Clinical trial NCT03533244
Conditions: Pterygium
Keywords: Hyperemia
Sponsor: Allgenesis Biotherapeutics Inc.
Start date: 2018-10-11; Completion date: 2019-10-25
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A pterygium is a wing-shaped, benign tissue growth which forms on the surface of the conjunctiva and grows towards the cornea. It can eventually lead to vision impairment. The precise cause of pterygium formation is unknown but new blood vessel growth and fibroblastic structures are characteristics of the disease. AG-86893 is an eye drop being developed to treat hyperemia (redness) and growth of the pterygium.

Hypothesis

1. AG-86893 dosed three times daily for 28 consecutive days has an acceptable safety profile as measured by the incidence and severity of adverse events (AEs) compared with vehicle
2. At least 1 concentration of AG-86893 is effective, as measured by the mean change from baseline in conjunctival hyperemia (redness), compared with vehicle

Detailed description:

Arms: arm 1: One drop, three times daily to the study eye for 28 days arm 2: One drop, three times daily to the study eye for 28 days arm 3: One drop, three times daily to the study eye for 28 days
Interventions: intervention 1: 0.1% AG-86893 Eye Drops intervention 2: 0.3% AG-86893 Eye Drops intervention 3: Vehicle Eye Drops
Intervention descriptions: intervention 1: One drop, three times daily to the study eye for 28 days intervention 2: One drop, three times daily to the study eye for 28 days intervention 3: One drop, three times daily to the study eye for 28 days

Protocol documents:
Prot_002.pdf: 
 
A Multicenter, Prospective, Randomized, Double-
Masked, Phase 2 Study Evaluating the Safety, 
Tolerability, and Efficacy of Topical AG-86893 in 
Patients with Pterygium 
Trial Name: SURPH – a StUdy of the Response to AG-86893 in patients with 
Pterygium Hyperemia 
 
Protocol Number P2-86893-001 
National Clinical Trial Identified 
Number NCT03533244 
Sponsor Allgenesis Biotherapeutics Australia Pty Ltd (“Allgenesis”) 
Australian Sponsor Trial Runners Australia Pty Ltd (“Trial Runners”) 
Level 8, 555 Bourke St 
Melbourne VIC  
Australia 3000 
Funded by Allgenesis Biotherapeutics Australia Pty Ltd 
 
Protocol Version Number:  V3.0 
20 Mar 2019 
 
 
 




 
iii  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
INVESTIGATOR SIGNATURE PAGE 
 
I agree to: 
a) Implement and conduct this clinical study diligently and in strict compliance with the 
protocol, Good Clinical Practice (GCP), and all applicable laws and regulations. 
b) Maintain all information supplied by Allgenesis Biotherapeutics Australia Pty Ltd. and 
Trial Runners Australia Pty Ltd in confidence and when this information is submitted 
to an Institutional Review Board (IRB), Human Research Ethics Committee (HREC), 
Independent Ethics Committee (IEC), or other review board, it will be submitted with 
a designation that the material is confidential. 
 
I have read this protocol, P2-86893-001, Version 3.0 dated 20 Mar 2019, in its entirety and 
agree to all aspects. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
 
 
Name of Facility 
 
 
Location of Facility (City, State) 
 
 
Please return to Trial Runners  
 
 
 


 
iv  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
STUDY TITLE 
A Multicenter, Prospective, Randomized, Double-Masked, Phase 2 Study Evaluating the 
Safety, Tolerability, and Efficacy of Topical AG-86893 in Patients with Pterygium 
SHORT NAME 
SURPH: a StUdy of the Response to AG-86893 in patients with Pterygium Hyperemia 
PROTOCOL NUMBER 
P2-86893-001 
 
STUDY PERSONNEL 
Allgenesis Biotherapeutics Australia Pty Ltd 
Director 
Madhu Cherukury 
madhu.cherukury@allgenesis.com 
+886-8787-1232 
Trial Runners Australia Pty Ltd 
Clinical Project Manager 
Ali Morrish 
alimorrish@trialrunners.com 
+61 413 331 479 
Senior Regional Monitor 
Bennett Maxwell 
bennettmaxwell@trialrunners.com 
+61 401 817 047 
Medical Monitor 
Robert David, MD 
robertdavid@trialrunners.com 
+1 949-246-8368 (mobile) 
Trial Statistician 
Jenny Song 
jennysong@trialrunners.com  
 
SAE EMAIL ADDRESS: SafetyAUS@trialrunners.com 


  
 
v  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
Table of Contents  
SPONSOR APPROVAL AND SIGNATURE PAGE ............................................................................................... ii 
INVESTIGATOR SIGNATURE PAGE .................................................................................................................... iii 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ................................................................................................................................. 1 
1.1 
Synopsis ................................................................................................................................................... 1 
1.2 
Schema ..................................................................................................................................................... 3 
1.3 
Schedule of Activities .............................................................................................................................. 4 
2 
INTRODUCTION .............................................................................................................................................. 5 
2.1 
Study Rationale........................................................................................................................................ 5 
2.2 
Background .............................................................................................................................................. 6 
2.3 
Risk/Benefit Assessment ........................................................................................................................ 8 
2.3.1 
Known Potential Risks ................................................................................................................... 8 
2.3.2 
Known Potential Benefits .............................................................................................................. 9 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................................. 9 
3 
OBJECTIVES AND ENDPOINTS .................................................................................................................. 9 
4 
STUDY DESIGN ............................................................................................................................................. 10 
4.1 
Overall Design ....................................................................................................................................... 10 
4.2 
Scientific Rationale for Study Design ................................................................................................. 11 
4.3 
Justification for Dose ............................................................................................................................. 11 
4.4 
End of Study Definition ......................................................................................................................... 11 
5 
STUDY POPULATION................................................................................................................................... 11 
5.1 
Inclusion Criteria .................................................................................................................................... 11 
5.2 
Exclusion Criteria ................................................................................................................................... 12 
5.3 
Lifestyle Considerations ....................................................................................................................... 13 
5.4 
Screen Failures ...................................................................................................................................... 13 
5.5 
Strategies for Recruitment and Retention .......................................................................................... 14 
6 
STUDY INTERVENTION ............................................................................................................................... 15 
6.1 
Study Interventions Administration ..................................................................................................... 15 
6.1.1 
Study Interventions Description ................................................................................................. 15 
6.1.2 
Dosing and Administration .......................................................................................................... 15 
6.2 
Preparation/Handling/Storage/Accountability .................................................................................... 15 
6.2.1 
Acquisition and Accountability .................................................................................................... 15 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .............................................................. 16 
6.2.3 
Product Storage and Stability ..................................................................................................... 16 
6.2.4 
Preparation .................................................................................................................................... 16 
6.3 
Measures to Minimize Bias: Randomization and Masking .............................................................. 16 
6.4 
Study Intervention Compliance ........................................................................................................... 17 
6.5 
Concomitant Therapy ............................................................................................................................ 17 
6.5.1 
Rescue Medicine .......................................................................................................................... 17 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 18 
7.1 
Discontinuation of Study Intervention ................................................................................................. 18 
7.2 
Participant Discontinuation/Withdrawal From the Study .................................................................. 18 
7.3 
Lost to Follow-Up ................................................................................................................................... 18 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................................ 19 
8.1 
Efficacy Assessments ........................................................................................................................... 19 
8.1.1 
Primary Efficacy Measure ........................................................................................................... 19 
8.1.2 
Secondary Efficacy Measure ...................................................................................................... 19 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
8.1.3 
Exploratory Measures .................................................................................................................. 19 
8.2 
Safety and Other Assessments ........................................................................................................... 19 
8.3 
Adverse Events and Serious Adverse Events ................................................................................... 21 
8.3.1 
Definition of Adverse Events....................................................................................................... 21 
8.3.2 
Definition of Serious Adverse Events ........................................................................................ 21 
8.3.3 
Classification of an Adverse Event ............................................................................................ 21 
8.3.4 
Severity of Event .......................................................................................................................... 21 
8.3.5 
Relationship to Study Intervention ............................................................................................. 21 
8.3.6 
Expectedness ............................................................................................................................... 22 
8.3.7 
Time Period and Frequency for Event Assessment and Follow-Up ..................................... 22 
8.3.8 
Adverse Event Reporting ............................................................................................................ 22 
8.3.9 
Serious Adverse Event Reporting .............................................................................................. 22 
8.3.10 
Reporting Events to Participants ................................................................................................ 23 
8.3.11 
Events of Special Interest ........................................................................................................... 23 
8.3.12 
Reporting of Pregnancy ............................................................................................................... 24 
9 
STATISTICAL CONSIDERATIONS ............................................................................................................. 24 
9.1 
Statistical Hypotheses .......................................................................................................................... 24 
9.2 
Sample Size Determination ................................................................................................................. 24 
9.3 
Populations for Analyses ...................................................................................................................... 25 
9.4 
Statistical Analyses ............................................................................................................................... 25 
9.4.1 
General Approach ........................................................................................................................ 25 
9.4.2 
Analysis of the Primary Efficacy Endpoint ................................................................................ 25 
9.4.3 
Analysis of the Secondary Endpoints ........................................................................................ 26 
9.4.4 
Safety Analyses ............................................................................................................................ 26 
9.4.5 
Baseline Descriptive Statistics ................................................................................................... 26 
9.4.6 
Planned Interim Analyses ........................................................................................................... 26 
9.4.7 
Subgroup Analyses ...................................................................................................................... 26 
9.4.8 
Tabulation of Individual Participant Data .................................................................................. 26 
9.4.9 
Exploratory Analyses ................................................................................................................... 27 
9.4.10 
Pharmacokinetic Analysis ........................................................................................................... 27 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ................................. 27 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .............................................................. 27 
10.1.1 
Informed Consent Process ......................................................................................................... 27 
10.1.2 
Study Discontinuation and Closure............................................................................................ 27 
10.1.3 
Confidentiality and Privacy .......................................................................................................... 27 
10.1.4 
Future Use of Stored Specimens and Data .............................................................................. 28 
10.1.5 
Key Roles and Study Governance ............................................................................................. 28 
10.1.6 
Safety Oversight ........................................................................................................................... 28 
10.1.7 
Clinical Monitoring ........................................................................................................................ 28 
10.1.8 
Quality Assurance and Quality Control ..................................................................................... 29 
10.1.9 
Data Handling and Record Keeping .......................................................................................... 29 
10.1.10 
Protocol Deviations ...................................................................................................................... 31 
10.1.11 
Publication and Data Sharing Policy ......................................................................................... 31 
10.1.12 
Conflict of Interest Policy ............................................................................................................. 31 
10.2 
Additional Considerations..................................................................................................................... 31 
10.3 
Abbreviations ......................................................................................................................................... 31 
10.4 
Protocol Amendment History ............................................................................................................... 32 
11 
REFERENCES................................................................................................................................................ 36 
 


  
 
1  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
STATEMENT OF COMPLIANCE 
This study is to be conducted in accordance with Institutional Review Board (IRB) regulations (United 
States [US] 21 Code of Federal Regulations [CFR] Part 56.103) or applicable Human Research Ethics 
Committee (HREC), or International Ethics Committee (IEC) regulations.  The investigator must 
obtain approval from a properly constituted HREC/IRB/IEC prior to initiating the study and re-
approval or review at least annually.  Allgenesis is to be notified immediately if the responsible 
HREC/IRB/IEC has been disqualified or if proceedings leading to disqualification have begun.  Copies 
of all HREC/IRB/IEC correspondence with the investigator should be provided to Allgenesis. 
 
The investigator should not implement any deviation from or changes to the protocol without 
approval by Allgenesis and prior review and documented approval/favourable opinion from the 
HREC/IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards to 
study participants, or when the changes involve only logistical or administrative aspects of the study 
(e.g., change in monitors, change of telephone numbers). 
 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
A Multicenter, Prospective, Randomized, Double-Masked, Phase 2 
Study Evaluating the Safety, Tolerability, and Efficacy of Topical AG-
86893 in Patients with Pterygium 
Short Name: 
SURPH: a StUdy of the Response to AG-86893 in patients with 
Pterygium Hyperemia 
Study Description: 
Study Hypotheses: 
• 
AG-86893 has an acceptable safety profile as measured by the 
incidence and severity of adverse events (AEs) compared with 
vehicle 
• 
At least 1 concentration of AG-86893 is effective, as measured 
by the mean change from baseline in conjunctival hyperemia, 
compared with vehicle 
Study Design: 
• 
This is a multicenter, randomized (1:1:1), double-masked, 
vehicle-controlled, parallel-group, dose-response (0.1% and 
0.3% AG-86893) study  
• 
Participants will administer a single eye drop of study drug 3 
times daily (TID) for 28 days to the study eye 
• 
The duration of the study is 12 weeks, with 4 weeks of 
treatment with study drug and 8 weeks of follow-up without 
medication 
Objectives: 
Safety Objective:   
• 
Evaluate the safety and tolerability of AG-86893 eye drops in 
participants with pterygium 
Efficacy Objectives:   
• 
Evaluate the dose response of AG-86893 on conjunctival 
hyperemia 
• 
Evaluate the dose response of AG-86893 on pterygium 
vascularity, volume and vessel length (exploratory) 
Pharmacokinetic Objective: 
• 
Determine plasma concentrations of AG-86893 


  
 
2  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
Endpoints: 
Safety Endpoints: 
• 
Changes in findings from vital signs, laboratory tests, 
electrocardiogram (ECG) 
• 
Changes in findings from best-corrected visual acuity (BCVA), 
biomicroscopy, tear film break-up time (TFBUT), lissamine 
green conjunctival staining, ophthalmoscopy 
• 
AEs 
• 
Participant assessment of ocular symptoms, including eye 
dryness, burning/stinging, itching, foreign body sensation, eye 
discomfort, photophobia, and ocular pain 
Efficacy Endpoints:   
• 
Change from baseline in overall conjunctival hyperemia score at 
Day 28 (Primary efficacy endpoint) 
• 
Change from baseline in overall conjunctival hyperemia score at 
Day 7 and Day 56 (Secondary efficacy endpoint) 
• 
Change from baseline in conjunctival hyperemia score in the 
quadrant with the pterygium at Days 7, 28 and 56 (Secondary 
efficacy endpoints) 
• 
Change from baseline in pterygium vascularity at Days 7, 28 and 
56 (Exploratory efficacy endpoints) 
• 
Change from baseline in pterygium volume, as assessed by AS 
OCT, at Days 7, 28 and 56 (Exploratory efficacy endpoints) 
• 
Change from baseline in pterygium vessel length at Days 7, 28 
and 56 (Exploratory efficacy endpoints) 
Pharmacokinetic Endpoint: 
• 
Concentration of AG-86893 in plasma over time 
Study Population: 
Approximately 70 adult male or female participants in good general 
health, with conjunctival hyperemia secondary to pterygium (score of 
≥2 in the quadrant with the pterygium and ≥1 in at least 2 other 
quadrants) will be enrolled 
Phase: 
2 
Description of 
Sites/Facilities 
Enrolling Participants: 
Approximately 12 sites 
Description of Study 
Intervention: 
AG-86893 is a sterile ophthalmic nanosuspension administered as an 
eyedrop.  Participants will administer a single drop of study drug (AG-
86893 vehicle, 0.1% AG-86893, or 0.3% AG-86893) into the study eye 
TID (approximately every 8 hours) for 4 weeks  
Study Duration: 
18 months 
Participant Duration: 
12 weeks from time of enrollment to completion of study 
 
 


  
 
3  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
1.2 
SCHEMA 
 
 
 
Screening
Day -14 to -2
•Informed consent
•Screen potential participants by inclusion and exclusion criteria
•Submit ocular photos OU to central reading center for qualification
Pre-randomization/ On study drug
Day 1
•Review all screening laboratory findings
•Concomitant medications, concurrent procedures, vital signs
•Pregnancy test, ECG, BCVA, IOP
•Confirm that participant meets all inclusion and none of exclusion criteria
•Randomization
•Select study eye; if both eyes qualify, then the eye with higher conjunctival hyperemia score will be study eye
•AS-OCT (at selected sites), ocular photography; submit to reading center
•Biomicroscopy, TFBUT, lissamine green conjunctival staining, ophthalmoscopy 
•Plasma drug monitoring (at selected sites)
•Study drug dispensing and administration
•Participant questionnaire
•AE evaluation
On study drug
Day 7
•Visit conducted as a phone call, or optional in-clinic visit at the discretion of the site Investigator
•Concomitant medications, compliance assessment, concurrent procedures, participant questionnaire
•AE evaluation
•If conducted on-site: Laboratory tests (hematology with differentials, serum chemistry, urinalysis), vital signs, 
ocular assessments (BCVA, ocular photography, AS-OCT [at selected sites], IOP, biomicroscopy)
Day 28 (Week 4)
•Study drug administration; compliance assessment
•Concomitant medications, concurrent procedures, participant questionnaire, physical characteristics, vital signs
•Pregnancy test, ECG
•Laboratory tests (hematology with differentials, serum chemistry, urinalysis)
•Ocular assessments (BCVA, ocular photography [1 hour post-dose], AS-OCT [at selected sites], IOP, 
biomicroscopy, TFBUT, lissamine green conjunctival staining, ophthalmoscopy)
•Plasma drug monitoring (at selected sites)
•AE evaluation
Off study drug
Day 56 (Week 8)
•Concomitant medications, concurrent procedures, participant questionnaire, vital signs
•Ocular assessments (BCVA, ocular photography, AS-OCT [at selected sites], IOP, biomicroscopy, TFBUT, 
lissamine green conjunctival staining)
•Plasma drug monitoring (at selected sites)
•AE evaluation
Off study drug/Exit
Day 84 (Week 12)
•Concomitant medications, concurrent procedures, participant questionnaire, physical characteristics, vital signs
•Pregnancy test, ECG
•Laboratory tests (hematology with differentials, serum chemistry, urinalysis)
•Ocular assessments (BCVA, IOP, biomicroscopy, TFBUT [optional], lissamine green conjunctival staining 
[optional], ophthalmoscopy)
•AE evaluation
On study drug


  
 
4  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
1.3 
SCHEDULE OF ACTIVITIES  
 
Procedures 
Screening 
Day -14 to -
2 
(SCR) 
Enrollment/ 
Baseline 
Visit 1, Day 1  
(V1D1) 
Study Visit 2 
Day 7 ±3 days 
(V2D7) 
* 
Study Visit 3 
Day 28 ±3 
days (V3D28) 
Study Visit 4 
Day 56 ±5 
days (V4D56) 
Final Study 
Visit 5 
Day 84 ±5 
days (V5D84) 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical, smoking, alcohol 
and drug history a 
X 
 
 
 
 
 
Concomitant medication  
X 
X 
X 
X 
X 
X 
Compliance assessment b 
 
 
X* 
X 
 
 
Concurrent procedures 
X 
X 
X 
X 
X 
X 
Participant questionnaire c 
 
X c 
X 
X c 
X 
X 
Physical characteristics k 
X 
 
 
X 
 
X 
Vital signs d 
X 
X 
X* 
X 
X 
X 
Hematology  
X 
 
X* 
X 
 
X 
Serum chemistry 
X 
 
X* 
X 
 
X 
Urinalysis 
X 
 
X* 
X 
 
X 
Urine pregnancy test e 
X 
X 
 
X 
 
X 
ECG (12-lead) 
X 
X 
 
X 
 
X 
BCVA 
OU 
OU 
OU* 
OU 
OU 
OU 
Ocular photography f 
OU 
SE 
SE* 
SE 
SE 
 
AS-OCT g 
 
SE 
SE* 
SE 
SE 
 
IOP 
OU 
OU 
OU* 
OU 
OU 
OU 
Biomicroscopy 
OU 
OU 
OU* 
OU 
OU 
OU 
TFBUT 
 
OU 
 
OU 
OU 
OU h 
Lissamine green staining 
 
OU 
 
OU 
OU 
OU h 
Ophthalmoscopy 
OU 
OU 
 
OU 
 
OU 
Plasma drug monitoring i 
 
X 
 
X 
X i 
 
Randomization 
 
X 
 
 
 
 
Study drug j 
 
X 
 
X 
 
 
AE review and evaluation 
 
X l 
X 
X 
X 
X 
* Study Visit 2 (V2D7) is a phone call follow-up but may be conducted as an optional in-clinic visit at the discretion of the 
Principal Investigator. Asterisked assessments will only be conducted during in-clinic visit 
a) 
Medical history will include history of sun exposure 
b) 
On Day 7, study drug bottle will be weighed and returned if the visit is conducted in-clinic. If the visit is via phone, 
participants will be verbally instructed to maintain compliance and use the provided diary. On Day 28, study drug 
will be collected after administration of last dose and study drug bottles will be weighed 
c) 
Participant questionnaire will be administered prior to study drug administration at Visits 1 & 28 
d) 
Blood pressure, pulse, temperature, and breathing rate  
e) 
Females of childbearing potential only  
f) 
Ocular photography will be submitted to central reading center for assessment of conjunctival hyperemia, 
pterygium vascularity and pterygium vessel length 
g) 
At selected sites, AS-OCT imaging will be performed and submitted to central reading center for assessment of 
pterygium volume 
h) 
Test is optional at Day 84; to be performed if test shows abnormal findings at Day 56 
i) 
At selected sites, blood (10 mL) for plasma drug monitoring will be collected on Day 1 and Day 28 pre-dose and 
post-dose at 0.5 and 1 hour after the morning dose; on Day 56, a single sample will be collected 
j) 
On Day 1, study drug will be dispensed and the first dose will be administered in the clinic after all study-related 
procedures  have been performed.  On Day 28 (the last day of treatment), the morning dose will be administered 
in the clinic prior to all study-related procedures, except the participant questionnaire 
k) 
Height and weight at screening; weight only at other timepoints 
l) 
Participants will be questioned on AEs approximately 1 hour after IP administration 
Additional examinations and unscheduled visits can be included as safety concerns arise. 
AE, adverse event; AS-OCT, anterior-segment optical coherence tomography; BCVA, best-corrected visual acuity; ECG, 
electrocardiogram; IOP, intraocular pressure; OU, both eyes; SE, study eye; TFBUT, tear film break-up time.   
 
 


  
 
5  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Pterygium is a wing-shaped, fibrovascular lesion on the ocular surface that usually originates from 
the nasal bulbar conjunctiva and extends onto the corneal limbus and beyond.  Although pterygium 
can form nasally or temporally, the predominant form occurs at the nasal limbus.  As the disease 
progresses, the lesion distorts the corneal topography, encroaches on the visual axis, and obscures 
the optical center of the cornea, causing visual impairment [1, 2].   
 
The pathogenesis of pterygium is mostly unknown; however, multiple mechanisms have been 
proposed.  These mechanisms include ultraviolet radiation, oxidative stress, cytokines, matrix 
metalloproteinases (MMPs), growth factors, cumulative DNA damage, viral infections, and anti-
apoptotic factors.  Growth factors can induce proliferation and/or migration of epithelial cells, 
fibroblasts, or vascular cells, which contribute to the formation of pterygium.  These include 
epidermal growth factor, heparin-binding growth factor, fibroblast growth factor-2 (FGF-2), nerve 
growth factor, ciliary neurotrophic factor, neurotrophin 4, platelet-derived growth factor (PDGF), 
transforming growth factor-β, vascular endothelial growth factor (VEGF), and insulin-like growth 
factor binding proteins [2-4].  FGF-2 is overexpressed in cultured fibroblasts of pterygium and is 
involved in the corneal healing process and neovascularization [3, 5].  
 
Multiple stimuli, such as ultraviolet radiation, hypoxia, cytokines, and growth factors, may induce 
VEGF expression [2].  VEGF serves as a major proangiogenic factor, which is expressed in tears, 
plasma, and ocular tissues of patients with pterygium [2].  VEGF regulates its tyrosine kinase 
receptors (VEGFR), which increased growth, migration, and survival of the endothelial cells [6].  
Elevated levels of MMPs and VEGF have been reported in the epithelial cells of a pterygium leading 
edge [7].  PDGF may also play a role and mediates the tyrosine kinase receptors (PDGFRβ) in the 
pterygium, which stimulate VEGF transcription and recruit pericytes to neovessels.  Inhibition of the 
PDGF signaling pathway disrupts pericyte recruitment, which results in apoptosis of VEGF signaling 
[6].  
 
Patients with pterygium suffer from dry eye-like symptoms, such as redness, irritation, and 
blurriness.  Patients also have reduced TFBUT [2].  Current treatment for pterygium requires a wait-
and-see observation until encroachment of the cornea, usually prompting treatment with artificial 
tears or lubricants until surgery is required.  Some patients opt for surgical removal early for 
cosmetic reasons.  Antimetabolites, such as mitomycin C, have been used in conjunction with 
surgery to minimize recurrence [1, 8], as have anti-VEGF therapies [9, 10].  However, antimetabolites 
have severe side effects, such as scleral necrosis, corneal perforation, corneal edema, secondary 
glaucoma, corneal calcification, and cataracts [11-14], and anti-VEGF monotherapies have had little 
success in controlling recurrence [15, 16].   
 
Pterygium prevalence rates vary widely across the world, depending on the population and region 
studied.  Pterygium occurs more commonly in tropical regions than in temperate climates.  Incidence 
and prevalence rates are highest in the “pterygium belt,” which ranges from 30° north to 30° south 
of the equator, and lower prevalence rates are found at latitudes >40°.  In tropical regions, up to 
52% prevalence rates can be observed [17-19].  The prevalence rate of pterygium for Caucasians 
residing in urban, temperate climates is estimated at 1.2% [20].  Pterygium occurs in about 2.9% of 
Americans in the US [21].  The pooled prevalence rate of pterygium from 6 studies from China is 
9.9% [22]. 
 


  
 
6  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
Currently, there is no approved drug for pterygium on the market.  The current treatment for 
pterygium is surgery, but recurrence and fibrosis are major sequelae of surgery.  Therefore, medical 
treatment for pterygium is still an unmet medical need.  Allgenesis’ AG-86893 (nintedanib, marketed 
oral drug reformulated as a topical ophthalmic nanosuspension) may fill this void. 
 
The purpose of this study is to evaluate the safety, tolerability, and efficacy of AG-86893 in patients 
with pterygium, and obtain preliminary data on its effect on the vasculature in the 
conjunctiva/pterygium.  The pharmacokinetics of AG-86893 have not been evaluated in humans 
after topical instillation.  Therefore, an objective of this study also includes the characterization of 
the plasma concentrations of AG-86893 following ocular administration.   
 
2.2 
BACKGROUND  
AG-86893 is a reformulation of an oral drug, nintedanib (marketed as Ofev®, indicated for the 
treatment of idiopathic pulmonary fibrosis and non-small cell lung cancer), that binds and inhibits 
the tyrosine kinase found on VEGFR 1-3, PDGFRα and β, and fibroblast growth factor receptor (FGFR) 
1-3 [23] .  AG-86893 binds competitively to the adenosine triphosphate binding pocket of these 
receptors and blocks the intracellular signaling that is crucial for the proliferation, migration, and 
survival of endothelial cells as well as perivascular cells (pericytes and vascular smooth muscle cells), 
and for the proliferation, migration, and transformation of fibroblasts [25, 26].  As such, AG-86893 is 
expected to be effective in inhibiting neovascularization and fibrosis. 
 
Non-clinical AG-86893 studies 
The efficacy of topical ophthalmic administrations of AG-86893 was demonstrated in animal models 
of corneal neovascularization.  Rabbits, whose corneas were sutured with silk threads to induce new 
blood vessel growth, were given topical eye drops, TID for 14 days following suturing (preventative 
model) or for 7 days after new blood vessels had grown (remedial model).  In both studies, AG-
86893 was able to inhibit and regress blood vessels at the doses tested (0.1%, 0.3%, and 1%).   
 
Following a single drop of 0.1% AG-86893 to rabbit eyes, AG-86893 absorbed well into target tissues, 
with a maximum plasma concentration (Cmax) of 821 ng/g in the cornea and 1000 ng/g in the 
conjunctiva.  These concentrations were at least 23 times higher than the half-maximal inhibitory 
concentration (IC50) values for VEGFR and PDGFR.  AG-86893 eliminated from cornea and 
conjunctiva with a half-life (T1/2) of 9 to 13 hours.  AG-86893 was well tolerated in rabbits dosed four 
times daily (QID) to both eyes for 7 days at 0.3%, 0.6%, and 1% dose strengths, and three times daily 
(TID) to both eyes in rabbits and monkeys for 28 days.  The one-month Good Laboratory Practice 
(GLP) ocular toxicology studies in rabbits and monkeys dosed with 0.3%, 0.6%, and 1% dose 
strengths, given to both eyes TID for 28 days showed no mortality or drug-related effects, and ocular 
histopathology examinations showed no adverse effects related to the study drug.  The NOAEL dose 
was identified as 1% TID in both rabbit and monkey. 
 
At the proposed highest clinical dose of 0.3%, the daily area-under-the-plasma concentration-time 
curve (AUC0-24hr) on Day 28 in rabbits and monkeys were 33.0 ng•hr/mL and 3.48 ng•hr/mL, 
respectively.  These values are at least 10 and 98 times lower, respectively, than that observed  
(AUC0-24hr of 342 ng•hr/mL) in humans with the reference listed drug (RLD) after oral dosing of 150 
mg twice daily for 28 days, which showed no dose-limiting toxicities [27].  The safety margin 
increases to 20 to 196-fold, when taking into account that the planned human study will dose only 1 
eye.     
 
 
Refer to the Investigator’s Brochure [28] for details on these non-clinical studies.   
 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
Clinical nintedanib studies 
The safety and tolerability of orally administered nintedanib have been well characterized by the 
Innovator for the reference listed drug (RLD) nintedanib (refer to the Investigator’s Brochure for 
details [28]).  
 
In a Phase 1 study following daily oral doses of nintedanib 50 mg (N = 2) and 100 mg (N = 1) and BID 
oral doses of nintedanib 150 mg (N = 6) for 29 days to patients with solid tumors, no dose-limiting 
toxicities were observed [27].   
 
Study P2-86893-001 is the first clinical study with topical AG-86893. With 24 participants dosed in 
this study (10 completed Day 84 follow-up and an additional 7 completed Day 28 treatment), the 
data suggest a favourable safety profile: 0 serious AEs (SAEs) and 9 AEs were reported, 7 of which 
were deemed unrelated to AG-86893. One AE was deemed possibly related to the product (“watery, 
heavy feeling in the eye” occurring 5 days after treatment commencement and resolving 4 days 
later). The final AE was determined by the PI to be related to AG-86893 (“yellow stained 
conjunctiva” occurring 14 days after treatment commencement and resolving 2 months after 
treatment cessation). Both AEs resolved without any treatment. 
 
Pharmacokinetic nintedanib studies 
Absorption:  Nintedanib reached Cmax between 1 and 4 hours following 150 mg oral doses of capsules 
(Table 2-1, Table 2-2, and Table 2-3).  The oral bioavailability of nintedanib in humans is roughly 5%.  
Exposures increased by approximately 20% in fed conditions [23] .  
 
Table 2-1 
Pharmacokinetic Parameters Following Twice Daily Oral Dosing of Nintedanib for 
14 Days to Patients With Idiopathic Pulmonary Fibrosis 
Dose 
N 
Cmax,ss 
(ng/mL) 
AUCτ,ss 
(ng•hr/mL) 
Tmax,ss 
(hr) 
T1/2 
(hr) 
BID x 14 days 
100 
4 
20.0 
115 
3.4 
23.4 
150 
9 
39.7 
218 
3.9 
27.5 
AUCτ,ss, area under the plasma concentration-time curve at steady state over a uniform dosing interval tau; BID, twice daily; 
Cmax,ss, maximum plasma concentration at steady-state; T1/2, half-life; Tmax,ss, time to reach maximum plasma concentration 
at steady-state. 
Source: Ogura et. al., 2015 [30] 
 
Table 2-2 
Pharmacokinetic Parameters Following Once Daily or Twice Daily Oral Dosing for 
29 Days of Nintedanib in Patients With Solid Tumors 
Dose 
N 
Cmax,ss 
(ng/mL) 
AUCτ,ss 
(ng•hr/mL) 
Tmax,ss 
(hr) 
T1/2 
(hr) 
QD x 29 days 
50 
1 
8.22 
32.1 
3.07 
14.7 
100 
1 
40.8 
207 
2.00 
11.8 
200 
8 
35.4 
223 
1.98 
15.3 
250 
6 
58.6 
479 
2.53 
13.7 
300 
3 
50.5 
482 
3.00 
14.1 
BID x 29 days 
150 
6 
34.8 
171 
1.03 
16.3 
150 + 200 
6 
48.0 
260 
2.13 
15.6 
200 
6 
44.9 
303 
2.72 
19.0 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
Dose 
N 
Cmax,ss 
(ng/mL) 
AUCτ,ss 
(ng•hr/mL) 
Tmax,ss 
(hr) 
T1/2 
(hr) 
250 
11 
44.2 
226 
2.08 
16.7 
300 
3 
68.6 
366 
2.00 
12.9 
AUCτ,ss, area under the plasma concentration-time curve at steady state over a uniform dosing interval tau; BID, twice daily; 
Cmax,ss, maximum plasma concentration at steady-state; QD, once daily; T1/2, half-life; Tmax,ss, time to reach maximum 
plasma concentration at steady-state. 
Source: Mross et.al, 2010 [27] 
 
Distribution:  In humans, the volume of distribution following an intravenous dose was 1050 L and 
was highly protein bound (serum albumin).  Nintedanib is preferentially distributed into plasma [23]  
Metabolism:  As with the animal species, the major metabolite of nintedanib is the hydrolytic 
cleavage product, BIBF 1202 (free acid), and its glucuronide.  Minimal cytochrome P450-dependent 
metabolites were found in human plasma.  The major metabolites were not considered active at 
clinically relevant concentrations [23, 31]. 
Table 2-3 
Pharmacokinetic Parameters of Nintedanib and Its Metabolites Following a Single 
Oral 100 mg Dose of Nintedanib to Healthy Volunteers 
Analyte 
N 
Cmax 
(ng/mL) 
AUC 
(ng•hr/mL) 
Tmax 
(hr) 
T1/2 
(hr) 
Single Dose 
Nintedanib 
12 
8.4 
56.2 
3.0 
11.7 
BIBF 1202 
10 
5.7 
42.4 
5.0 
3.2 
BIBF 1202 
glucuronide 
12 
11.1 
630 
10.0 
36.8 
AUC, area under the plasma concentration-time curve; Cmax, maximum plasma concentration; T1/2, half-life; Tmax, time to 
reach maximum plasma concentration.  
Source: Dallinger et. al, 2016 [32] 
 
Following a 100-mg dose of 14C-nintedanib in humans, BIBF 1202 free acid and its glucuronide 
accounted for 32% and 47% of total radioactivity [23, 31]. 
 
Elimination:  Total plasma clearance of nintedanib was 1390 mL/min, with over 90% of the drug 
excreted in feces/biliary excretion.  The plasma T1/2 was between 10 and 15 hours [23, 31] . 
 
2.3 
RISK/BENEFIT ASSESSMENT 
 
2.3.1 KNOWN POTENTIAL RISKS  
Risks of long-term (52-week) orally dosed nintedanib are described in the Ofev package insert and 
summarized in the AG-86893 Investigator’s Brochure [28].  In brief, there was a dose-dependent 
increase in liver enzyme levels in patients.  Liver enzyme increases were reversible with dose 
modification or discontinuation and were not associated with clinical signs or symptoms of liver 
injury.  The most common side effects were gastrointestinal irritation (diarrhea, nausea, abdominal 
pain, vomiting, and decreased appetite), headache, weight decrease, and hypertension [33].  As with 
most anti-VEGF therapies, arterial thromboembolic events have been reported. 
 
For AG-86893, the risk to the participant is expected to be low.  In this study, the highest proposed 
dose of 0.3% given TID will expose participants to 0.36 mg of nintedanib per day (3 mg/mL x 0.040 
mL x 3), which is over 800 times less than what has been approved for the RLD (300 mg; 150 mg 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
BID).  Furthermore, the duration of treatment (28 days) is similar to the above Phase 1 study, in 
which no dose-limiting toxicities were observed at the 150 mg BID dose [27]. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
The commercial product (Ofev®; nintedanib ethanesulfonate) has been approved for the treatment 
of idiopathic pulmonary fibrosis due to its antifibrotic mechanism, and for non-small cell lung cancer, 
due to its antiangiogenic mechanism. 
 
For AG-86893, there is potential for the reduction of conjunctival hyperemia with short-term use, as 
well as reduction of new blood vessel growth and fibrosis that may contribute to the growth of the 
pterygium with longer-term use. 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
This study incorporates standard laboratory assessments as well as general and ocular examinations 
to detect risk to participants.  Because the potential systemic and ocular risks to 4 weeks’ exposure 
of AG-86893 are readily detectible and limited, the opportunity to assess the potential benefit for an 
unmet need is justified. 
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Safety 
 
 
• 
Evaluate the safety 
and tolerability of 
topical eye drops of 
AG-86893 in 
participants with 
pterygium 
 
• 
Changes in findings detected by 
vital sign assessment, 
laboratory tests, ECG 
• 
Changes in findings detected by 
BCVA testing, biomicroscopy, 
TFBUT, lissamine green 
conjunctival staining, 
ophthalmoscopy 
• 
Adverse events 
• 
Participant assessment of 
ocular symptoms via 
questionnaire, including eye 
dryness, burning/stinging, 
itching, foreign body sensation, 
eye discomfort, photophobia, 
and ocular pain 
• 
These tests are standard 
investigations of general systemic 
health 
• 
These tests comprise a standard 
eye examination to investigate 
ocular health 
• 
Severity and causality of AEs are 
standard endpoints 
• 
Because pterygia may be 
associated with ocular symptoms, 
it will be important to investigate 
whether treatment has any effect 
on these symptoms 
Efficacy 
 
 
• 
Evaluate the dose 
response of 
AG-86893 on 
conjunctival 
hyperemia 
• 
Change from baseline in overall 
conjunctival hyperemia score at 
Day 28 (primary efficacy 
endpoint) 
• 
Change from baseline in overall 
conjunctival hyperemia score at 
Day 7 and Day 56 (secondary 
efficacy endpoint) 
• 
Change from baseline in 
conjunctival hyperemia score in 
the quadrant with the 
• 
Red eye (e.g. Conjunctival 
hyperemia) is a chief complaint in 
participants with pterygia.  The 
assessment will be done as a sum 
of all 4 quadrants to ensure 
appropriate benefit: risk (i.e., no 
increase in hyperemia in one 
quadrant, while decrease in 
quadrant with pterygium) 
• 
This will be assessed to 
differentiate overall conjunctival 


  
 
10  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
pterygium at Days 7, 28 and 56 
(secondary efficacy endpoint) 
hyperemia from that of the 
quadrant with the pterygium 
Pharmacokinetic 
 
 
• 
Determine plasma 
concentrations of 
AG-86893 
• 
Plasma concentrations of AG-
86893  
• 
Plasma concentrations of AG-
86893 will be monitored to 
evaluate the amount of systemic 
exposure following ocular dosing 
Exploratory  
 
 
• 
Evaluate the dose 
response of AG-
86893 on pterygium 
vascularity 
• 
Evaluate the dose 
response of 
AG-86893 on 
pterygium volume 
• 
Evaluate the dose-
response of AG-
86893 on pterygium 
vessel length  
• 
Change from baseline in 
pterygium vascularity at Days 7, 
28 and 56 
• 
Change from baseline in 
pterygium volume, as assessed 
by AS-OCT, at Days 7, 28 and 56 
• 
Change from baseline in 
pterygium vessel length at Days 
7, 28 and 56 
• 
Pterygium vascularity is a known 
factor to affect hyperemia 
• 
While the ultimate goal of 
treatment is to reduce the volume 
of the pterygium lesion, this is 
likely to only be accomplished with 
longer dosing than what is 
provided in this study 
• 
Findings from a rabbit corneal 
neovascularization study 
demonstrated regression of vessel 
length in the pterygia over 7 days 
of treatment 
AS-OCT, anterior-segment optical coherence tomography; BCVA, best-corrected visual acuity; ECG, electrocardiogram; 
TFBUT, tear film break-up time. 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
The clinical hypotheses for this study are: 
• 
AG-86893 has an acceptable safety profile, as measured by the incidence and severity of 
AEs compared with vehicle 
• 
At least 1 concentration of AG-86893 is effective, as measured by the mean change from 
baseline in overall conjunctival hyperemia compared with vehicle 
 
This will be a Phase 2, multicenter, prospective, randomized, parallel-group, double-masked study 
evaluating the safety, tolerability, and efficacy of AG-86893 topical eye drops in participants with 
pterygium who are at least 18 years of age with overall conjunctival hyperemia score ≥2 in the study 
eye.  A central reading center will assess conjunctival hyperemia from ocular photography at the 
screening visit to qualify participant eligibility; in addition, the reading center will assess subsequent 
visits for conjunctival hyperemia, pterygium vascularity, pterygium volume and vessel length in a 
masked fashion, to determine efficacy. 
 
The study will have 3 treatment groups—vehicle, 0.1% AG-86893, and 0.3% AG-86893—with 
participants being randomly assigned in a 1:1:1 ratio to study drug.  Study drug will be administered 
only to the selected study eye, until the Day 28 visit.  Compliance with the study drug regimen will 
be estimated by weighing both eye drop bottles at Day 7 (if visit conducted in-clinic) and again at 
Day 28. 
 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
There will be 6 possible clinic visits, including a 14-day screening period (from Day -14 to -2), 
followed by a treatment/observation period (Day 1, Day 7 [may be conducted as a phone follow-up], 
and Day 28), and 2 post-treatment follow-up visits for safety monitoring (Day 56 and Day 84). 
 
Collection of anterior-segment optical coherence tomography (AS-OCT) imaging will be done at sites 
with the requisite equipment and certified by the reading center.  Plasma drug monitoring will be 
done at selected sites with the required facilities. 
 
Primary database lock will occur after all participants exit the study on Day 84.  Assessment of 
safety, tolerability, efficacy, and plasma concentrations of AG-86893 requires participants to 
participate for 12 weeks from Baseline to Study Exit (Day 84), plus the 2- to 14-day screening period.   
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
A placebo control is the gold standard clinical trial design appropriate for conditions without any 
approved treatments so that variability in the disease can be assessed.  The use of vehicle of AG-
86893 has the potential to provide some relief to the participant because of actions similar to an 
artificial tear, lubricating the ocular surface and reducing irritation.  However, the alternative of an 
open-label study without a control group introduces too many biases.   
 
It is essential to investigate the dose-response of the proposed treatment in order to select a dose 
for further study to confirm any potential treatment effects.   
 
4.3 
JUSTIFICATION FOR DOSE 
The doses selected in this study were based on the doses that were found to be effective in 
inhibiting new blood vessel growth on the cornea in a rabbit model.  In that study, doses of 0.1%, 
0.3%, and 1% were equally effective in inhibiting the blood vessel growth caused by suture 
placement.  Rabbits dosed QID bilaterally for 7 days at doses of 0.3%, 0.6%, and 1% showed no signs 
of discomfort or ocular irritation.  These doses were tested for safety and ocular histopathology in a 
28-day GLP rabbit and monkey study after topical TID dosing of AG-86893.  All the doses tested were 
safe and 1% identified as the NOAEL (no-observed-adverse-effect-level) dose.  It is therefore 
expected that the doses of 0.1% and 0.3% administered TID will be tolerable and safe, and that at 
least 1 concentration will be effective in reducing hyperemia in participants with pterygium. 
 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the 
study, including the last visit or the last scheduled procedure shown in the Schedule of Assessments 
(Section 1.3).  Furthermore, the study will be completed when all participant’s images have been 
assessed by central reading center. 
 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Signed an IRB-/IEC-approved informed consent form (ICF) prior to any study-specific 
procedures 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
2. Willingness to comply with the study procedures and study drug administration and to 
return for all study visits 
3. Male or female, 18 years of age or older 
4. Body mass index between 18 and 38 kg/m2, inclusive 
5. Females of childbearing potential must have a negative pregnancy test at baseline and must 
be on established, adequate contraception (e.g., oral contraceptive or bilateral tubal 
ligation) and males must use condoms if their partner is of childbearing potential and their 
female partner should also use an additional effective means of contraception (e.g., oral 
contraceptive or bilateral tubal ligation), or they must agree to abstain from sexual 
intercourse with a female partner for the duration of the study; contraception should be 
continued for 3 months after the last dose.  Females of non-reproductive potential are 
permitted to enter the study without the need for a pregnancy test.  Non-reproductive 
potential is defined as one or more of the following: (1) women who are postmenopausal 
(≥47 years of age who have been amenorrheic for at least 12 consecutive months), (2) 
women who do not possess a uterus (e.g., previous hysterectomy), (3) women who do not 
possess both ovaries (e.g., previous bilateral oophorectomy), and (4) women with a bilateral 
tubal ligation 
6. Good health with no clinically significant findings based on the medical history, ECG, vital 
signs, blood chemistry, hematology, and urinalysis findings, as determined by the 
investigator.  Abnormal laboratory results must be determined as not clinically significant by 
the investigator 
7. Presence of pterygium, extending beyond the limbus, with associated conjunctival 
hyperemia in the quadrant containing the pterygium of grade ≥2 at screening, as assessed by 
the central reading center based on ocular photography using a 5-point scale of 0 = none, 1 = 
mild, 2 = moderate, 3 = severe, and 4 = very severe, AND a conjunctival hyperemia score of 
≥1 in at least 2 of the remaining quadrants of the same eye at screening (study eye).  If both 
eyes are affected and meet the inclusion criteria, the eye with the higher overall hyperemia 
score will be used as the study eye. If both eyes are eligible and have the same hyperemia 
score, the right eye will be selected as the default study eye 
 
5.2 
EXCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must not meet any of the following 
criteria: 
Ocular criteria 
a) 
BCVA in either eye of 35 ETDRS letters or worse (Snellen equivalent of 20/200) at screening or 
baseline 
b) 
History or presence of any ocular diseases other than pterygium or its sequelae, including 
neoplasia  
c) Diagnosis of ocular hypertension or glaucoma requiring use of intraocular pressure (IOP)-
lowering medication 
d) Use of contact lenses during the study in the study eye 
e) Aphakia or torn posterior capsule in the study eye  
f) History or evidence of the following surgeries in the study eye at any time, unless specified: 
a. 
Pterygium removal 
b. 
Corneal transplant 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
c. 
Glaucoma surgery, shunt, or microstent 
d. 
Refractive surgery 
e. 
Surgery on ocular muscles 
f. 
Any retinal surgery 
g. 
Cataract surgery within 3 months or yttrium aluminium garnet (YAG) 
capsulotomy within 1 month prior to baseline 
g) Current use of any ophthalmic medications in the study eye other than artificial tears or ocular 
decongestants; ocular decongestants must be washed out for a minimum of 7 days prior to 
baseline and use is prohibited 2 days before any study visit 
h) History of any intravitreal, subconjunctival medication in the study eye within 12 months prior to 
baseline 
 
Non-ocular criteria 
1. Presence of a non-healing/oversize wound, ulcer, or fracture 
2. Inadequate liver function, as demonstrated by total bilirubin >1.5 × upper limit of normal 
(ULN) at screening (unless participant has a documented history of Gilbert’s syndrome),  
aspartate transaminase (AST) and alanine transaminase (ALT) ≥2.5 × ULN or serum albumin 
<3.5 g/dL 
3. Any malignancy other than adequately treated nonmelanomatous skin cancer, or adequately 
treated prostate cancer in men over the age of 70 
4. Any uncontrolled systemic disease, including cardiac disease; hypertension; diabetes 
mellitus; mental, neurological, respiratory, gastrointestinal, renal, or hepatic dysfunction; 
infectious disease; or malignancy 
5. Use of any immunosuppressive therapy during the study  
6. Use of marijuana during the study or within 2 days prior to screening   
7. Any disease or condition that the medical monitor or the investigator believes will impact 
the participant's ability to adhere to the study schedule or may confound the results 
8. Participation in any investigational study within 30 days prior to baseline or exposure to an 
investigational drug must be fully washed out (at least 5 half-lives) 
9. Donation of ≥450 mL (e.g., 1 unit) of blood or blood products within 56 days prior to baseline 
(for participants participating in the plasma concentration blood draw), or plans to donate 
blood during the study (all participants) 
10. Pregnancy, plans for pregnancy, or breastfeeding during the study 
11. History of active alcohol or substance abuse as defined by Diagnostic and Statistical Manual 
of Mental Disorders, Fifth Edition (DSM V) criteria 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Not applicable. 
 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
assigned to the study intervention or entered into the study.  A set of screen failure information is 


  
 
14  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
required to ensure transparent reporting of screen failure participants, to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements, and to respond to queries from 
regulatory authorities.  This information includes participants’ demographic information, screen 
failure details, eligibility criteria, and any SAEs. 
 
In some cases, individuals who do not meet the criteria for participation in this trial (screen failure) 
may be rescreened (e.g., a hypertensive individual with high blood pressure due to missed 
medication on the day of the screening visit, or an individual willing to discontinue use of ocular 
decongestants for the duration of the study).  Rescreened participants should be assigned the same 
participant number as for the initial screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Sites will recruit participants from their database as well as locally.  Any advertisement must be 
approved by the IRB/IEC.  Refer to the Manual of Procedures (MOP) for additional information. 
 
 
 


  
 
15  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTIONS ADMINISTRATION 
 
6.1.1 STUDY INTERVENTIONS DESCRIPTION 
The active study treatment will be the investigational agent AG-86893, which is a topical ophthalmic 
nanosuspension formulation of nintedanib (Ofev®, Boehringer Ingelheim), delivered at 
concentrations of either 0.1% or 0.3%, depending on randomized treatment assignment.  The 
control treatment will be AG-86893 vehicle.  All 3 study interventions will be delivered to the study 
eye as a single eye drop TID, using the provided white, opaque, low-density polyethylene (LDPE) eye 
dropper bottle.   
 
6.1.2 DOSING AND ADMINISTRATION 
Once study entry procedures have been completed (see Section 4.1), the independent drug 
administrator not affiliated with the assessment of the participant will obtain the randomization 
assignment and drug kit number from the Interactive Web Response System (IWRS).  The 
independent (unmasked) drug administrator will vigorously shake the eye dropper bottle for 10 
seconds prior to administration to the study eye. 
 
A single eye drop (~40 μL eye drop) of AG-86893 or AG-86893 vehicle control will be applied TID 
(morning, afternoon, and evening, approximately 8 hours apart) to the study eye until the Day 28 
visit.  A single study treatment will be administered to each participant in this study by the 
independent drug administrator on the morning of the clinic visits on Day 1 and Day 28.  The 
participant will be instructed on Day 1 how to self-dose using the eye dropper bottle for the 
remaining doses with written instructions provided on a participant dosing diary. Two bottles of AG-
86893 or vehicle will be provided to each participant at Day 1; participants will be instructed to bring 
both of these bottles with them when they return to the clinic for the Day 7 (optional) and Day 28 
visits, or to any unscheduled visits during this period. Participants will be required to remain in the 
clinic for assessment of Adverse Events for at least 1 hour after the first administration on Visit 1 
(V1D1). 
 
Study drug should be consistently dosed approximately 8 hours apart on each day (e.g., at 07:00, 
15:00, and 23:00).  Specific instructions for participants to self-dose are provided in the MOP, 
including instruction that in the event of a forgotten/delayed dose, the delayed dose is to be skipped 
if there is less than 2 hours until the next scheduled dose.   
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
The investigator designee or independent drug administrator (not directly involved in the 
assessment of study participants) must keep an accurate accounting of the number of investigational 
units received from Allgenesis, and the number of units returned to Allgenesis or designee during 
and at the completion of the study.  A detailed inventory must be completed for the study drug.  
 
The used study bottles from each participant will be weighed at the Day 7 (if conducted in-clinic) and 
Day 28 visits to estimate compliance; weight will be recorded on the electronic Case Report Form 
(eCRF).  Participants will be reminded to return both of their study bottles at the Day 28 visit. 
 
All clinical study drug and/or supplies will be returned to Allgenesis or its designee for destruction. 


  
 
16  
P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
 
 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
AG-86893 is a topical ophthalmic nanosuspension formulation of nintedanib.  AG-86893 is yellowish, 
while AG-86893 vehicle is clear. 
 
Each active study treatment bottle contains AG-86893 (~5 mg or 15 mg), tyloxapol, hypromellose 
(HPMC), benzalkonium chloride, sodium chloride, ethylenediaminetetraacetic acid (EDTA) disodium, 
monobasic potassium phosphate, and sodium hydroxide, at pH 7.0.   
 
Each control treatment bottle contains AG-86893 vehicle, which contains tyloxapol, HPMC, 
benzalkonium chloride, sodium chloride, EDTA disodium, monobasic potassium phosphate, and 
sodium hydroxide, at pH 7.0. 
 
AG-86893 and AG-86893 vehicle will be packaged in white, 5-mL LDPE ophthalmic bottles and 
supplied by Allgenesis or designee.  Study medication will be provided in 2 separate bottles.  All 
study medications will be labeled with the protocol number and medication kit numbers.  The label 
will also specify the storage conditions (room temperature) and state that the study medication is 
limited to investigational use. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
The study drug must be stored at room temperature (15° – 30°C). Temperature will be monitored 
while stored at sites, and participants in the P2-86893-001 trial will be instructed not to expose the 
product to refrigerated or frozen temperatures, and that bottles should be protected from direct 
sunlight.   
 
6.2.4 PREPARATION 
Not applicable.   
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND MASKING 
Prior to initiation of study treatment, randomization will occur by site personnel via the IVRS or IWRS 
once it is confirmed that the participant meets the final study entry criteria (see Section 4.1).  The 
IVRS/IWRS will provide the participant identification number used on all study documents and will 
be used to manage the randomization and treatment assignment based on a central randomization 
scheme prepared by Trial Runners.  Study drug will be labeled with medication kit numbers, and the 
IVRS/IWRS will provide each site with the specific medication kit number(s) for each randomized 
participant at the time of randomization.  Sites will dispense study drug according to the IVRS/IWRS 
instructions.  Sites will receive the IVRS/IWRS confirmation notifications for each transaction.  All 
notifications are to be maintained with the study source documents. 
 
To prevent possible unmasking, access to study drug kits will be limited to staff not involved in the 
care and evaluation of participants or the handling of data throughout the study.  To maintain the 
double mask, an independent drug administrator not affiliated with the care of the participant will 
apply the single eye drop to the participant at the Day 1 and Day 28 visits.  Since AG-86893 and 
vehicle are different colors, it will be important to advise the participant to not discuss what the 
medication looks like.  In addition, when the used study medication is returned at the Day 28 visit (2 
bottles per participant), the unmasked drug administrator should be responsible for collecting and 
weighing the bottles. 
 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
Masking of individual participant treatment assignments will be maintained throughout the study for 
all participants and required site personnel until the database is locked for the final analysis.  If it is 
necessary for the safety and appropriate treatment of a participant, the treatment assignment can 
be unmasked by the site via the IVRS/IWRS.  When possible, the medical monitor should be notified 
prior to the unmasking, and the reason for breaking the mask will be documented in the source 
documentation.  The investigator should inform the medical monitor of the unmasking if there is no 
notification prior to the unmasking.  The treatment assignment for the participant can be 
determined by designated site personnel calling into the IVRS/IWRS via password-protected access.  
The reason for breaking the code should be recorded in the participant’s source documents. 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Participants who are inadvertently enrolled, despite significant deviation from protocol-specified 
inclusion/exclusion criteria, will be discontinued from participation in the study.  Participants will be 
scheduled for follow-up visits and followed for 8 weeks post-treatment for safety per protocol. 
 
At each post-baseline visit, participants will be questioned as to concomitant medications, as well as 
exclusionary criteria to ensure protocol compliance.  Urine drug screens will be performed during 
the screening visit (Day -14 to Day -2), at the Days 7 (if conducted in-clinic), 28, and 84 visits for all 
participants.  Dosing compliance will be assessed when the participant returns the study drug (both 
bottles) to the investigator, at which time the study drug bottles will be weighed. 
 
6.5 
CONCOMITANT THERAPY 
Ocular medications, other than artificial tears and ocular decongestants, are prohibited.  Ocular 
decongestants must be washed out for a minimum of 7 days prior to baseline and use is prohibited 2 
days before any study visit.  Topical drops for examination procedures, such as anesthetics, dilating 
agents, fluorescein and lissamine green, are permitted. 
 
Systemic medications that may interfere or confound the evaluation of conjunctival hyperemia are 
prohibited and should be washed out in the 7 days prior to baseline.  Washout should not 
commence until after written informed consent has been obtained.  Refer to the MOP for examples 
of prohibited medications. 
 
Participants will be instructed on all study procedures and requirements as appropriate.  Participants 
will be instructed on use of permissible topical eye drops and on prohibited medications.   
 
Medication considered necessary for the participant's welfare may be given at the discretion of the 
investigator.  Participants should be instructed to maintain a stable dose of chronic medications 
during the study whenever possible.  All concurrent medications (prescription, over-the-counter and 
supplements), adjunct therapies, and concurrent procedures will be recorded on the appropriate 
eCRF page. 
 
The decision to administer a prohibited medication/treatment is done with the safety of the study 
participant as the primary consideration.  Whenever possible, the medical monitor should be 
notified before the prohibited medication/treatment is administered. 
 
6.5.1 RESCUE MEDICINE 
As there is no pharmacologic treatment for pterygium, no rescue medication is proposed in this 
study.  Investigators may direct participants to the use of eye drops (e.g., artificial tears, 
decongestant drops, etc.) as appropriate, to alleviate any symptoms related to the participant’s 
condition.   
 
 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
The investigator may discontinue the study drug at any time if there is a safety concern.  If the study 
drug is discontinued, then the participant will early exit from the study.  If the participant has 
discontinued the study drug because of an SAE related to the study drug, that participant should be 
monitored for at least 30 days or until the SAE has resolved or stabilized.   
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to discontinue the study at any time, for any reason, and without prejudice to 
further treatment.  The investigator may remove a participant if, in the investigator’s judgment, 
continued participation would pose unacceptable risk to the participant or to the integrity of the 
study data.  Reasons for removal or withdrawal might include: 
• 
Withdrawal of consent 
• 
Administrative decision by the investigator or Sponsor 
• 
Significant protocol deviation 
• 
Participant noncompliance, or other significant protocol deviation 
• 
Safety concern by the investigator or Sponsor 
• 
Lost to follow-up 
With the exception of withdrawal of consent, participant withdrawal should be discussed with the 
Medical Monitor, when possible, prior to withdrawing.  Notification of early participant 
discontinuation from the study and the reason for discontinuation will be made to Allgenesis and will 
be clearly documented on the appropriate eCRF.  If a participant discontinues prior to completing 
the study, the procedures outlined for the Exit visit should be performed at the last visit the 
participant attends.   
 
7.3 
LOST TO FOLLOW-UP 
At any point during the trial, if a participant fails to return for a scheduled visit and is unable to be 
contacted by the site staff, he or she will be considered lost to follow-up. This does not include a 
single missed visit of which the site was notified or a missed visit with subsequent contact from the 
participants indicating an intention to continue on the study.  The following actions must be taken if 
a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within the 
visit window and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study.  If 
this make-up visit is outside the allowable window, a protocol deviation will be recorded 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods).  These contact attempts should be documented in the participant’s 
medical record or study file 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up, and a protocol 
deviation will be recorded 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
Refer to the MOP for details on the efficacy measures. 
8.1.1 PRIMARY EFFICACY MEASURE 
• 
Overall conjunctival hyperemia.  Digital slit-lamp photos will be captured and submitted to 
the central reading center for assessment.  Conjunctival hyperemia will be measured in 4 
quadrants of the ocular surface and graded using a 5-point scale of 0 = none, 1 = mild, 2 = 
moderate, 3 = severe, and 4 = very severe.  The overall conjunctival hyperemia is the 
average of the score of each quadrant 
 
8.1.2 SECONDARY EFFICACY MEASURE 
• 
Localized pterygium conjunctival hyperemia.  Using the above digital slit-lamp photos and 
grading, the localized pterygium conjunctival hyperemia is the score of the quadrant with 
the pterygium as assessed by the central reading center. 
 
8.1.3 EXPLORATORY MEASURES 
• 
Pterygium vascularity.  Using the above digital slit-lamp photos, the vascularity of the body 
of the pterygium will be quantified by pixel analysis as assessed by the central reading 
center. 
• 
Pterygium volume.  AS-OCT images will be captured at selected sites and submitted to the 
central reading center for assessment of pterygium volume 
• 
Pterygium vessel length.  Using the above digital slit-lamp photos, the length of the vessels 
within the pterygium will be assessed by the central reading center 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
Findings that are of clinical significance will be recorded as AEs on the eCRF.  Refer to the MOP for 
details on the assessments. 
• 
Demographics. Includes age, gender, race, ethnicity and lifestyle questions (sun exposure; 
alcohol, drug and contraceptive use) 
• 
Physical characteristics.  Includes height and weight measured at screening; weight only at 
other timepoints indicated 
• 
Pregnancy testing.  Will be performed using a human chorionic gonadotropin pregnancy 
urine dipstick test 
• 
Vital signs.  Includes pulse rate, blood pressure, respiratory rate and temperature 
• 
Hematology.  Includes hematocrit, hemoglobin, mean corpuscular hemoglobin, mean 
corpuscular hemoglobin concentration, mean corpuscular volume, platelets, red blood cell 
(RBC) count, RBC morphology, total white blood cell (WBC) count, and differential 
(neutrophils, bands, lymphocytes, monocytes, basophils, and eosinophils) 
• 
Non-fasting serum chemistry.  Includes albumin, alkaline phosphatase, ALT, AST, 
bicarbonate, calcium, chloride, creatine kinase, creatinine, direct bilirubin, gamma-


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
glutamyltransferase, indirect bilirubin, magnesium, non-fasting glucose, HgbA1C, 
phosphorous, potassium, sodium, total bilirubin, total cholesterol, total protein, urea 
nitrogen, and uric acid 
• 
Urinalysis.  Includes clarity, color, bilirubin, creatinine, blood, glucose, ketones, leukocyte 
esterase, nitrite, pH, protein, specific gravity, urobilinogen, microscopic sediment (WBCs, 
RBCs, casts, bacteria, crystals, and epithelial cells), and screen for drug use 
• 
Electrocardiogram.  Electrocardiograms will be obtained using a 12-lead standard 
equipment.  The investigator will be responsible for the initial review of the ECG to assess 
whether the ECG is within the reference limits.   All ECGs will be sent to a central reader for 
interpretation, including confirmation of eligibility and ongoing safety assessments, and 
assessed for the following measures: P wave, QRS complex, U wave, QRS duration, QT 
interval, T wave, ST segment, RR interval, PR interval, and qualitative results 
• 
Participant questionnaire.  The participant will complete a questionnaire querying about the 
severity of symptoms either in the last month (V1D1) or since the last visit (subsequent 
visits), including burning/stinging, grittiness, and conjunctival hyperemia, which are scored 
on a 4-point scale of 0 = none, 1 = mild, 2 = moderate, and 3 = severe. This will be 
administered prior to application of study drug (visit V1D1 and V3D28, and at any time at 
other visits) to ensure immediate effects of the eye drops do not confound the results. Any 
immediate effects of the eye drops will be collected through AE reporting.  
• 
Best-corrected visual acuity.  Will be quantified using the Early Treatment Diabetic 
Retinopathy Study visual acuity protocol and the number of letters read correctly will be 
recorded on the eCRF 
• 
Intraocular pressure.  Will be measured with a Goldmann applanation tonometer 
• 
Biomicroscopy.  Will be performed by slit-lamp examination of conjunctiva, cornea, and iris 
with findings reported on a scale of 0 = none, 0.5 = trace, 1 = mild, 2 = moderate, and 3 = 
severe.  The status of the lens will be assessed using the Age-Related Eye Disease Study scale 
• 
Tear film break-up time.  Will be performed by instilling between 1.0 to 5.0 μL of non-
preserved, 2% sodium fluorescein onto the bulbar conjunctiva without inducing reflex.  If 
both eyes are being assessed, the study eye will be assessed first 
• 
Lissamine green conjunctival staining.  Will be performed using 1 drop (10 μL) of 1% 
lissamine green solution by pipette, with finding reported on a scale of 0 = none, 1 = mild, 2 
= moderate, and 3 = severe.  If both eyes are being assessed, the study eye will be assessed 
first 
• 
Ophthalmoscopy.  A dilated fundus examination will be performed to evaluate any posterior 
segment abnormalities 
• 
Plasma drug monitoring.  In a subset of at least 6 participants per study group (at select 
study sites), blood samples (~10 mL per sample) will be collected for monitoring the plasma 
concentrations of AG-86893 on Day 1 and Day 28 at pre-dose and at 0.5 and 1 hour after the 
morning dose from participating participantsAt Day 56, a single blood sample will be 
collected at the study visit.  Plasma drug concentrations will be measured using a validated 
liquid chromatography, tandem mass spectrometry assay, with a target lower limit of 
quantitation of 0.020 ng/mL.  Allgenesis shall have full ownership rights to any biological 
samples derived from the study.  
Unscheduled visits can be included if safety concerns arise.  Additional examinations may be 
performed as necessary to ensure the safety and wellbeing of participants during the study.  
Electronic Case Report Forms should be completed for each unscheduled visit. 
   
 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS  
An AE is any untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product and that does not necessarily have a causal relationship with 
this treatment.  An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to that product.  Worsening of the pterygium is not 
an AE, unless the lesion growth is greater than expected. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS  
An SAE is any AE occurring at any dose that results in any of the following outcomes: death, a life-
threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant disability/incapacity, or a congenital anomaly/birth defect.  Important medical events that 
may not result in death, be life-threatening, or require hospitalization may be considered an SAE 
when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition.  See 
Section 8.3.9 for procedures for reporting an SAE. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.4 SEVERITY OF EVENT 
For AEs not included in the protocol-defined grading system, the following guidelines will be used to 
describe severity.  
• 
Mild:  Event requires minimal or no treatment and do not interfere with the participant’s 
daily activities 
• 
Moderate:  Event results in a low level of inconvenience or concern with the therapeutic 
measures.  Moderate events may cause some interference with functioning 
• 
Severe:  Event interrupts a participant’s usual daily activity and may require systemic drug 
therapy or other treatment.  Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious” 
 
8.3.5 RELATIONSHIP TO STUDY INTERVENTION 
A determination will be made of the relationship (if any) between an AE and the study drug.  A 
causal relationship is present if a determination is made that there is a reasonable possibility that 
the AE may have been caused by the drug. 
• 
Not related:  A causal relationship can be excluded and another documented cause of the 
AE is most plausible 
• 
Unlikely related: A causal relationship is improbable and another documented cause of the 
AE is most plausible 
• 
Possibly related: A causal relationship is clinically/biologically plausible and there is a 
plausible time sequence between onset of the AE and administration of the study drug 
• 
Related:  A causal relationship is clinically/biologically highly plausible, there is a plausible 
time sequence between onset of the AE and administration of the study drug, and there is a 
reasonable response on withdrawal 
 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
8.3.6 EXPECTEDNESS  
The investigator will be responsible for determining whether an AE is expected or unexpected based 
on the information provided in the Investigator’s Brochure.  An AE will be considered unexpected if 
the nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study intervention. 
 
8.3.7 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
Any medical condition that is present at the time that the participant is screened will be considered 
as medical history and not reported as an AE.  However, if the study participant’s condition 
deteriorates at any time after the time of Informed Consent, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented in the source and eCRF to allow an assessment 
of the duration of the event at each level of severity to be performed.  The AE will be recorded in the 
CRF under the highest level of severity achieved; i.e. if an event progresses from mild to moderate, 
the severity of the AE will be changed in the CRF, but the date of onset will remain unchanged. 
Adverse events characterized as intermittent require documentation of onset and duration of each 
episode. 
 
 The collection of AEs and SAEs will commence from the time the Informed Consent Form is signed 
and continue until the last day of study participation (D84). Events will be followed for outcome 
information until resolution or stabilization during the study or continue until 7 days (for non-serious 
AEs) or 30 days (for SAEs) after the last day of study participation (D84).  
 
Adverse events will be monitored throughout the study beginning at the time of Informed Consent.  
After the first administration of AG-86893, participants will be observed for AEs by remaining in the 
clinic until at least 1 hour after dosing. At this 1 hour post-intial dose timepoint, and at each post-
screening visit, the investigator will begin by querying for AEs by asking each participant a general, 
non-directed question, such as “How have you been feeling since the last visit?”  Directed 
questioning and examination will then be done as appropriate.  All reported AEs will be documented 
on the appropriate eCRF, including seriousness, severity, relationship to study drug, action taken, 
and outcome (including date of resolution or stabilization, if AE is not ongoing).  If AEs occur, the first 
concern will be the safety of the study participants.  
 
8.3.8 ADVERSE EVENT REPORTING  
Any AE should be recorded on the appropriate eCRF.  All AEs that are drug-related and unexpected 
(not listed as treatment-related in the current Investigator’s Brochure [28]) are to be reported to the 
governing HREC/IRB/IEC as required by the HREC/IRB/IEC, local regulations, and the governing 
health authorities. 
 
8.3.9 SERIOUS ADVERSE EVENT REPORTING  
Any SAE occurring during the study period should be immediately (i.e., within 24 hours of learning of 
the event) reported via the Trial Runners SAE email address listed on the protocol page iii.  The SAE 
is recorded on the appropriate eCRFs.  In the event of an early termination within the first 4 weeks 
after study drug administration, the occurrence of an SAE within 8 weeks from Baseline/Day 1 
should be reported immediately to Trial Runners personnel.  All participants with an SAE that is 
related to study drug must be followed for at least 30 days and the outcomes reported until the 
event is resolved or stabilized.  The investigator should supply the sponsor and the HREC/IRB/IEC 
with any additional requested information (e.g., autopsy reports and terminal medical reports). 
 
In the event of an SAE, the investigator must: 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
• 
Notify the Trial Runners safety office and the medical monitor immediately by email using 
the SAE reporting forms provided by Trial Runners (see page iv of the protocol for the SAE 
email address).  A fax number will be provided for reporting in the event internet access is 
unavailable during the required reporting period. Emergency phone numbers and relevant 
personnel contacts are also on page iii of the protocol 
• 
Obtain and maintain in the participant’s files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
participant 
• 
Provide Allgenesis with a complete, written case history (SAE report form) which includes a 
statement as to whether the event was or was not related to the use of the investigational 
drug 
• 
Promptly inform the governing HREC/IRB/IEC of the SAE if it is drug-related.  For other SAEs, 
notify the governing HREC/IRB/IEC as required by the HREC/IRB/IEC, local regulations, and 
the governing health authorities 
Adverse drug reactions that are both serious and unexpected (suspected unexpected serious 
adverse reactions [SUSARs]) will be subject to expedited reporting by the Sponsor to HREC and TGA 
as required by the relevant regulations.  TGA reporting must occur within 15 calendar days of first 
knowledge, or for fatal or life-threatening events, an initial or full report must be made within 7 
calendar days and a follow-up report must be made, if necessary, within the 15-calendar day 
timeframe. 
 
8.3.10 REPORTING EVENTS TO PARTICIPANTS  
Not applicable. 
 
8.3.11 EVENTS OF SPECIAL INTEREST  
Based on the observed reversible liver enzyme increases in animal models and humans in a clinical 
setting using the oral formulation nintedanib, abnormal liver function test results meeting the 
criteria below will be monitored and may trigger a meeting of the Independent Data Monitoring 
Committee (IDMC): 
 
• 
ALT or AST >8x ULN 
• 
ALT or AST >5x ULN for more than 2 weeks 
• 
ALT or AST >3x ULN and (total bilirubin >2x ULN or International Normalized Ratio [INR] >1.5) 
• 
ALT or AST >3x ULN with the appearance of worsening of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia 
• 
Any other safety signals observed during routine data review that warrant convening of the 
IDMC, in the opinion of the Medical Monitor 
 
Any of these parameters also represent a trigger for interruption of dose for the participant until the 
IDMC has been convened and a recommendation provided.  
 
In the event of an increase in serum AST or ALT to >3x ULN, the following monitoring will be 
required: 
• 
Repeat testing within 48 to 72 hours of ALT, AST, ALP, and total bilirubin to confirm the 
abnormalities and to determine if they are increasing or decreasing 
• 
Participants will be questioned on the presence of symptoms (eg appearance of worsening 
of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia)  


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
• 
If symptoms persist or repeat testing shows ALT/AST >3x ULN for the participants with 
normal baseline measures or 2-fold increases above baseline values for participants with 
elevated values before drug exposure, the following measures will be initiated to determine 
whether the abnormalities are improving or worsening: 
o Interupt study treatment dosing until advice from the Medical Monitor is provided 
o Repeat liver tests (ALT, AST, ALP, and total bilirubin) 2 or 3 times weekly. Frequency 
of testing can decrease to once a week or less if abnormalities stabilize or study drug 
has been discontinued and participant is asymptomatic 
o Obtain a more detailed history of symptoms and prior or concurrent diseases 
o Obtain a history of concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
o Obtain a history of exposure to environmental chemical agents 
o Obtain additional tests to evaluate liver function, as appropriate (e.g., INR) 
o Consider gastroenterology or hepatology consultation 
 
Ocular AEs of special interest include the following and will also be monitored by the Medical 
Monitor and the IDMC:  
• 
Ocular inflammation, including iritis and uveitis 
• 
≥2 grade increase in corneal edema, corneal staining or edema 
• 
≥2 grade increase in any cataract 
• 
IOP change of ±7 mmHg from baseline 
• 
Loss of 15 letters or more BCVA 
 
8.3.12 REPORTING OF PREGNANCY  
If a female participant, or the female partner of a male participant, becomes pregnant during the 
study, the investigator will notify Trial Runners and the medical monitor immediately after the 
pregnancy is confirmed and the female participant will be exited from the study.  The investigator 
will (1) notify the participant’s/partner’s physician that the participant was being treated with AG-
86893, and (2) follow the progress of the pregnancy to term and the health of the child to 12 months 
of age, by the participant or partner as appropriate, providing written informed consent for release 
of this data.  The investigator should document the outcome of the pregnancy and provide a copy of 
the documentation to Allgenesis. 
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
The null hypothesis is that there is no difference between AG-86893 and AG-86893 vehicle in the 
change from baseline to Day 28 in the overall conjunctival hyperemia score.  The alternative 
hypothesis is that the active group is different from vehicle in the change from baseline to Day 28 in 
the overall conjunctival hyperemia score. 
 
9.2 
SAMPLE SIZE DETERMINATION 
As this is an exploratory study, an empirical sample size has been used. 
 
Per sample size calculation using SAS Proc Power procedure, assuming the standard deviation of the 
mean overall hyperemia score is around 1.0, a study with 20 participants in each group (N=60) 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
should have at least 90% statistical power to detect a minimal difference of 1 in mean overall 
hyperemia scores among the three study groups at 95% confidence level.  
 
For each of the 3 AG-86893 dose groups (vehicle, 0.1%, and 0.3%), approximately 20 participants 
with pterygium exhibiting conjunctival hyperemia are planned to complete the study.  Therefore, a 
total of approximately 70 participants will be enrolled at up to 12 sites in order to achieve an 
estimated 60 evaluable participants after accounting for potential drop-outs.  No more than a total 
of 70 participants will be enrolled in the study unless requested by Allgenesis. 
 
9.3 
POPULATIONS FOR ANALYSES 
Three analysis populations will be defined and used in the statistical analyses: (1) a safety 
population, (2) a modified intent-to-treat (mITT) population, and (3) a per-protocol (PP) population. 
 
Safety analyses will evaluate all randomized participants who received at least 1 dose of study drug 
and attended a post-baseline visit.  Results will be presented based on the treatment received. 
 
The primary statistical analyses will evaluate the mITT population, defined as all randomized 
participants who received at least 1 dose of study drug and had conjunctival hyperemia evaluated at 
both the Day 1 and Day 28 visits.  Results will be presented based on the treatment assigned during 
randomization. 
 
As a sensitivity analysis, the primary efficacy endpoint of conjunctival hyperemia will also be 
evaluated in the PP population of participants, who had no major protocol violations.  Nominal data 
will be analyzed using the Pearson chi-square test or Fisher exact test.  Conjunctival hyperemia, 
pterygium vascularity, BCVA, ophthalmoscopy, AS-OCT, and IOP data will be analyzed using analysis 
of variance models with dose strength as main effects.  The analysis will be based on observed data.  
Missing values will not be imputed. 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
The database will be locked after all participants exit the study and all data clarification forms or 
queries have been resolved.  Prior to database lock, a detailed Statistical Analysis Plan (SAP) will be 
finalized and approved.  Final analysis and unmasking of participants’ treatment code will occur after 
database lock. 
 
Wherever appropriate, summary statistics will include the sample size, mean, standard deviation 
(SD), median, minimum, and maximum for continuous and ordinal variables, and frequency counts 
and percent for categorical variables.  Data will be presented by treatment (0.1% AG-86893, 0.3% 
AG-86893, AG-86893 vehicle).  Additional analyses between vehicle and active drug will be explored, 
the details of which will be described in the SAP.  All testing will be two-sided and will be performed 
without adjustment for testing multiple measures. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
The primary efficacy measure is overall conjunctival hyperemia score of the study eye using the 
average of the scores of each quadrant, as assessed by the reading center.  The primary endpoint is 
the change from baseline in overall conjunctival hyperemia score at Day 28, so scores from Days 1 
and 28 will be analyzed.  The primary efficacy analysis will be based on the mITT population.  Refer 
to the MOP for details on the collection of ocular photography. 
 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
Statistical analyses will be performed as described in Section 9.4.1 for continuous variables. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINTS 
Secondary endpoints include: 
• 
Change from baseline in overall conjunctival hyperemia score at Day 7 
• 
Change from baseline in conjunctival hyperemia score in the quadrant with the pterygium at 
Days 7 and 28  
• 
Concentration of AG-86893 in plasma over time 
 
Statistical analyses will be performed as described in Section 9.3 for continuous and categorical 
variables. 
 
9.4.4 SAFETY ANALYSES 
All safety analyses will be conducted on the safety population using the following safety variables:  
• 
Adverse events 
• 
Concomitant medications 
• 
Concurrent procedures 
• 
Vital signs 
• 
Laboratory tests (urinalysis, hematology, and serum chemistry parameters)  
• 
Electrocardiogram 
• 
Best-corrected visual acuity 
• 
Intraocular pressure using a Goldmann applanation tonometer  
• 
Biomicroscopy  
• 
Tear film break-up time 
• 
Lissamine green conjunctival staining 
• 
Ophthalmoscopy  
 
The Medical Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to code AEs.  
For each AE reported, the number and percent of participants will be tabulated based on the 
preferred term.  The tables will be generated by relationship to treatment as well as by system organ 
class and severity. Treatment-emergent AEs will be considered, as will AEs occurring prior to first 
dose and post-treatment. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Baseline and demographic assessments will be presented descriptively. 
 
9.4.6 PLANNED INTERIM ANALYSES  
No interim analyses are planned. 
 
9.4.7 SUBGROUP ANALYSES 
No subgroup analyses are planned. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
Line listings will be provided for each participant. 
 
9.4.9 EXPLORATORY ANALYSES 
Exploratory endpoints include: 
• 
Pterygium vascularity scores at Days 1, 7, and 28 visits 
• 
Pterygium volume at Days 1, 7, and 28 visits 
• 
Pterygium vessel length at Days 1, 7, 28, and 56 visits 
 
9.4.10 PHARMACOKINETIC ANALYSIS 
The plasma AG-86893 concentrations will be summarized for each dose for the Days 1 and 28 visits. 
 
A model-independent approach will be used to calculate plasma PK parameters for AG-86893, 
including AUC0-t, and Cmax, whenever possible. 
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks, that have 
been reviewed and approved by the relevant HREC/IRB/IEC, will be given to the participant and 
written documentation of informed consent will be required prior to starting study intervention.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
The study will be discussed with the participant, and each participant wishing to participate must 
give written informed consent prior to enrollment into the study and prior to any study-related 
procedures or change in treatment.     
 
Each participant who provides informed consent will be assigned a participant number by the 
IVRS/IWRS that will be used on participant documentation throughout the study. 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
The study may be stopped at the participant’s study site at any time by the site investigator.  
Allgenesis may stop the study (and/or the study site) for any reason with appropriate notification. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
A report of the results of this study may be published or sent to the appropriate health authorities in 
any country in which the study drug may ultimately be marketed, but the participant’s name will not 
be disclosed in these documents.  The participant's name may be disclosed to Allgenesis, the 
governing health authorities, or the US Food and Drug Administration or the Therapeutic Goods 
Administration if they inspect the study records as required by law.  Appropriate precautions will be 
taken to maintain confidentiality of medical records and personal information. 
 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
Every precaution must be taken to protect the privacy of research participants and the 
confidentiality of their personal information in accordance with the Australian Privacy Act 1988. 
 
In accordance with Health Insurance Portability and Accountability Act Standards for Privacy of 
Individually Identifiable Health Information (HIPAA) requirements, additional purposes of this study 
include (1) the publishing of anonymous participant data from the study, and (2) the creation and 
maintenance of a data repository.   
 
All study-related correspondence, participant records (i.e., source documents listed in Section 
11.4.1), ICFs, participant privacy documentation, records of the distribution and use of all 
investigational products, and participant questionnaires, correspondence with HREC/IRB/IEC, and 
other essential documents should be maintained on file. 
 
Local regulatory requirements should be followed regarding the retention of clinical study 
documentation (TGA requires retention for at least 15 years after study completion; the Sponsor will 
advise once documents can be destroyed). 
 
Allgenesis requires that it be notified in writing if the investigator wishes to relinquish ownership of 
the data so that mutually agreed-upon arrangements can be made for transfer of ownership to a 
suitably qualified, responsible person. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Not applicable.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Global Medical Monitor 
Robert David, MD 
Trial Runners 
116 W. Villard 
Dickinson, ND 58601 USA 
+1 949-200-7988 
+1 949-246-8368 (mobile) 
+1 949-544-0234 (fax) 
RobertDavid@trialrunners.com 
 
No leadership committees will be used during this study. 
 
10.1.6 SAFETY OVERSIGHT 
Should there be any findings of concern that warrant further investigation, the Medical Monitor will 
convene a meeting of the IDMC to determine whether any changes in the study conduct should be 
made. Targeted AEs / findings of interest are summarised in section 8.3.11 and described in detail in 
the IDMC Charter, along with the qualifications for the independent safety experts.   
 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is in compliance with the currently approved protocol/amendment(s), with ICH Good 
Clinical Practice (GCP), and with applicable regulatory requirement(s).  


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
• 
A representative of Allgenesis will monitor the study on a periodic basis.  The determination 
of the extent and nature of monitoring will be based on considerations, such as the 
objective, purpose, design, complexity, masking, size, and endpoints of the study 
• 
Authorized representatives of Allgenesis or regulatory authority representatives will 
conduct on-site visits to review, audit, and copy study-related documents.  These 
representatives will meet with the investigator(s) and appropriate staff at mutually 
convenient times to discuss study-related data and questions 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation, and completion.   
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data 
QC checks that will be run on the database will be generated.  Any missing data or data anomalies 
will be communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures, the monitors will verify that the clinical trial is 
conducted and data are generated and biological specimens are collected, documented (recorded), 
and reported in compliance with the protocol, ICH GCP, and applicable regulatory requirements 
(e.g., GLP, Good Manufacturing Practice).  
 
The investigational site will provide direct access to all trial-related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
This study is to be conducted in compliance with the regulations on electronic records and electronic 
signature. 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator.  The investigator is responsible for ensuring that data are properly recorded on 
each participant's eCRFs and related documents in a timely manner.  An investigator who has signed 
the protocol signature page should electronically sign the eCRFs to ensure that the observations and 
findings are recorded on the eCRFs correctly and completely.  All source documents should be 
completed in a neat, legible manner to ensure accurate interpretation of data.   
• 
Clinical data will be entered into eCRFs.  Data entered into the eCRF will correspond with 
and be supported by source documentation maintained at the site(s).  A final report of all 
participant data will be provided to each site at the end of the study to serve as eCRF 
documentation 
• 
Blood chemistry panel, hematology, and urinalysis will be analyzed at a central clinical 
laboratory 
• 
Electrocardiogram data will be collected and provided to a centralized reading center for 
analysis and interpretation, including eligibility for study entry.  A final report of all 
participant ECG data will be provided to each site at the end of the study to serve as ECG 
documentation 
• 
IVRS/IWRS will be used for randomizing the participant population 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
• 
Images for conjunctival hyperemia/pterygium vascularity scoring, and AS-OCT lesion volume 
data will be collected and provided to a centralized reading center for analysis and 
interpretation, including eligibility for study entry.  A report of all participant hyperemia/ 
vascularity data and lesion volume will be provided to each site  
• 
Plasma drug concentration samples will be analyzed using validated assays to measure drug 
concentrations 
Source documents may include a participant's medical records, diaries, hospital charts, clinic charts, 
the investigator's participant study files, as well as the results of diagnostic tests, such as x-rays, 
laboratory tests, and ECGs.  The investigator's copy of the eCRFs serves as part of the investigator's 
record of a participant's study-related data.   
 
The following information should be entered into the participant's medical record: 
• 
Participant’s name 
• 
Participant’s contact information 
• 
Date that the participant entered the study, participant number, and participant medication 
kit number 
• 
Study title and/or the protocol number of the study and the name of Allgenesis  
• 
Statement that informed consent was obtained (including the date) prior to any study 
procedures being performed and that the participant was provided a copy of the signed 
informed consent.  A statement that country and local participant privacy-required 
documentation for this study has been obtained (including the date) 
• 
Dates of all participant visits 
• 
All concurrent medications (List all prescription and non-prescription medications being 
taken at the time of enrollment.  At each subsequent visit, changes to the list of medications 
should be recorded.) 
• 
Occurrence and status of any AEs (including any procedure-related AEs) 
• 
The date the participant exited the study, and a notation as to whether the participant 
completed the study or reason for discontinuation 
• 
The results of laboratory tests performed by the central laboratory (hematology, serum 
chemistry, urine analysis, urine culture and sensitivity) 
• 
The results of laboratory tests performed by the site (e.g., urine pregnancy test) 
• 
The results, if applicable, of any procedures performed to confirm eligibility criteria  
• 
Concurrent procedures performed during the study 
• 
Documentation of the participant’s medical history 
• 
Vital signs and physical characteristics (height and weight) 
• 
Electrocardiogram traces  
• 
Results of biomicroscopy/ophthalmoscopy exams 
• 
Documentation of whether any procedure, including study treatment administration, was 
performed according to the protocol, noting any deviations (if applicable) 
• 
Study drug accountability and reconstitution records (stored separately with the 
accountability logs in order to maintain masking status for site staff with direct contact with 
participant and/or data) 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
 
10.1.9.2 STUDY RECORDS RETENTION  
According to the TGA in Australia, study documents should be retained for a minimum of 15 years 
after the last approval of a marketing application.  These documents should be retained for a longer 
period, however, in the event of product liability claims.  No records will be destroyed without the 
written consent of the sponsor, if applicable.  It is the responsibility of the sponsor to inform the 
investigator when these documents no longer need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any non-compliance with the clinical trial protocol, ICH GCP, or MOP 
requirements.  The non-compliance may be either on the part of the participant, the investigator, or 
the study site staff.  As a result of deviations, corrective actions may be required by the site and 
implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Non-compliance, sections 5.20.1, and 5.20.2 
 
It is the responsibility of the site investigator to use continuous vigilance to identify, document, and 
report protocol deviations.  All deviations must be addressed in study source documents and 
reported to Allgenesis or its designee.  Protocol deviations must be sent to the reviewing IRB per 
their policies.  The site investigator is responsible for knowing and adhering to the reviewing IRB 
requirements.  Further details about the handling of protocol deviations will be included in the MOP.   
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
Allgenesis, as the sponsor, has proprietary interest in this study.  Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and Allgenesis 
personnel.  Authorship will be established prior to the writing of the manuscript.  As this study 
involves multiple centers, no individual publications will be allowed prior to completion of the final 
report of the multicenter study except as agreed with Allgenesis. 
 
This study will be registered on the ClinicalTrials.gov registry.  
 
10.1.12 
CONFLICT OF INTEREST POLICY 
Due to potential conflict of interest, participants or members of the participant’s household who are 
employees of the investigative site are not eligible for enrollment in the study. 
 
10.2 ADDITIONAL CONSIDERATIONS 
Not applicable. 
 
10.3 ABBREVIATIONS 
 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BCVA 
best-corrected visual acuity 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
BID 
twice daily 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
DSM V 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDTA 
ethylenediaminetetraacetic acid 
FGF-2 
fibroblast growth factor-2 
FGFR 
fibroblast growth factor receptor 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIPAA 
Health Insurance Portability and Accountability Act Standards for Privacy of Individually 
Identifiable Health Information  
HPMC 
hypromellose; hydroxypropyl methylcellulose 
HREC 
Human Research Ethics Committee 
IC50 
half-maximal inhibitory concentration  
ICF 
informed consent form 
ICH 
International Conference on Harmonisation  
IDMC 
Independent Data Monitoring Committee 
IEC 
International Ethics Committee 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System  
IWRS 
Interactive Web Response System  
LDPE 
low-density polyethylene 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMPs 
matrix metalloproteinases 
MOP 
Manual of Procedures 
NOAEL 
no-observed-adverse-effect-level 
PDGFR 
platelet-derived growth factor  
PDGFRβ 
platelet-derived growth factor receptor β 
PK 
pharmacokinetic(s) 
PP 
per-protocol 
RBC 
red blood cell 
RLD 
reference listed drug 
QC 
quality control 
QID 
4 times daily 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
half-life 
TID 
3 times daily 
ULN 
upper limit of normal 
US 
United States 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
WBC 
white blood cell 
YAG 
yttrium aluminium garnet 
 
10.4 PROTOCOL AMENDMENT HISTORY 
 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
Version 
Date 
Section 
affected 
Description of 
Change  
Brief Rationale 
1.0 
25 
Apr 
2018 
 
Original Document 
 
2.0 
21 
Jun 
2018 
Cover page  
National Clinical 
Trial Identified 
Number provided 
Trial registration completed 
1.3 Schedule of 
activities 
Correction: 
participant 
questionnaire 
administered pre-
IP administration 
Correction of error; pre-IP administration 
of questionnaire will ensure an average of 
all symptoms from last month/since last visit 
is not confounded by immediate effects of IP 
5.1 Inclusion 
criteria 
BMI upper limit 
increased from 30 
to 35 kg/m2 
Increase recruitment capacity: the non-
clinical data, nor the clinical data on the 
active ingredient, suggests a safety risk in 
moderately obese 
6.1.2 Dosing 
and 
administraion 
Participants will be 
questioned on 
Adverse Events 1 
hour after first IP 
administration on 
V1D1 
Additional safety measure 
Table 8.1 
Laboratory 
and Vital Sign 
Criteria for 
Serious 
Adverse 
Events 
INR flag for SAE 
removed 
Not necessary to ensure participant safety; 
remaining safety measures more 
appropriate 
8.3.12 
Preganacy 
reporting 
Detail added on 
collecting data until 
child is 12 months 
of age 
As per Bellberry HREC guidelines 
9.2 Sample size 
determination 
Provided additional 
information on 
sample size and 
power 
N/A 
10.1.6 Safety 
Overview 
The involvement of 
independent 
experts in safety 
monitoring has 
been added  
Additional safety measure 
3.0 
20 
Mar 
2019 
1.1 Synopsis 
Added the 
exploratory 
endpoints and 
outcomes to the 
synopsis 
Clarification: missing from Versions 1.0 and 
2.0 of the protocol 
1.1 Synopsis 
Changed 12 sites 
throughout 
Australia to 
Approximately 12 
sites 
It is unlikely 12 sites will be inititated 
1.2 Schema 
 
4.1 Overall 
Design 
 
Day 7 visit: Visit 
conducted as a 
phone call, or 
optional in-clinic 
visit at the 
Due to participant burden and favourable 
safety profile observed, sites are able to 
conduct the Day 7 follow-up visit as a phone 
follow-up to conduct AE questioning, 
participant symptom questionnaire, 
concomitant medications and procedures, 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
6.2.1 IP 
Acquisition 
and 
Accountability 
 
6.4 Study 
Intervention 
Compliance 
 
discretion of the 
site Investigator 
and discussion and re-training on dosing 
compliance. The in-clinic component will 
remain in the protocol as an optional visit at 
the discretion of the PI, in the event of any 
safety concerns or signals.  
 
4.1 Overall 
Design 
 
Removed the 
requirement for 
30% of participants 
to contribute to the 
PK data 
As this is an exploratory endpoint, this 
endpoint is not powered so there is no 
minimum amount of data required. 
5.1 Inclusion 
criteria (#4) 
BMI upper limit 
increased from 35 
to 38 kg/m2 
Increase recruitment capacity: neither the 
non-clinical data, nor the clinical data on 
the active ingredient, suggest a safety risk in 
those not morbidly obese 
5.1 Inclusion 
criteria (#7) 
Guidance provided 
to sites on how to 
select study eye if 
both eyes are 
affected to the exact 
same severity 
Missing from Versions 1.0 and 2.0 of the 
protocol 
5.2 Exclusion 
criteria (non-
ocular #2) 
Amended the Liver 
dysfunction 
criterion  
This criterion is too restrictive. The FDA 
guidance on Drug-Induced Liver Injuries 
will be adhered to in order to reduce impact 
on recruitment without compromising 
participant safety 
https://www.fda.gov/downloads/guidances/ 
UCM174090.pdf   
5.2 Exclusion 
criteria (non-
ocular #11) 
Added exclusion 
criterion: History of 
active alcohol or 
substance abuse as 
defined by DSM V 
criteria 
Added to exclude potential participants 
likely to have abnormal liver function due to 
lifestyle factors 
 
6.1.2 Dosing 
and 
Administration 
Updated dosing and 
administration 
instructions to 
include vigorous 
shaking  
New information has confirmed the 
nanosuspension can settle after a period, so 
vigorous shaking for 10 seconds is 
recommended to ensure adequate dosing 
 
6.2.2 
Formulation, 
Appearance,  
Packaging, and 
Labelling 
Corrected the fill 
volumes from 4 mg 
and 12 mg for the 
0.1% and 0.3% 
active IP 
respectively to 5 mg 
and 15 mg 
An error in Versions 1.0 and 2.0 of the 
protocol now corrected 
8.2 Safety and 
Other 
Assessments 
 
Schedule of 
Assessments 
Clarified that 
“physical 
assessments” 
involves weight and 
height at screening 
and weight only at 
subsequent visits  
Height not expected to change over trial 
duration – included in error 
8.2 Safety and 
Other 
Assessments 
Reduced the PK 
sampling protocol 
to pre-dose then 0.5 
Reduced sampling presents a lower 
participant burden and possibly an 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
 
Schedule of 
Assessments 
and 1 hour after 
dosing  
increased uptake of those consenting to PK 
blood draws 
8.3.2 Definition 
of SAEs 
Removal of 
Laboratory and 
Vital Sign Criteria 
for Serious Adverse 
Events 
These criteria do not represent SAEs unless 
also resulting in one or more of the 
following outcomes: death, a life-
threatening AE, inpatient hospitalization or 
prolongation of existing hospitalization, a 
persistent or significant 
disability/incapacity, or a congenital 
anomaly/birth defect 
8.3.11 Events 
of Special 
Interest 
Provided detail on 
the safety signals 
that would trigger a 
meeting of the 
Independent Data 
Monitoring 
Committee, as well 
as guidance to sites 
on the clinical 
management of 
such events 
This detail was not present in Versions 1.0 
and 2.0 of the protocol 
10.1.6 Safety 
Oversight 
Clarified that the 
safety experts 
engaged for this 
trial are in the 
format of an 
Independent Data 
Monitoring 
Committee 
This detail was not present in Versions 1.0 
and 2.0 of the protocol 
 
 
 


  
 
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P2-86893-001 SURPH Protocol V3.0 20 Mar 2019  
 
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