindness [Nussenblatt, 1990; 
Merida et al., 2015]. Anterior uveitis accounts for approximately 80% of non-infectious uveitis 
cases in the United States [Thorne et al., 2016].  
Uveitis is characterized by an inflammatory process that may be acute, recurrent, chronic or 
acute-on-chronic. Untreated, recurrent bouts of uveitis eventually lead to tissue destruction from 
direct inflammation or from complications such as cataract, glaucoma and macular edema.  
Topical corticosteroids represent first line treatment for both non-infectious uveitis and 
postoperative inflammation. In the US, topical corticosteroids are routinely prescribed with four 
times daily (QID) dosing for at least 2 weeks following cataract surgery [Kim et al., 2019]. 
The side effects associated with steroid use, significantly limit prolonged treatment. The most 
common adverse effects of ocular steroids are cataract and elevated IOP which can lead to 
steroid related glaucoma. 
Given the limitations of treatment, there is a need for an effective anti-inflammatory drug that 
does not have an IOP-elevating effect. Tarsius Pharma has developed a novel therapeutic 
approach for local prevention and treatment of ophthalmic inflammatory diseases. 
 
 
 
 
  
 
 
 
 




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Subjects are expected to self-administer, or have a care provider administer, one drop four times per 
day (QID) of TRS01
, TRS01-
, TRS01-
 or vehicle control.  
Double-masked doses will be assigned through the randomization program. The treatment 
schedule is shown in FIGURE 1. TRS01 will be administered no more frequently than four times 
daily (QID) per protocol. 
 
 


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TABLE 2: COMPOSITION OF TRS01 
 INVESTIGATIONAL PRODUCT 
Ingredient 
Ingredient name 
According to USP 
Function 
Concentration (%w/v) 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wa
 
 
 
 
 
 
 
 
 
 
 




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2 
STUDY OBJECTIVES 
The primary objective of this study is to evaluate the safety of TRS01 eye drops at 
concentrations of 
w/v) compared to vehicle in subjects who have 
undergone uncomplicated cataract surgery. 
The exploratory objective of the study is to assess the preliminary efficacy of TRS01 eye drops 
in reducing inflammation as compared to vehicle. 
 
 


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3 
STUDY DESIGN 
This is a phase I/IIa multicenter, double-masked, randomized, vehicle-controlled, dose-ranging 
study. 
It is designed to evaluate the safety and preliminary efficacy of TRS01 eye drops (
 
) compared to vehicle in subjects with post-surgical inflammation.  
 
3.1 
SAFETY ENDPOINTS 
The primary safety parameter in this study is the incidence and severity of treatment-emergent 
and treatment-related adverse events (AEs), both systemic and ocular events in subjects with 
post-cataract inflammation. Changes that are expected due to uncomplicated cataract surgery will 
not be classified as AEs but will be recorded. 
1. Snellen distance visual acuity (VA) by pinhole method  
2. Slit lamp biomicroscopy 
3. IOP measurement 
4. Dilated ophthalmoscopy 
5. Change from baseline (1-day post-surgery) to each post-surgery visit in ocular signs: 
o Conjunctival hyperemia 
o Corneal Edema 
All Relevant clinical findings will be recorded in the electronic case report form (eCRF). 
3.2 
EXPLORATORY EFFICACY ENDPOINTS 
1. Anterior Chamber Cell count on slit lamp biomicroscopy. 
 
2. Anterior chamber flare 
3. Subject-rated ocular pain assessment 
3.3 
DESCRIPTION OF THE STUDY DESIGN 
This is a Phase I/IIa Multicenter, Double-Masked, Randomized, Vehicle-Controlled, Dose-
ranging study designed to evaluate the safety and preliminary efficacy of TRS01 eye drops at 
three dose levels compared to vehicle in subjects with post-surgical inflammation.  
Approximately 60 subjects with ocular inflammation following cataract surgery will be 
randomized at  approximately five centers, in the USA and in France. 


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Subjects who provide informed consent and meet all study randomization criteria will be 
enrolled in the study and randomized in a 1:1:1:1 ratio to receive TRS01
%, TRS01-
, 
TRS01- % or vehicle eye drops four times daily.  
Treatment assignments will be masked to Tarsius, study subjects, Investigators, and site staff. In 
order to prevent unmasking, all study medications during the Treatment Period will be supplied 
in identical packages. 
The study design includes 14-days of a double-masked treatment period, with the endpoint 
assessment conducted on Day 15 (FIGURE 1 summarizes the study phases, anticipated visits and 
number of subjects at each phase and Appendix 1 summarizes the schedule of assessments from 
Screening through Day 15). 
Randomization is employed as an unbiased method of assigning subjects to four groups in equal 
allocation.  
Male and female subjects aged 18 or older and 1-day post cataract surgery with anterior chamber 
cells ≥ grade 2 in the study eye, are eligible to be randomized to participate in the treatment 
phase of the study.   
Double-masked eye drops will be administered four times daily from Day 1 through Day 14 by 
the study participant (or care provider) to the study eye. The safety endpoint is on Day 15. 
Exploratory efficacy measurements will be collected.   
Visits (including the surgery day): 
1. Visit 1/Days -30 to -1 – Screening: Initial screening for eligibility – 1-30 days before the 
surgery. 
2. Visit 2/Day 0 – Surgery: Eligible subjects will undergo routine cataract surgery according to 
investigator’s standard procedures. No steroid or NSAID will be given before, during or after 
the surgery. Acetaminophen on the day of surgery is allowed. 
3. Visit 3/Day 1 – Randomization: Subjects who meet the post-surgery qualification criteria of 
≥ grade 2 anterior chamber cells in the study eye will be randomized and will initiate dosing 
with IP. The subject’s first dose will occur after randomization under the observation of an 
Unmasked staff member.  
3.1. 40 minutes ± 10 minutes post first dose, AEs, if any, will be recorded. Changes that are 
expected due to uncomplicated cataract surgery (such as discomfort, scratchy feeling, 
significant brightness, changes in the perception of the operated eye, corneal edema) will 
be collected, but will not be classified as AEs. Subjects will be given one bottle of IP and 
instructed to dose three more times that day and to begin dosing four times a day on the 
following day and onward. 
The eye that underwent cataract surgery is defined as the study eye. TRS01 should not be 
administered  in the fellow eye. 




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3.3.3 Method to minimize bias 
In order to prevent unmasking during the study, the three doses of TRS01 and the vehicle will be 
supplied in identical packages. 
Treatment assignments during the treatment period will be masked to all Tarsius staff, subjects 
and investigators, except delegated unmasked site personnel. The designated unmasked site 
personnel should collect all AEs related to IP and will handle all IP related responsibilities but 
will not perform any study related assessments.  
The first dose will be administered under the supervision of an unmasked staff member and will 
serve as confirmation that the subject was adequately trained on drop administration at the 
screening visit. In the event that it becomes necessary to unmask a specific subject’s treatment 
assignment, the Principal Investigator will contact Tarsius Medical Officer or the back-up 
Medical Officer. Unmasking will be allowed for individual subjects after it is determined 
necessary by the Medical Officer and the Principal Investigator, thus leaving the masking of the 
remaining subjects intact 
 
 


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4 
SELECTION OF STUDY POPULATION 
4.1 
SUBJECT INCLUSION CRITERIA 
Pre-operatively, individuals of either gender or any race will be eligible for study 
participation if they are: 
1. 18 years of age or older. 
2. Able to provide informed consent, follow instructions and complete all required study 
visits for the duration of the study. 
3. Scheduled for routine cataract surgery (phacoemulsification or extracapsular 
extraction) with posterior chamber intraocular lens (IOL) implantation, and not 
combined with any other surgery. 
4. Have vision ≥ 20/200 in the non-study eye. 
5. Able to self-administer eye drops (tested during screening by self-administration of 
“artificial tears”), or have a care provider that can administer the drops. 
6. Have no known sensitivity /allergy to the TRS01 or formulation excipients as detailed 
in TABLE 2 and TABLE 3. 
7. Using adequate birth control by men and women, if of reproductive potential and 
sexually active. Adequate birth control is defined as agreement to consistently practice 
an effective and accepted method of contraception throughout the duration of the 
study and for 2 weeks after the last dose of investigational product. 
a. For females, adequate birth control methods will be defined as hormonal 
contraceptives, intrauterine device or double barrier contraception, i.e., condom + 
diaphragm, condom or diaphragm + spermicidal gel or foam. 
b. For males, adequate birth control methods will be defined as double barrier 
contraception, i.e., condom + diaphragm, condom or diaphragm + spermicidal gel 
or foam. 
c. For females, menopause is defined as one year without menses; if in question, a 
follicle-stimulating hormone of >40 IU/L must be documented. Hysterectomy, 
bilateral oophorectomy, or bilateral tubal ligation must be documented, as 
applicable. 
4.2 
SUBJECT EXCLUSION CRITERIA 
In order for subject to be eligible at Visit 1 they may not:  
1. Be scheduled to undergo cataract surgery in the non-study eye for 2 months prior to Visit 
1 and during the study. 
2. Require use of any topical ophthalmic medication (either eye)  for 14 days prior to 
surgery and for the duration of the trial.  Note: Use of PRN artificial tears up to twice a 
day is allowed and should not be dosed within 10 minutes of investigational product 
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3. Require topical ocular therapy (either eye) with antibiotics for 30 days prior to surgery 
except antibiotic eye drops used as part of the Investigator’s routine pre-op, intra-op, 
and post-op routine care.  
4. Require treatment with systemic NSAIDs, within 14 days prior to the surgery and for 
the duration of the trial. Occasional use (≤ 2 times per week) of NSAIDs or over the 
counter (OTC) painkillers to treat minor non ocular conditions is acceptable. Low-dose 
aspirin (81 mg) for cardiovascular prophylaxis is allowed. Acetaminophen is the 
preferred treatment for post-op pain on the day of surgery. 
5. Require treatment with systemic or ocular immunosuppressants or immunomodulators 
including systemic steroids (oral, inhaled, injectable) for 30 days prior to surgery and 
for the duration of the trial. Require treatment with nasal, topical dermal steroids or 
immunosuppressants within 14 days prior to surgery and for the duration of the trial.  
Require treatment with alpha-1 antagonists within 30 days of surgery and for the 
duration of the trial.   
6. Use any ocular, topical or systemic medication that could interfere with wound healing, 
the test agent, or the interpretation of study results, within 30 days prior to the day of 
surgery and for the duration of the trial.  
7. Use of contact lenses in the study eye are prohibited for the duration of the study. 
8. Have history of glaucoma surgery or any incisional ocular surgery in the study eye. 
History of uncomplicated refractive surgery 3 years prior to the cataract surgery is 
acceptable. 
9. Have any significant ocular disease in the study eye in addition to the cataract that may 
confound the trial results per the Investigator’s judgement. 
10. Have proliferative diabetic retinopathy (PDR), not stable for at least one year in the study 
eye. 
11. Be currently being treated for wet macular degeneration. 
12. Have current or history of herpes keratitis in the study eye. 
13. Be diagnosed with Fuchs Corneal Dystrophy (FCD). 
14. Have current or history of prior ocular inflammation in the study eye not related 
to prior allowed surgical procedure. 
15.  In the opinion of the Investigator, have current clinically significant dry eye 
requiring therapy of greater than twice a day (BID) eye drops in the study eye. 
Use of PRN artificial tears up to twice a day is allowed and should not be dosed 
within 10 minutes of investigational product dosing. 
16. Use any Cannabidiol products during the trial. 
17. Have history of glaucoma or uncontrolled IOP >22mmHg in the study eye on day of 
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18. Have floppy iris syndrome noted for the contralateral eye prior to surgery in the study 
eye. 
19. Have any clinically significant systemic disease or condition (e.g. hematological 
diseases) that, in the Investigator's opinion, may confound the trial results, pose a safety 
risk to the subject or preclude the subject from adhering to the protocol or completing the 
trial per protocol and installing eye drops. 
20. Have a known history of alcohol and/or drug abuse. 
21. Be an employee of the site that is directly involved in the management, administration, or 
support of this study or be an immediate family member of the same.  
22. Have been exposed to an investigational drug or investigational medical device within 60 
days prior to Visit 1. 
23. Be pregnant or lactating. 
 
4.3 
RANDOMIZATION INCLUSION CRITERIA 
To qualify for randomization at the Day 1 (Visit 3), a subject must: 
1. Have undergone routine, uncomplicated cataract surgery (phacoemulsification or 
extracapsular extraction) with posterior chamber IOL implantation, not combined with 
any other surgery  (including but not limited to use of iris retractors, capsular fixation 
ring or anterior capsule staining with dye). Specifically, have NOT had any cataract 
surgery complication such as a posterior capsular rupture, vitreous loss or significant 
iris damage. 
2. Have an IOP of ≤ 30 mmHg.  Notes:  Fluid release from the anterior chamber through 
the surgical incision is allowed (manual burping). The final IOP post release of fluid 
must be  ≤ 30 mmHg and will be recorded as the visit IOP value.  Use of IOP 
lowering medications are allowed beginning on Day 0, with the exception of 
prostaglandins.  IOP lowering eye drops should be dosed at least 30 minutes before 
investigational product dosing. 
3. Have anterior chamber cells ≥ grade 2.  
4. Continue to meet inclusion/exclusion criteria with respect to current ocular and 
medical conditions and must not be taking prohibited medications (section 6.4).  


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4.3.1 Masking and Randomization Methodology 
Eligible subjects will be randomized in a 1:1:1:1 ratio to receive TRS01-
, TRS01
, 
TRS01
% or vehicle dose on Day 1. 
Randomization will occur after subjects meet all eligibility requirements at Screening and Day 
1/Visit 3 (1-day post-surgery). Each subject will be assigned a unique subject number.  
Each kit package (containing two IP bottles) will contain a kit number that can be later corelated 
to the subject number at the site. 
Randomization for the US sites will be separate from the French site. 
The randomization codes and all data sets will be stored in a secure area accessible only to 
delegated study personnel and only released on completion of the study and after the study 
database has been locked. 
In this study all parties are to be masked to the allocated treatment; investigators, study staff  and 
subjects. At the site, there will be designated unmasked study staff that will train the subject on 
all study procedures related to IP administration. 
In emergency situations for reasons of subject safety (e.g. serious unexpected /unlisted drug 
related event; medical emergency; potentially life-threatening drug interaction) the masking code 
may need to be broken. In those cases, whenever possible, a request for unmasking should be 
discussed with the sponsor (or designee) prior to unmasking. Detailed instruction on the method 
for breaking the mask will be provided during site training and noted in the Investigator study 
file. 
Following the first IP administration, if the subject perceives any AE that may be attributed to 
the IP, these should be reported to the unmasked site personnel.  
4.4 
INFORMED CONSENT  
Prior to undergoing any study-related activity, the Principal Investigator or his/her designee will 
discuss the purpose and pertinent details of the study with each potentially eligible subject. The 
explanation will be sufficiently detailed to allow the subject to make an informed decision to 
participate in the study. If the subject is willing to participate in the study, he/she will be 
requested to give written informed consent. A copy of the Informed Consent Form (ICF) will be 
signed by both the subject and the Principal Investigator or his/her designee. 
The signed and dated ICF will be retained with the study records, and a copy of the signed and 
dated ICF will be given to the subject.  
 
 


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5 
STUDY ASSESSMENTS 
5.1 
TIMING OF STUDY ASSESSMENTS 
All procedures will be performed according to the following schedule unless otherwise specified. 
See also the summary of assessments in Appendix 1 that outlines this schedule in tabular form. 
Note:
 
 
5.1.1 Visit 1: Screening (Day (-30) to Day (-1)).  
This visit is a period where assessments can be collected. Ocular assessments are to be 
performed on both eyes. 
• Signed and dated informed consent 
• Demographic information including iris color 
• Medical and Ophthalmic History  
• Inclusion/exclusion criteria 
• Concomitant Medications 
• Urine pregnancy test (if female of child-bearing potential) 
• Snellen Distance Visual Acuity (VA) by Pinhole Method  
• Slit-lamp biomicroscopy  
• Intraocular pressure by Goldmann Applanation Tonometry  
• Dilated Ophthalmoscopy  
• Self-administration eye drop assessment (self-administration/care provider 
administration of “artificial tear eye drop”) 
• Assessment of adverse events 
5.1.2 Visit 2: Day 0 – Surgery 
This visit will occur no more than 30 days and no less than 1 day after Visit 1 and the following 
will be performed/assessed:  
• Concomitant medication update 
• Occurrence of any AEs since the last visit 
• Routine pre-surgical care and procedures as determined by the Investigator 
5.1.3 Visit 3: Day 1 (1-day post-surgery) 
This visit should be scheduled to occur in the morning, if possible, to allow for QID dosing on Day 
1 for randomized subjects.  Perform the following assessments. Ocular assessments are to be 
performed on both eyes, unless otherwise noted: 


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• Subject-Rated Ocular Pain Assessment – prior to any other assessments 
• Assessment of adverse events following subject rated ocular pain assessment. 
Changes that are expected due to uncomplicated cataract surgery will not be classified 
as AEs but will be recorded. 
• Concomitant medication update 
• Snellen Distance VA by Pinhole Method  
• Slit-lamp biomicroscopy  
• Intraocular pressure by Goldmann Applanation Tonometry  
• Randomization:  subjects that meet eligibility criteria (section 1) should be 
randomized to one of the treatment groups through the Interactive Web Response 
System (IWRS). 
• 
 
• Dispensation of IP and Dosing Diary: the subject will receive one bottle from the 
study kit and will be instructed to self-administer the first drop prior to leaving the 
clinic, under the supervision of the unmasked personnel. The subject will be 
instructed to record this first dose and all subsequent doses in the dosing diary. 
• 40 minutes ± 10 minutes post IP administration the subject will be assessed for AEs 
in both eyes. If any AEs are reported at visit 3 that may be attributed to the IP, these 
should be handled by the unmasked personnel.  
• The subject will be instructed to take the bottle home and administer the IP three 
more times that day. Following the day of this visit the subject will be instructed to 
begin using the drops four times a day and to continue for the duration of the study. 
5.1.4 Visit 4: Day 3 (± 1 day) post surgery 
Perform the following assessments. Ocular assessments are to be performed on both eyes, 
unless otherwise noted: 


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• Subject-Rated Ocular Pain Assessment – prior to any other assessments 
• Assessment of adverse events. Changes that are expected due to uncomplicated 
cataract surgery will not be classified as AEs but will be recorded. 
• Concomitant medication update 
• Snellen Distance VA by Pinhole Method  
• Slit-lamp biomicroscopy  
• Intraocular pressure by Goldmann Applanation Tonometry  
• 
 
• Review subject’s dosing diary for compliance by unmasked personnel 
5.1.5 Visit 5: Day 8 (± 1 day) post surgery 
Perform the following assessments. Ocular assessments are to be performed on both eyes, 
unless otherwise noted: 
• Subject-Rated Ocular Pain Assessment – prior to any other assessments 
• Assessment of adverse events. Changes that are expected due to uncomplicated 
cataract surgery will not be classified as AEs but will be recorded.  
• Concomitant medication update 
• Slit-lamp biomicroscopy  
• Snellen Distance VA by Pinhole Method  
• Intraocular pressure by Goldmann Applanation Tonometry  
• 
 
• Collect used IP and review subject’s dosing diary for compliance by unmasked 
personnel 
• Dispense second bottle of IP from subject’s  assigned kit by unmasked personnel. 
Subject should be reminded to withhold dosing on the day of Visit 6. 
5.1.6 Visit 6/Early Termination: Day 15 (± 1 day) post surgery 
Perform the following assessments. Ocular assessments are to be performed on both eyes, 
unless otherwise noted: 
• Subject-Rated Ocular Pain Assessment – prior to any other assessments 
• Assessment of adverse events. Changes that are expected due to uncomplicated 
cataract surgery will not be classified as AEs but will be recorded. 
• Concomitant medication update 
• Urine pregnancy test (if female of child-bearing potential) 


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• Snellen Distance VA by Pinhole Method 
• Slit-lamp biomicroscopy  
• Intraocular pressure by Goldmann Applanation Tonometry 
• Dilated ophthalmoscopy 
• 
 
• Collect used IP and the subject’s dosing diary by unmasked personnel 
• Confirm study completion  
5.1.7 Unscheduled Visits 
If at any time during the study, outside of the above scheduled visits, the subject requests 
or the physician determines the subject should be assessed for retreatment or of an AE, an 
unscheduled visit may occur. Adverse events and concomitant medications will be 
recorded and the following assessments should be performed on the study eye (and non-
study eye if applicable/necessary.): 
• Snellen Distance VA by Pinhole Method 
• Slit lamp biomicroscopy 
• IOP by Goldmann Applanation Tonometry 
• Dilated ophthalmoscopy, if indicated 
5.2 
WITHDRAWAL CRITERIA / EARLY TERMINATION 
Subjects have the right to withdraw from the study at any time, for any reason, without jeopardizing 
their medical care. Where possible, subjects will be followed for safety and encouraged to return 
for follow-up visits for any unresolved safety events. 
In addition, the Investigator or Tarsius’ Medical Officer can discontinue a subject from further 
study medication administration for other reasons related to the best interest of the subject. 
If a subject is discontinued from study medication administration at any point of the Treatment 
Period, he or she will be encouraged to remain in the study for follow up through Day 15.   
The reason a subject discontinued from the study is to be clearly described on the Study Exit 
electronic case report form (eCRF). 
Subjects who withdraw from the study will not be replaced. Subjects who withdraw from the study 
prior to Visit 6 (Day 15) will be asked to complete all procedures outlined in Visit 6. 
 
 
 
 


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6 
TREATMENT OF SUBJECTS 
6.1 
PRIOR AND CONCOMITANT THERAPY  
At the Screening visit, medications that were taken within the previous 30 days will be collected. 
At each study visit thereafter, subjects will be questioned concerning any new medications or 
changes in their current concomitant medications since their previous study visit. 
For all medications, the generic name, indication, route of administration, frequency, dose, start 
date and end date (if applicable) will be collected. 
6.2 
PERMITTED MEDICATIONS  
Therapy considered necessary for the subject’s welfare that does not interfere with the evaluation 
of the study medication will be permitted to be given at the discretion of the Principal 
Investigator.  
The decision to administer a prohibited medication or treatment would be taken with the safety 
of the subject as the primary consideration. Whenever possible, the Tarsius Medical Monitor will 
be notified before any prohibited medications or treatments are administered. The Tarsius 
Medical Monitor should also be contacted if the permissibility of a specific medication or 
treatment is in question.   
Any subject placed on rescue therapy will discontinue use of the study medication and continue 
study participation through Visit 6. 
Subjects on rescue will be considered treatment failures, but the need for rescue therapy will not 
be considered an AE. Rescued subjects experiencing an AE at the time of rescue will be 
followed through stabilization or resolution of the AE or the end of the study (whichever comes 
last). Rescued subjects should not be withdrawn from the study, but rather followed to resolution 
of signs and symptoms or until the Investigator has deemed the subject is stable. 
6.3 
RESCUE MEDICATION USE 
Rescue medications will be administered in cases detailed in section 7.2.2. Rescue therapy will 
be defined as any treatment that would have a therapeutic effect on inflammation in the anterior 
segment, other than the IP (e.g., systemic treatment with an immunosuppressant agent, or topical 
corticosteroids in the study eye), regardless of the purpose of administration and whether it was 
recorded as a rescue therapy on the eCRF.  
Systemic immunosuppressive therapy (e.g., methotrexate, cyclosporine, cyclophosphamide, 
chlorambucil, mycophenolate mofetil, tacrolimus, azathioprine, or adalimumab) or other therapy 
considered as a rescue therapy, would be administered based on the Investigator’s best judgment 
and only after discussion with Tarsius’ Medical Director. Prior to treatment with rescue 
medication, the subject should answer the “Subject-Rated Ocular Pain Assessment”. Only then, 
rescue medication can be administered and treatment will be recorded as a rescue therapy in the 
Medications eCRF.   
 
 


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6.4 
MEDICATIONS NOT PERMITTED 
Use of the following medication is not permitted during the study and 14 days prior to Visit 2 
(Day of Surgery): 
1. Any topical ophthalmic medications (either eye) other than study required 
medications. Note: Use of PRN artificial tears up to twice a day (BID) is allowed, and 
should not be dosed within 10 minutes of investigational product dosing. 
2. Prostaglandins.  Use of IOP lowering medications, other than prostaglandins, are 
allowed beginning on Day 0 and during the study, as needed. IOP lowering eye 
drops should be dosed at least 30 minutes before investigational product dosing. 
3. Systemic NSAIDs. Occasional use (≤ 2 times per week) of Systemic NSAIDs or OTC 
painkillers to treat minor non-ocular conditions is acceptable. Low- dose aspirin for 
cardiovascular prophylaxis is allowed.  Acetaminophen may be administered pre and 
post-operatively as needed for pain on the day of surgery.  
4. Treatment with nasal, topical dermal steroids or immunosuppressants. 
Use of the following medication is not permitted during the study and 30 days prior to Visit 2 
(Day of Surgery): 
1. Use of topical ocular therapy (both eyes) with antibiotics. Note: Antibiotic eye drops 
that are routinely administrated prior/during and post cataract surgery are allowed.  
2. Use of systemic or ocular immunosuppressants or immunomodulators including 
steroids (oral, inhaled, injectable, nasal, topical dermal). 
3. Use of systemic alpha-1 antagonists. 
4. Any ocular, topical or systemic medication that could interfere with wound healing, 
the test agent, or the interpretation of study results. 
5. Other investigational drugs or devices 
6.5 
TREATMENT COMPLIANCE 
In order to obtain reliable safety and efficacy data, it is critical that each subject comply with the 
dosing schedule specified in the protocol.  
Subjects will be instructed to record administration information from Day 1 and for the duration 
of the study in a dosing diary . 
 
 


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7 
SAFETY AND EFFICACY VARIABLES 
7.1 
SAFETY VARIABLE 
Incidence and severity of treatment-related AEs and SAEs, both systemic and ocular events. 
7.2 
SAFETY VARIABLES 
Safety measures include AEs/SAEs and clinical assessments from the slit-lamp biomicroscopy 
findings, IOP, and dilated ophthalmoscopy findings. 
AEs and ocular safety measures to be collected in this study are listed in Table 4.  
TABLE 4: OCULAR SAFETY MEASURES  
Safety Measure 
Note 
Slit-lamp biomicroscopy: 
Lid hyperemia, lid edema, 
conjunctival hyperemia, 
chemosis, corneal edema, 
conjunctival discharge/exudate  
The status of each of these biomicroscopy parameters will be rated 
as 0 = None, 1 = Mild, 2 = Moderate, or 3 = Severe. For each 
abnormal record, the clinical significance (Clinically Significant or 
Not Clinically Significant) will also be determined. Slit-lamp 
biomicroscopy will be performed at all study visits, except Visit 2 
(Surgery).   
Intraocular pressure 
The IOP measurements will be performed by Goldmann 
applanation tonometry. IOP pressure recorded in mmHg (e.g., 
18mmHg). IOP measurements will be performed at all study 
visits, except Visit 2 (Surgery).   
 Dilated Ophthalmoscopy: 
IOL (post-surgery), vitreous haze, 
retina vessels, macula, optic 
nerve, cup/disc ratio.  
The status of IOL position, macula and optic nerve will be 
determined as Normal or Abnormal. The cup/disc ratio will be 
recorded with two decimal points (e.g., 0.80). Dilated 
ophthalmoscopy will be performed at Visit 1 (Screening) and at 
Visit 6 (Day 15).  
 
Intraocular Pressure (IOP) – IOP will be measured using Goldmann Applanation Tonometry 
with a single measurement.  
These ocular safety measures will be summarized using descriptive statistics. For continuous 
ocular safety measures, changes from Baseline (Day 1 / Visit 3) variables will also be 
summarized descriptively.  
 
 
 


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7.2.1 Adverse Events 
Adverse events will be collected for subjects following signing of the ICF through the end of the 
study. The information will include at least a description of the event, onset date, and resolution 
date, as well as seriousness, severity and relation to study medication (as determined by the 
Investigator), location (right eye [OD], left eye [OS], both eyes [OU] or other), action taken, and 
outcome. All AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) dictionary, current version. Ocular and non-ocular AEs will be summarized 
separately.   
Suspected adverse reactions (SARs), also known as adverse drug reactions or suspected adverse 
drug reactions, are AEs considered by the Investigator to be related to the study medication and 
included in the Investigator’s Brochure. 
An AE will be considered as an ocular AE if the Investigator selects ‘OD’, ‘OS’, or ‘OU’ for the 
AE eCRF field “Eye(s) affected”. 
Any AE that causes loss of vision of 15 or more letters (i.e., 3 lines) should be recorded as a 
serious adverse event (SAE). Examples include endophthalmitis, retinal vascular occlusion, 
retinal detachment involving the macula/fovea, etc. AEs that cause loss of 15 or more letters (i.e., 
3 lines) that are expected to resolve should not be recorded as an SAE.  Examples include 
corneal edema, corneal abrasion, cystoid macular edema or other conditions that are known to 
affect vision but expected to resolve and not results in a permanent impact on vision.  
7.2.2 Criteria for Rescue Therapy  
Rescue therapy will be offered if one or more of the following criteria are met and a rescue 
therapy treatment plan is discussed with the Tarsius Medical Director.   
• 
 
 
 
 
 
 
 
 
 
 
 
If rescue therapy is administered, the generic name, indication, route of administration, 
frequency, dose, start date, and stop date (if applicable) will be recorded on the eCRF. In 
addition, if other local therapy (i.e., periocular or intravitreal corticosteroids) is administered in 
the non-study eye, then the generic name, indication, route of administration, frequency, dose, 
start date and end date (if applicable) would also be recorded on the eCRF. 
 
 
 


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7.2.3 Other Safety Variables 
Other safety measures are discussed in section 7.2 above.  
 
7.3 
ADVERSE EVENT DEFINITIONS 
 
Adverse Event (AE): Any untoward medical occurrence associated with the use of an 
investigational product in humans, whether or not considered drug related.  
 
Adverse Reaction (AR): any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions where there is reason to conclude that the drug caused the event.  
 
Suspected Adverse Reaction (SAR):  
Any AE for which there is a reasonable possibility that the drug caused the AE. For the purposes 
of IND safety reporting, “reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the AE. A SAR implies a lesser degree of certainty about 
causality than adverse reaction, which means any AE caused by a drug.  
 
Unexpected: An AE or SAR is considered “unexpected” if it is not listed in the Investigator’s 
Brochure or is not listed at the specificity or severity that has been observed; or, if an 
Investigator’s Brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
  
Life-threatening: An AE or SAR is considered “life-threatening” if, in the view of either the 
Investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more severe form, 
might have caused death. 
 
A SERIOUS ADVERSE EVENT (SAE) is any AE or suspected adverse reaction occurring at 
any dose that:  
• Results in death.  
• Is life-threatening.  
• Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions.  
• Requires inpatient hospitalization.  
• Prolongs inpatient hospitalization.  
• Is a congenital anomaly/birth defect.  
• Is a significant medical event (i.e., one that may jeopardize the subject or may require 
intervention to prevent one or more of the other outcomes listed above).  
 
A NON-SERIOUS ADVERSE EVENT is any AE that does not meet the definitions for SAEs 
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Each AE will be classified as SERIOUS or NON-SERIOUS using the definitions provided 
above.  
 
The SEVERITY of each AE will be classified as MILD, MODERATE, or SEVERE.  
The Investigator will review each event and assess its RELATIONSHIP to use of 
investigational product (unrelated,  probably, definitely). The AE will be assessed using the 
following definitions:  
 
Unrelated:  
• Event occurring before dosing.  
• Event easily explained by uncomplicated cataract surgery 
• Event or intercurrent illness due wholly to factors other than investigational product 
use.  
 
Probable:  
• Reasonable temporal relationship with investigational product use.  
• Likely to be known reaction to agent or chemical group, or predicted by known 
pharmacology.  
• Event cannot easily be explained by subject’s clinical state or other factors.  
 
Definite:  
• Distinct temporal relationship with investigational product use.  
• Known reaction to agent or chemical group, or predicted by known pharmacology.  
• Event cannot be explained by subject’s clinical state or other factors.  
 
7.4 
PROCEDURES FOR AE REPORTING BY THE INVESTIGATOR 
AEs will be monitored throughout the study and will be recorded on the CRF with the date and 
time of onset, date and time of resolution, severity, seriousness, causality (relationship to use of 
investigational product), treatment required, and the outcome.  
 
To elicit AEs, simple questions with minimal suggestions or implications should be used as the 
initial questions at all evaluation points during the trial. For example:  
• How have you felt since your last assessment?  
• Have you had any health problems since your last assessment?  
 
The severity of each AE should be categorized as mild, moderate, or severe.  
 
The causality of use of investigational product in relation to the AE will be assessed by the 
Principal Investigator after careful medical consideration and categorized as unrelated, probable, 
or definite.  
 
If an AE occurs, the Investigator will institute support and/or treat as deemed appropriate. If a 
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up until the AE is resolved or stabilized, the subject is lost to follow-up, or there is some other 
resolution of the event.  
 
7.5 
SERIOUS ADVERSE EVENT REPORTING BY THE INVESTIGATOR 
Serious Adverse Event Reporting  
It is the responsibility of the Investigators or their designees to report any event of this nature to 
the sponsor or a designee within 24 hours of the event being brought to the Investigators’ or their 
staffs’ attention. It is also the responsibility of the Investigator to report all SAEs reported at their 
site to their Institutional Review Board (IRB), as required. The Investigator should make every 
attempt to follow all SAEs to resolution. 
 
The following information should be provided when an SAE is reported to the sponsor or 
designee:  
1. Protocol Number  
1. Site Number  
2. Subject Number  
3. Subject Demographic information, including:  
• Date of Birth  
• Sex  
• Race  
4. Investigational product start date  
5. Date of last dose of investigational product  
6. Date investigational product reinitiated (if investigational product interrupted)  
7. SAE information, including:  
• SAE term (diagnosis only; if known or serious signs/symptoms)  
• Description of SAE/narrative  
• Date/time of onset  
• Severity  
• Outcome  
• Date/time of resolution or death (if duration < 24 hours)  
• Relationship to investigational product  
• Action taken with investigational product  
8. Criteria for classifying the event as serious, including whether the SAE:  
• Resulted in death.  
• Was life-threatening  
• Required inpatient hospitalization.  
• Prolonged inpatient hospitalization.  
• Resulted in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions.  
• Was a congenital anomaly/birth defect  


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• Important medical events that may not result in death, were not life-threatening, or 
did not require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.  
 
9. Concomitant medications  
10. Relevant history  
11. Possible causes of SAE other than investigational product  
12. Copy of AE page from the CRF  
 
NOTE: If an SAE occurs in any study involving TRS01 that is unexpected and is determined to 
be related or possibly related to investigational product, all sites will be notified by the sponsor 
and each site should report it to its IRB. 
 
 
 
 


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8 
EXPLORATORY EFFICACY  
Measures of efficacy will be based on Investigator assessments of ACC and flare.
 
 
  
8.1 EFFICACY VARIABLES 
Efficacy of TRS01 will be assessed by evaluation of anterior chamber inflammation by 
Investigator assessment with slit-lamp biomicroscopy,
 
 
Slit-lamp biomicroscopy of the both eyes will be used to examine eye structures at each study 
visit. At Day1/Visit 3 (1-day post-surgery), slit-lamp biomicroscopy will be performed prior to 
IP administration. Areas assessed will include lids, conjunctiva, cornea, anterior chamber cells 
and flare, iris, pupil, lashes, ocular motility, lens and cataract status.   
8.1.1 Anterior Chamber Cells 
Note:  The same investigator must assess and score anterior chamber cells and flare at Visit 3, 
Visit 4, Visit 5 and Visit 6 for an individual subject. 
 
8.1.1.1 Slit-lamp biomicroscopy  
At each visit, slit-lamp biomicroscopy under halogen illumination system will be performed by 
the Investigator on both eyes to assess ACC.  
The following scoring scale for anterior chamber cells will be used: 
 
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
8.1.2 Flare 
The level of flare in the anterior chamber will be assessed by the Investigator at each study visit 
for both eyes, using slit-lamp biomicroscopy and recorded according to the following scale: 
• 0 = None 


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• 1= Mild (trace to clearly noticeable, visible) 
• 2 = Moderate (without plastic aqueous humor) 
• 3 = Marked (with plastic aqueous humor)  
• 4 = Severe (with fibrin deposits and/or clots) 
8.1.3 Subject-Rated Ocular Pain Assessment   
In the clinic, subjects will be handed a laminated card on which is printed the Subject-Rated 
Ocular Pain Assessment. Each subject will be asked to subjectively rate their pain at Visit 3 to 6 
based on this scale. This information will be provided to study personnel to enter into the 
subject’s source documentation.  
The grading scale for pain to be used will be as follows:  
0 = None: Absence of pain.  
1 = Minimal: Presence of mild sensation or discomfort typical of post cataract surgery (e.g., 
diffuse or focal foreign body sensation, mild transient burning or stinging, etc.)  
2 = Mild: Mild, tolerable aching of the eye.  
3 = Moderate: Moderate or more prolonged aching sufficient to have desire to use over the 
counter (OTC) analgesics (e.g. acetaminophen).  
4 = Moderately Severe: More prolonged aching requiring the use of an OTC analgesic  
other than acetaminophen.  
5 = Severe: Aching or throbbing pain that is not tolerable  (e.g. constant or nearly constant sharp 
stabbing pain, throbbing or aching, etc.) requiring prescription analgesics. 
 
 


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9 
STATISTICS 
9.1 
STATISTICAL METHODS 
Continuous measures (e.g., age) will be summarized descriptively by the mean, standard 
deviation, median, minimum and maximum values. Categorical measures will be 
summarized by the number and percent of subjects.The statistical analyses will be performed in 
accordance with the Statistical Analysis Plan. All study data will be listed by treatment, subject 
and visit (as applicable). 
 
9.1.1 Subject Disposition, Demographic and Background Characteristics 
 
Subject disposition, demographic characteristics, and background variables will be 
summarized by treatment group. 
 
9.1.2 Analysis of Safety 
Analysis of safety data will be presented for all subjects. AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA, most current version) and categorized by system 
organ class using preferred terms. Treatment emergent AEs will be listed by study group. 
Treatment related AEs will be tabulated by study group and will be reported by incidence (both 
number of events and number of subjects) with respect to their intensity and relationship to the 
IP. Ophthalmoscopy findings will be summarized descriptively. IOP measurements, VA, and slit 
lamp biomicroscopy will be summarized as safety outcomes. 
 
9.1.3 Analysis of Efficacy 
Efficacy measures will be ACC and flare, as well as Subject-rated Ocular Pain Assessment.  
Both Investigator-rated ACC and flare data will be assessed as a change from baseline (Visit 
3/Day 1) on Days 3, 8 and 15 and a descriptive comparison of the active treatment groups to the 
vehicle group will be performed. 
 
 
  
The Subject-rated Ocular Pain Assessment will be assessed as a change from baseline (Visit 
3/Day1) on Days 3, 8 and 15 and a descriptive comparison of the active treatment groups to the 
vehicle groups will be performed. 
 


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9.2 
SAMPLE SIZE ESTIMATION 
 
 
 
 
9.3 
LEVEL OF SIGNIFICANCE 
Level of significance to be outlined in the Statistical Analysis Plan. 
 
 
9.4 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA 
Any missing, unused, or spurious data will be noted in the final clinical study report. 
 
 
9.5 
PROCEDURE FOR REPORTING DEVIATIONS FROM THE STATISTICAL PLAN  
Any deviations from the statistical analysis plan will be described and a justification given in 
the final clinical study report. 
 
 
9.6 
SUBJECTS TO BE INCLUDED IN THE ANALYSIS 
Intent-to-Treat (ITT) Population: The ITT population will include all randomized subjects 
who took at least 1 dose of investigational product.  The Safety Population will include all 
randomized subjects. 
 
Per Protocol (PP) Population: The PP population is a subset of the ITT population, which will 
include those subjects who did not have significant protocol deviations.  The PP population will 
be defined and documented by the clinical study team and the biostatistician prior to database 
lock and unmasking of the subjects. 
 


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10 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator will permit trial-related monitoring, audits, IRB review, and regulatory 
inspection(s) by providing direct access to source data and documents (such as tests performed as 
a requirement for participation in the study and other medical records required to confirm 
information contained in the case report form such as medical history) to the monitor. 


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11 QUALITY CONTROL 
The progress of the study will be monitored by on-site, written, e-mail, and telephone 
communications between personnel at the study center and the sponsor (or designated monitor). 
The Investigator will allow Tarsius Pharma, Ltd. monitors or designee to inspect all CRFs; 
subject records (source documents); signed informed consent forms; records of investigational 
product receipt, storage, and disposition; and regulatory files related to the study. 
 
 


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12 ETHICS 
12.1 
INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD 
The clinical study protocol, protocol amendments, ICF, and all other appropriate study-related 
documents will be reviewed and approved by an appropriate Independent Ethics Committee 
(IEC) according to local laws and regulations for study sites outside the United States (US), or 
Institutional Review Board (IRB) constituted in accordance with US Title 21 Code of Federal 
Regulations Part 56 for sites in the US. A copy of the letter indicating EC/IRB approval will be 
provided to Tarsius Pharma, Ltd. (Tarsius) prior to study initiation or implementation of each 
relevant protocol amendment.   
 
 
 


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13 AMENDMENTS TO THE PROTOCOL 
Amendments to the protocol shall be planned, documented, and signature authorized prior to 
implementation. 
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor (or its representative). The written amendment must be reviewed and approved 
by the Sponsor and submitted to the IRB for approval. 
Amendments specifically involving change to trial design, risk to subject, increase of dosing or 
exposure, subject number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the appropriate IRB. The amendment will be submitted formally to 
regulatory authorities by the Sponsor as applicable, after IRB approval and specifically when an 
increase of dosing or subject exposure and/or subject number has been proposed; or, when the 
addition or removal of an Investigator is necessitated. 
 
 


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14 DATA HANDLING AND RECORDKEEPING 
All procedures for the handling and analysis of data will be conducted using GCP and will meet 
ICH guidelines and US FDA regulations, for sites in the US, for the handling and analysis of 
data for clinical trials. All personal data will be collected and processed in compliance with the 
requirements arising out of the European General Data Protection Regulation – GDPR 
(Regulation n. 2016/679) and French regulation MR001 2018-153 3 May 2018 
14.1 
DATA QUALITY CONTROL AND REPORTING 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database. Query reports pertaining to data 
omissions and discrepancies will be forwarded to the clinical Investigator and monitor(s) for 
resolution. The study database will be updated in accordance with the resolved query reports. All 
changes to the study database will be documented.  
14.2 
RECORDS RETENTION  
The study center will retain all records related to the study in accordance with local and ICH 
GCP guidelines.  
 


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15 PUBLICATION POLICY 
The institution and Investigators participating in this trial shall have no right to publish or present the 
results of this study without the prior written consent of Tarsius Pharma. 
 
 
 
 
 


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16 APPENDICES 
Appendix 1: Schedule of Assessments 
  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6/ET8 
Assessment 
schedule: 
Screening 
Surgery 
Treatment Period 
  
(-30) to  
(-1) days 
Day 0 
Day 1 – 1-day 
post-surgery 
 
Day 3 
±1 
Day 8 
±1 
Day 15  
±1 
 
  
  
Pre1 
Post2 
  
  
  
Signed and dated 
Informed Consent 
x 
  
 
  
  
  
  
Medical & Ophthalmic 
History  
x 
  
 
  
  
  
  
Demographics 
including Iris color 
x 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
  
x 
  
  
  
  
Concomitant 
Medications 
x 
x 
x 
 
x 
x 
x 
Urine pregnancy test3 
x 
  
  
  
  
  
x 
Randomization criteria 
  
  
x 
  
  
  
  
Subject-Rated Ocular 
Pain Assessment4 
 
 
x 
 
x 
x 
x 
Snellen Distance Visual 
Acuity (VA) by Pinhole 
Method  
x 
  
x 
  
x 
x 
x 
Slit-lamp 
biomicroscopy5 
x 
  
x 
  
x 
x 
x 
Intraocular pressure 
x 
  
x 
  
x 
x 
x 
Dilated 
ophthalmoscopy 
x 
  
  
  
  
  
x 
Self administration eye 
drop assessment 
x 
 
 
 
 
 
 
  
  
  
 
  
 
 
 
Adverse events 
Assessment (AEs)7 
x  
x 
x 
x 
x 
x 
x 
Dispense 
investigational product 
  
  
x 
  
 
x 
  
Collect investigational 
product and compliance 
  
  
  
  
 
x  
x 
1. Visit 3/Day 1 prior to randomization 
2. 40 min ± 10 min post first administration of investigational product 
3. Required for female subjects of childbearing potential 
4. The Subject-Rated Ocular Pain Assessment must be performed prior to any other assessments 


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5. The same investigator must assess and score anterior chamber cells and flare at Visit 3, Visit 
4, Visit 5 and Visit 6 for an individual subject. 
6. May be conducted at select sites, on study eye only 
7. Changes that are expected due to uncomplicated cataract surgery will not be classified as AEs 
but will be recorded 
8. Visit 6 is also the Early Termination visit 
 
 
 


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17 REFERENCES 
1. Aptel F, et al. Management of postoperative inflammation after cataract and complex 
ocular surgeries: a systematic review and Delphi survey. Br J Ophthalmol. 
2017;101:1451–1460.  
2. Deschenes J, et al. International Uveitis Study Group (IUSG) Clinical Classification of 
Uveitis. Ocular Immunology and Inflammation 2008;16:1-2. 
3. Kim T, et al. Safety and efficacy of twice daily administration of KPI-121 1% for ocular 
inflammation and pain following cataract surgery. Clin Ophthalmol. 2019; 13: 69–86. 
4. Mérida S, et al. Macrophages and Uveitis in Experimental Animal Models. Mediators of 
Inflammation. 2015; ID 671417. 
5. Nussenblatt RB.  The natural history of uveitis. International Ophthalmology. 1990; 14: 
303-308. 
6. Sharma S, et al. Automated Analysis of Anterior Chamber Inflammation by Spectral-
Domain Optical Coherence Tomography. Ophthalmology. 2015 Jul;122(7):1464-70. 
7. Thorne JE, Suhler E, Skup M, Tari S, Macaulay D, Chao J, Ganguli A. Prevalence of 
Noninfectious Uveitis in the United States: A Claims-Based Analysis. JAMA 
Ophthalmol. 2016; 1;134(11):1237-1245.