Conditions: Rhegmatogenous Retinal Detachment - Macula Off
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 14
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and tolerability of ONL1204 in participants with Macula-off, Rhegmatogenous Retinal Detachment (RRD). RRD is an acute and serious vision threatening condition in which a tear in the retina, typically resulting from a vitreous detachment, allows liquid to accumulate under the retina, detaching the photoreceptor (PR) layer of the retina from the retinal pigment epithelium (RPE). As the RPE is the principal source of nutritional support for the PR layer, the photoreceptors begin a cascade of inflammation and cell death. Photoreceptor cell death is the primary mechanism of vision loss after retinal detachment.

ONL1204 is a first-in-class inhibitor of Fragment Apoptosis Stimulator receptor (Fas)-mediated cell death. ONL1204 has demonstrated protection of multiple retinal cell types in numerous preclinical models of acute ocular injury. This will be a first-in-human (FIH) study to evaluate safety and tolerability of a single-dose of ONL1204 in participants with macula-off RRD. The standard of care for surgical repair of macula-off RRD is reattachment surgery within 7 days of the macula detaching. Participants in this study will receive a single intravitreal injection upon diagnosis and enrollment in the study, followed by standard of care surgery. The surgery includes vitrectomy, a procedure that removes the bulk of drug remaining in the vitreous.

Detailed description:

Arms:
arm 1: Intravitreal injection of 50 μl of ONL1204 liquid formulation to deliver dose 1 arm 2: Intravitreal injection of 100 μl of ONL1204 liquid formulation to deliver dose 2 arm 3: Intravitreal injection of 50 μl of ONL1204 liquid formulation to deliver dose 3 arm 4: Intravitreal injection of 100 μl of ONL1204 liquid formulation to deliver dose 4

Interventions: intervention 1: ONL1204 intervention 2: Intravitreal Injection intervention 3: Collection of ocular fluids
Intervention descriptions: intervention 1: Administration of ONL1204 - inhibitor of Fas(CD95) signaling by intravitreal injection intervention 2: Injection of study drug into the eye intervention 3: vitreous and aqueous fluid collection by a tap and during vitrectomy

Protocol document:
Prot_000.pdf: 
16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 1 of 52 
  
 
 
CLINICAL RESEARCH PROTOCOL 
DRUG: 
ONL1204 Ophthalmic Solution 
STUDY NUMBER: 
ONL1204-RRD-001 
PROTOCOL TITLE: 
A Phase 1 Open-Label, Dose Escalation Study to 
Assess the Safety and Tolerability of Intravitreal 
ONL1204 in Patients with Macula-off, 
Rhegmatogenous Retinal Detachment 
SPONSOR: 
ONL Therapeutics 
1600 Huron Pkwy 
Building 520, Second Floor 
Ann Arbor, MI 48109 
ORIGINAL PROTOCOL 
DATE: 
26 November 2018 
VERSION NUMBER: 
v.1.6 
VERSION DATE: 
27 JULY 2020 
 




16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 3 of 52 
  
 
 
ONL1204-RRD-001 
A Phase 1 Open-Label, Dose Escalation Study to 
Assess the Safety and Tolerability of Intravitreal 
ONL1204 in Patients with Macula-off, Rhegmatogenous 
Retinal Detachment. 
 
Confidentiality and Investigator Statement 
The information contained in this protocol and all other information relevant to ONL1204 
Ophthalmic Solution are the confidential and proprietary information of ONL 
Therapeutics, and except as may be required by federal, state or local laws or regulation, 
may not be disclosed to others without prior written permission of ONL Therapeutics. 
I have read the protocol, including all appendices, and I agree that it contains all of the 
necessary information for me and my staff to conduct this study as described.  I will 
conduct this study as outlined herein, in accordance with the regulations stated in the 
International Conference on Harmonisation guidelines, and will make a reasonable effort 
to complete the study within the time designated. 
I will provide all study personnel under my supervision copies of the protocol and any 
amendments, and access to all information provided by ONL Therapeutics or specified 
designees.  I will discuss the material with them to ensure that they are fully informed 
about ONL1204 Ophthalmic Solution and the study. 
 
 
Principal Investigator Name (printed) 
Signature 
 
______________________________ 
______________________ 
 
Date 
Site Number 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 4 of 52 
  
 
 
Study Summary 
Title:   
A Phase 1 Open-Label, Dose Escalation Study to Assess the Safety and 
Tolerability of Intravitreal ONL1204 in Patients with Macula-off, 
Rhegmatogenous Retinal Detachment. 
Rationale:   
The purpose of this study is to evaluate the safety and tolerability of 
ONL1204 in Patients with Macula-off, Rhegmatogenous Retinal 
Detachment (RRD).  RRD is an acute and serious vision threatening 
condition in which a tear in the retina, typically resulting from a 
vitreous detachment, allows liquefied vitreous to enter the subretinal 
space, detaching the photoreceptor (PR) layer of the neurosensory 
retina from the retinal pigment epithelium (RPE).  As the RPE is the 
principal source of nutritional support for the PR layer, the 
photoreceptors begin a cascade of inflammation and cell death.  
Photoreceptor cell death is the primary mechanism of vision loss after 
retinal detachment.   
ONL1204 is a first-in-class inhibitor of Fragment Apoptosis Stimulator 
receptor (Fas)-mediated cell death.  ONL1204 has demonstrated 
protection of multiple retinal cell types in numerous preclinical models 
of acute ocular injury. 
This will be a first-in-human (FIH) study to evaluate safety and 
tolerability of a single-dose of ONL1204 in patients with macula-off 
RRD.   
The standard of care for surgical repair of macula-off RRD is 
reattachment surgery (typically by vitrectomy with or without scleral 
buckling) within 7 days of the macula detaching.  Patients will receive 
a single intravitreal injection upon enrollment in the study on the day of 
diagnosis.  The vitrectomy procedure will remove the bulk of drug 
remaining in the vitreous.  
Target 
Population: 
Patients who present between 1 week (7 days) to 4 weeks (28 days) of 
a macula-off RRD (based on patient-reported history of loss of central 
vision) for whom standard retinal reattachment surgery by means of a 
pars plana vitrectomy and gas tamponade is indicated.  


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 5 of 52 
  
 
 
Number of 
Patients: 
Approximately 16 patients will be enrolled in this study. 
• 4 ascending dose groups; 4 active. The first patient in each dose 
group will be observed for at least 14 days post-surgery (through 
visit 6) prior to enrolling the remainder of the patients in that dose 
group. 
• Patients may be replaced who do not receive an injection of study 
medication, or for discontinuing from the study for reasons 
unrelated to treatment before completing Visit 4.  All patients 
receiving injection of study drug will be followed for safety and 
tolerability. 
Study Visits 
There is a minimum of 8 scheduled study visits: 
• Visit 1:  Day 1 (baseline/drug injection) 
• Visit 2:  Day 2 (1 day post-injection*)  
• Visit 3:  Day of Vitrectomy (3 + days post-injection in accordance 
with standard of care vitrectomy)  
• Visit 4:  Postoperative visit (1 day post-surgery)  
• Visit 5: Post-operative visit (2 weeks post-surgery and clearance of 
sentinel patient/cohort (14 days +4 days post-surgery)) 
• Visit 6:  Week 6 (±7 days) 
• Visit 7:  Week 9 (±7 days) 
• Visit 8:  Week 24/Exit (±14 days) 
*additional visits between visit 2 and 3 per investigator’s discretion 
Objectives: 
To evaluate safety and tolerability of a single intravitreal injection of 
ONL1204 in patients with macula-off, RRD. 
Study Design: 
This is a single-injection, open-label dose escalation study. 
Primary 
Objective: 
 
The primary objective will be to determine the Maximum Tolerated 
Dose (MTD) of ONL1204 and select doses for Phase 2.  Determination 
of this will be through review of the parameters measured in the 
Schedule of Assessments, as well as adverse event (AE) reports. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 6 of 52 
  
 
 
Exploratory 
Objective: 
During the study, ocular fluid samples will be collected at the time of 
study drug injection and at the time of vitrectomy.  These samples will 
be used for pharmacokinetic and pharmacodynamic analyses, the 
results of which will help inform the dose selection for the Phase 2 
trial(s). 
 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 7 of 52 
  
 
 
STUDY SCHEMATIC 
Figure 1 
Study Schematic 
16 patients will be enrolled and treated, starting with the lowest dose, Cohort 1.  The first 
patient in each cohort will be observed for at least 14 days post surgery (through Visit 5) 
before the rest of the cohort can be enrolled. The safety review committee will review the 
data prior to clearing the sentinel patient and enrolling the remainder of the cohort. After 
all 4 patients in a cohort have completed Visit 5, the safety review committee will review 
available safety data to determine if dose limiting toxicity exists that prohibits enrolling 
the next higher dose cohort. The respective IRB’s will be informed of the outcome of the 
SRC meetings. 
If there are no safety concerns, the next cohort will start treatment.  
 
*Patients may be replaced who do not receive an injection of study medication, or for discontinuing from 
the study for reasons unrelated to treatment before completing Visit 4. 
 
16 patients to be enrolled*
Cohort 1
4 patients: 1 sentinel patient, 3 patients 
25 μg ONL1204
Cohort 2
4 patients: 1 sentinel patient, 3 patients
50 μg ONL1204
Cohort 3
4 patients: 1 sentinel patient, 3 patients
100 μg ONL1204
Cohort 4
4 patients: 1 sentinel patient, 3 patients
200 μg ONL1204


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 8 of 52 
  
 
 
TABLE OF CONTENTS 
CLINICAL RESEARCH PROTOCOL .......................................................................... 1 
Clinical Protocol Approval Form ..................................................................................... 2 
Confidentiality and Investigator Statement .................................................................... 3 
Study Summary ................................................................................................................. 4 
TABLE OF CONTENTS .................................................................................................. 8 
Table of Tables ................................................................................................................. 10 
Table of Figures ............................................................................................................... 10 
LIST OF ABBREVIATIONS ......................................................................................... 11 
1 
INTRODUCTION AND RATIONALE ................................................................. 14 
1.1 
Background .......................................................................................................... 14 
1.2 
ONL1204 .............................................................................................................. 14 
1.2.1 
Preclinical Experience ................................................................................... 14 
1.2.2 
Clinical Experience ........................................................................................ 16 
1.3 
Study Rationale .................................................................................................... 16 
1.3.1 
Rationale for the Proposed Doses ................................................................ 16 
1.3.2 
Rationale for Pharmacokinetic testing ........................................................ 17 
1.3.3 
Rationale for Vitreous Tap and Pharmacodynamic Analysis ................... 17 
1.4 
Potential Risks and Benefits ............................................................................... 18 
1.4.1 
Potential Risks of Study Product ................................................................. 18 
1.4.2 
Potential Risk to Fetal Development ............................................................ 18 
1.4.3 
Potential Risks of Intravitreal Injection, Vitreous Tap, Pupil 
Dilation and Blood Draw .............................................................................. 19 
1.4.4 
Potential Risks of Vitrectomy ....................................................................... 20 
1.4.5 
Potential Benefit of Study Product .............................................................. 20 
2 
STUDY OBJECTIVE .............................................................................................. 20 
2.1 
Primary Objective ............................................................................................... 20 
2.2 
Exploratory Objective ......................................................................................... 20 
3 
STUDY ENDPOINTS .............................................................................................. 20 
3.1 
Primary Endpoints .............................................................................................. 20 
3.2 
Exploratory Endpoints ........................................................................................ 21 
4 
STUDY DESIGN ...................................................................................................... 21 
4.1 
Overview of Study Design ................................................................................... 21 
4.1.1 
Treatment Masking ....................................................................................... 22 
4.2 
Dose Limiting Criteria and Maximum Tolerated Dose ................................... 22 
4.2.1 
Dose Limiting Criteria .................................................................................. 22 
4.2.2 
Dose Escalation Decisions ............................................................................. 23 
4.3 
Schedule of Assessments ..................................................................................... 24 
5 
STUDY POPULATION ........................................................................................... 29 
5.1 
Number of Patients .............................................................................................. 29 
5.2 
Inclusion Criteria ................................................................................................. 29 
5.3 
Exclusion Criteria ................................................................................................ 29 
6 
STUDY CONDUCT ................................................................................................. 30 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 9 of 52 
  
 
 
6.1 
Study Personnel and Organizations ................................................................... 30 
6.2 
Treatment Assignment ........................................................................................ 31 
6.3 
Recruitment of Patients ...................................................................................... 31 
6.4 
Study Procedures and Assessments ................................................................... 31 
6.4.1 
Study Visits ..................................................................................................... 31 
6.4.2 
Study Procedures ........................................................................................... 32 
6.4.3 
Informed Consent .......................................................................................... 33 
6.4.4 
Patient Demographics ................................................................................... 33 
6.4.5 
Medical History and Prior Medications ...................................................... 33 
6.4.6 
Patient Height and Weight ........................................................................... 33 
6.4.7 
Vital Signs ....................................................................................................... 33 
6.4.8 
Pregnancy Test ............................................................................................... 33 
6.4.9 
Contraception and Pregnancy Avoidance Measures ................................. 34 
6.4.10 
Clinical Laboratory Tests ............................................................................. 34 
6.4.11 
Concomitant Medications and Procedures ................................................. 34 
6.5 
Pharmacokinetics ................................................................................................ 34 
6.6 
Ocular Pharmacodynamics ................................................................................ 35 
6.7 
Protocol Deviations .............................................................................................. 35 
6.8 
Premature Discontinuation ................................................................................. 35 
7 
STUDY DRUG .......................................................................................................... 35 
7.1 
Description ........................................................................................................... 35 
7.2 
Formulation .......................................................................................................... 35 
7.3 
Storage .................................................................................................................. 35 
7.4 
Packaging and Shipment .................................................................................... 35 
7.5 
Route, Dose and Administration ........................................................................ 36 
7.6 
Permitted Concomitant Therapy ....................................................................... 36 
7.7 
Prohibited Concomitant Therapy ...................................................................... 36 
7.8 
Potential for Drug-Drug Interactions ................................................................ 36 
7.9 
Accountability ...................................................................................................... 36 
7.10 
Compliance ........................................................................................................... 37 
7.11 
Documenting Adverse Events ............................................................................. 37 
8 
ADVERSE EVENTS ................................................................................................ 37 
8.1 
Pretreatment Event Definition ........................................................................... 37 
8.2 
Adverse Event Definition .................................................................................... 37 
8.3 
Assessment of Intensity ....................................................................................... 38 
8.4 
Assessment of Causality ...................................................................................... 38 
8.5 
Clinical Laboratory Changes ............................................................................. 38 
8.6 
Adverse Event Follow-up .................................................................................... 38 
8.7 
Serious Adverse Events ....................................................................................... 38 
8.8 
Serious Adverse Event Definition ...................................................................... 38 
8.9 
Reporting Serious Adverse Events ..................................................................... 39 
8.10 
Overdose ............................................................................................................... 40 
9 
STATISTICS ............................................................................................................ 40 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 10 of 52 
  
 
 
9.1 
Statistical Design .................................................................................................. 40 
9.1.1 
Statistical Hypotheses .................................................................................... 40 
9.1.2 
Sample Size ..................................................................................................... 40 
9.1.3 
Analysis Populations ..................................................................................... 40 
9.2 
Study Endpoints ................................................................................................... 41 
9.2.1 
Primary Endpoints ........................................................................................ 41 
9.2.2 
Exploratory Endpoints .................................................................................. 41 
9.3 
Statistical Methods .............................................................................................. 41 
9.3.1 
Safety Analyses .............................................................................................. 42 
9.3.2 
Ocular PK Analyses ...................................................................................... 43 
9.3.3 
PD Analyses .................................................................................................... 44 
9.3.4 
Demographic and Baseline Characteristics ................................................ 44 
9.4 
Interim Analysis ................................................................................................... 44 
10 ETHICS AND RESPONSIBILITIES ..................................................................... 44 
10.1 
Good Clinical Practice ........................................................................................ 44 
10.2 
Safety Review Committee ................................................................................... 44 
10.3 
Human Research Ethics Committee .................................................................. 45 
10.4 
Informed Consent ................................................................................................ 45 
10.5 
Records Management .......................................................................................... 45 
10.6 
Source Documentation ........................................................................................ 45 
10.7 
Study Files and Record Retention ...................................................................... 46 
11 AUDITING AND MONITORING ......................................................................... 46 
12 AMENDMENTS ....................................................................................................... 46 
13 STUDY REPORT AND PUBLICATIONS ............................................................ 47 
14 STUDY DISCONTINUATION ............................................................................... 47 
15 CONFIDENTIALITY .............................................................................................. 47 
16 APPENDICES .......................................................................................................... 48 
16.1 
APPENDIX I – Sponsor Contact Information ................................................. 48 
16.2 
APPENDIX II – Declaration of Helsinki ........................................................... 48 
 
Table of Tables 
Table 4-1 
Schedule of Study Procedures and Assessments ......................... 24 
Table of Figures 
Figure 1 
Study Schematic .................................................................. 7 
 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 11 of 52 
  
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase  
ALT 
Alanine Transaminase  
AST 
Aspartate Transaminase  
BCVA 
Best Corrected Visual Acuity  
BUN 
Blood Urea Nitrogen  
°C 
Degrees Centigrade 
CRA 
Clinical Research Associate 
CRO 
Contract Research Organization 
CV 
Coefficient of Variation 
dUTP 
Deoxynucleotidyl Transferase 
eCRF 
Electronic Case Report Form  
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
°F 
Degrees Fahrenheit 
Fas 
Fragment Apoptosis Stimulator 
FIH 
First-in-human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HCT 
Hematocrit 
HGB 
Hemoglobin 
HREC 
Human Research Ethics Committee 
ICB 
Iris-Ciliary Body 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IL 
Interleukin 
IOP 
ITT 
Introcular Pressure 
Intent to Treat 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 12 of 52 
  
 
 
IVT 
Intravitreal 
LLOQ 
Lower Limit of Quantitation 
MARS 
Muenster Aging and Retina Study 
mg 
Milligram 
mL 
Milliliter 
mM 
Millimolar 
mmHg 
Millimeters Mercury 
MOP 
Manual of Procedures 
MTD 
Maximally Tolerated Dose 
ng 
nanogram 
ONL 
ONL Therapeutics 
OU 
Both Eyes (oculus uterque) 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
Post-op 
Postoperative;  
PR 
Photoreceptor 
PT 
Prothrombin Time 
RIPK3 
Receptor Interacting Protein Kinase 3  
RPE 
Retinal Pigment Epithelium  
RRD 
Rhegmatogenous Retinal Detachment 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD OCT 
Spectral Domain Optical Coherence Tomography 
SE 
SOC 
Study Eye 
Standard of Care 
SRC 
Safety Review Committee  
SUN 
Standardization of Uveitis Nomenclature 
TUNEL 
Terminal dUTP Nick End Labeling 
UA 
Urine analysis 
µg 
Microgram 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 13 of 52 
  
 
 
µM 
Micromolar 
WBC 
White Blood Cell  


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 14 of 52 
  
 
 
1 INTRODUCTION AND RATIONALE 
1.1 
Background 
Retinal detachment is an ocular condition that involves the retina being separated from 
the underlying layer of cells, including the retinal pigment epithelium (RPE).  This 
separation often results in the death of key retinal cells, including photoreceptors, which 
can lead to vision impairment and/or loss. 
The most prevalent form of retinal detachment is rhegmatogenous retinal detachment 
(RRD), which involves a tear in the retina.  While standard of care (SOC) surgical 
reattachment results in high rates of anatomic surgical success, in many cases, especially 
those involving the macula (central vision), patients have significant loss of vision even 
with successful surgery.  In part, this is due to the fact that photoreceptors begin to die 
once the detachment takes place and cell death continues up to the time of surgery 
(sometimes as long as a week after the detachment). 
ONL Therapeutics (ONL) is developing ONL1204, a first-in-class inhibitor of Fragment 
Apoptosis Stimulator (Fas)-mediated cell death that has demonstrated protection of 
multiple retinal cell types in numerous preclinical models of acute ocular injury.  The 
development of ONL1204 addresses an unmet medical need:  the prevention of vision 
loss in patients suffering from deterioration of visual function after acute retinal injury 
such as from macula-off RRD.   
Refer to the Investigator’s Brochure (IB) for more information. 
1.2 
ONL1204 
The investigational study agent is ONL1204 Ophthalmic Solution.  The drug product 
consists of the drug substance ONL1204 dissolved in a vehicle consisting of purified 
water containing mannitol, poloxamer 407, and glacial acetic acid.  The pH is adjusted to 
pH 4.5 by sodium hydroxide solution.  ONL1204 Ophthalmic Solution is provided as a 
sterile liquid in single-use vials stored at 2 to 8°C (36 to 46°F) and is administered by 
intravitreal (IVT) injection.  
1.2.1 
Preclinical Experience 
The sponsor has observed a pharmacological effect of ONL1204 in preventing Fas-
mediated cell death in 3 models of acute retinal injury – namely the rat retinal detachment 
model, the rabbit sodium iodate model, and the mouse microbead model of glaucoma.   
ONL1204 disrupts the binding of human Fas ligand to the human Fas receptor in vitro, 
while ONL1204 analog Met12 has been shown to bind to Fas receptor and prevent Fas 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 15 of 52 
  
 
 
ligand activated cell death in human Jurkat cells in vitro. The available nonclinical data 
from completed studies indicates that ONL1204 has efficacy towards the Fas ocular 
receptor based on the in vitro inhibition of caspase activity with a potency of 0.4 to 
0.45 µM.   
In vivo, administration of ONL1204 by IVT injection at doses of up to 10 µg/eye resulted 
in a reduction of terminal deoxynucleotidyl transferase (dUTP) nick end labeling 
(TUNEL) positive staining cells in a rat model of retinal detachment.  There was an 
approximate 75% reduction in the percent positive staining cells across the dose range 
examined.  The minimal, maximally effective dose for ONL1204 was 0.1 to 0.3 µg.  
Pharmacological activity towards the Fas receptor did not differ with different 
formulations of ONL1204, though poloxamer formulations appeared to have preferable 
pharmaceutical properties. 
To study the potential role of ONL1204 in geographic atrophy, ONL conducted a sodium 
iodate study in rabbits.  Sodium iodate is highly toxic to the retinal pigment epithelium 
and is a commonly used model for geographic atrophy.  IVT injection of ONL1204 at 0.1 
or 0.025 mg 4 days prior to sodium iodate injection preserved the RPE, suggesting that 
ONL1204 may also be useful in treating geographic atrophy. 
In a microbead model of glaucoma, data suggest that ONL1204 can also inhibit the 
production of macrophage and Receptor Interacting Protein Kinase 3 (RIPK3)-dependent 
inflammasome activation, which exacerbates retinal detachment-induced photoreceptor 
cell death through the release of interleukin (IL)-1β. 
In pharmacokinetic (PK) studies, ONL1204 is distributed to the retina, iris-ciliary body 
(ICB), and vitreous with IVT injection.  Following injection, the drug is slowly 
eliminated from these ocular structures.  The prolonged elimination of the drug is 
considered clinically meaningful for use in RRD where patients may not undergo surgical 
repair for several days following injection.  However, the clinical plan for retinal 
detachment includes a vitrectomy within 7 days after injection, which will remove the 
bulk of the drug remaining in the vitreous.   
Based on the pharmacodynamic (PD) and preliminary toxicity data, ONL has chosen the 
4.5% mannitol, 0.4% poloxamer 407, and 10 mM acetic acid (pH 4.5) formulation to be 
used in further development of ONL1204.  There was acceptable (minimal to mild) 
ocular toxicity in the rabbit with this formulation and the current drug formulation of 
ONL1204.  Moreover, ONL1204 was undetectable in the rabbit plasma (lower limit of 
quantification [LLOQ]:  1 ng/mL) following a total dose equal to the planned top dose in 
humans resulting in no systemic toxicity after full histopathologic examination of all 
major organs.   
Good Laboratory Practice (GLP) compliant toxicity studies using this formulation of 
ONL1204 are completed. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 16 of 52 
  
 
 
 
Preclinical data thus far indicate the intended clinical formulation at the top dose (200 µg) 
to be used in clinical trials should have an acceptable safety profile over a 14-day period 
following IVT injection.  
Refer to the IB for detailed information on the nonclinical studies conducted using 
ONL1204.  
1.2.2 
Clinical Experience 
ONL1204 has not been previously studied in humans; this will be the first-in-human 
(FIH) study of ONL1204.  Since there are no clinical data for ONL1204, the observed 
findings in nonclinical studies with ONL1204 will guide the monitoring in this study. 
1.3 
Study Rationale 
The purpose of this Phase 1 study is to collect safety information of ONL1204 in patients, 
establish a safe dose range, and collect PK and ocular PD information.   
The study population will be patients with newly diagnosed macula-off RRD.  Patients 
with RRD have an acute and serious vision threatening condition where a tear in the 
retina, typically resulting from a vitreous detachment, allows liquefied vitreous to enter 
the subretinal space, thereby detaching the photoreceptor (PR) layer of the neurosensory 
retina from the RPE.  As the RPE is the principal source of nutritional support for the PR 
layer, the photoreceptors begin a cascade of inflammation and cell death.  Nonclinical 
data on ONL1204 suggest that ONL1204 may inhibit the cell death pathway in RRD, 
preventing vision loss in patients suffering from acute retinal injury such as from macula-
off RRD. 
In clinical use, ONL1204 will be delivered to patients by intravitreal injection at the time 
of diagnosis to protect photoreceptors from death until surgery can be completed, with 
the hope of improving positive patient outcomes from already anatomically successful 
surgeries.  
1.3.1 
Rationale for the Proposed Doses 
As described in 1.2.1 the minimal, maximally effective dose in the rat model of retinal 
detachment delivered by an IVT injection was 0.1 to 0.3 ug per eye. Based on scaling of 
this MMED from the rat eye to the human eye, the calculation is as follows:  the vitreous 
volume of a rat eye is 13-20 microliters, while that of the human is approximately 4,400 
microliters (a factor of 220-338x).  With the MMED being estimated at 0.1 micrograms 
in the rat, this scales to a dose of 22-34 micrograms in the human eye. This dose 
escalation study starts at a 25 microgram dose and increases to 50 micrograms in the next 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 17 of 52 
  
 
 
cohort, followed by a 100 microgram cohort and 200 micrograms in last dose escalation 
cohort. 
As stated, the maximum dose planned for this trial is 200 µg.  In animal studies, using 
Dutch Belted rabbits, this dose was intravitreally injected into one eye while the 
contralateral eye served as an untreated control.  The findings from this study suggested 
the current formulation at the top dose (200 µg) to be used in GLP-compliant nonclinical 
studies and in clinical trials should have an acceptable safety profile over a 14-day period 
following IVT injection, especially given that the allometrically scaled dose in the rabbit 
is approximately 2-fold greater than the planned high dose intended for this initial 
clinical trial.  
The following doses will be evaluated:  25 µg, 50 µg, 100 µg and 200 µg ONL1204.  
ONL1204 will be administered as a sterile liquid by intravitreal injection. Patients 
randomized to receive the treatment will be given one injection of the drug.  
1.3.2 
Rationale for Pharmacokinetic testing 
Systemic PK will be evaluated following IVT administration of ONL1204.  ONL1204 is 
not expected to be detected in the plasma and this will be confirmed in this study, which 
will preclude additional systemic PK evaluation in future studies. 
ONL1204 will also be measured in the vitreous samples taken at the time of the 
vitrectomy to evaluate clearance of the drug from the vitreous.   
1.3.3 
Rationale for Vitreous Tap and Pharmacodynamic 
Analysis 
A vitreous tap will be performed at the time of diagnosis/IVT injection of drug, and an 
undiluted vitreous sample as well as aqueous sample will be taken at time of surgery.  
This will allow for assessment of the cytokine profile before and several days after 
administration of ONL1204.  This will allow for the potential identification of a 
biomarker for proof of principle of target engagement, via analysis of cytokines and other 
potential molecular biomarkers that impact visual acuity after surgical repair of retinal 
detachment.  The described procedures are routine for retinal surgeons, with the risk of 
endophthalmitis thought to be similar to that of IVT injections (1 in 2000-3000 patients).   


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 18 of 52 
  
 
 
1.4 
Potential Risks and Benefits 
1.4.1 
Potential Risks of Study Product 
There could be a risk of an adverse reaction to the ONL1204 drug product or vehicle.   
Although unlikely, potential risks include: 
• Intraocular inflammation 
• Elevated intraocular pressure 
• Visual loss 
• Retinal cell death 
• Less favorable surgical outcome following repair 
• Systemic adverse reaction 
Patients will be carefully monitored after vitreous tap and intravitreal injection of 
ONL1204, with multiple post procedure visits with the investigator.  At these visits, 
visual acuity will be assessed, intraocular pressure measured, the eyes examined 
according to assessments listed in 6.4.2, and any adverse events (AEs) reviewed.  Based 
on these assessments, additional visits may be scheduled at investigator discretion.  This 
close monitoring for inflammation, infection, and changes in vision will help reduce 
associated risks.   
There is a remote risk of systemic adverse reaction in response to intravitreal injection of 
ONL1204.  This risk is greatly mitigated by the study molecule’s long half-life in 
vitreous (most drug stays in the eye until surgery) and extremely short half-life in plasma.  
Patients will undergo clinical blood testing, with assessment of complete blood count, 
renal function tests and hepatic function tests to monitor for any such systemic adverse 
reactions. 
1.4.2 
Potential Risk to Fetal Development 
Potential risk to fetal development is unknown.  Therefore, all female patients of 
childbearing potential must have a negative pregnancy test before being enrolled in this 
study, and all participants must use adequate contraceptive precautions during the study, 
Section 6.4.9. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 19 of 52 
  
 
 
1.4.3 Potential Risks of Intravitreal Injection, Vitreous Tap, Pupil 
Dilation and Blood Draw 
Intravitreal injection and vitreous tap are common procedures, but both do carry the risk 
of possible adverse reaction including: 
• Infection  
• Inflammation 
• Irritation 
• Pain 
• Bleeding 
• Increased intraocular pressure 
• Retinal holes/retinal tears 
• Retinal detachments 
• Cataract 
• Worsened vision/vision loss/loss of eye 
• Corneal abrasion 
 
Pupil dilation is also a common procedure during an eye exam but carries a risk of 
possible adverse reaction including: 
• Redness 
• Stinging/discomfort 
• Allergic reactions 
• Sensitivity to light 
• Blurred vision 
 
The procedure of blood draw, even though a common procedure carries the risk of 
possible adverse reactions such as: 
• Pain/discomfort 
• Bruising 
• Infection 
• Fainting 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 20 of 52 
  
 
 
 
Care will be taken to reduce the risk of infection at the time of the tap and intravitreal 
injection through antisepsis, sterile technique and expert care as these procedures will be 
performed by experienced retinal surgeons. 
1.4.4 
Potential Risks of Vitrectomy 
Any surgical intervention has risk, and the risks associated with retinal detachment repair 
are not insignificant.  Patients in this trial, however, will receive the same retinal surgery 
whether they participate in this trial or not so retinal surgery is not a study specific risk. 
Potential participants in this study have been diagnosed with macula-off, rhegmatogenous 
retinal detachment and will be undergoing standard retinal reattachment surgery by 
means of a pars plana vitrectomy (with or without scleral buckle) and gas tamponade. 
The surgeon will fully discuss the possible risks of this surgery with the patient prior to 
the surgery.  
1.4.5 
Potential Benefit of Study Product 
There is a possibility that ONL1204 could prevent photoreceptor cell death, ultimately 
resulting in better visual acuity in patients treated with ONL1204; however, this is not 
known. 
2 
STUDY OBJECTIVE 
2.1 
Primary Objective 
The primary objective will be to determine the Maximum Tolerated Dose (MTD) of 
ONL1204 and select doses for Phase 2.  Determination of this will be through review of 
the parameters measured in the Schedule of Assessments, as well as adverse event (AE) 
reports.  
2.2 
Exploratory Objective 
During the study, ocular fluid samples will be collected at the time of study drug injection 
and at the time of vitrectomy.  These samples will be used for pharmacokinetic and 
pharmacodynamic analyses, the results of which will help inform the dose selection for 
the Phase 2 trial(s). 
3 STUDY ENDPOINTS 
3.1 
Primary Endpoints 
The primary endpoints will be the safety profile demonstrated in this study, including: 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 21 of 52 
  
 
 
• Adverse event reporting 
• Clinical evaluations including BCVA  
• Clinical laboratory evaluation 
3.2 
Exploratory Endpoints 
The exploratory endpoints will be the pharmacokinetic and pharmacodynamic analyses 
performed in this study, including: 
• Measurement of ONL1204 drug levels in plasma and vitreous fluid for PK analysis 
• Cytokine and other potential molecular biomarker measurement in aqueous and 
vitreous samples, taken by vitreous tap, and at vitrectomy 
4 STUDY DESIGN 
This proposed study is a single-injection, open-label, dose escalation study to assess the 
use of intravitreal ONL1204 in patients with macula-off RRD.  Approximately 
16 patients with RDD will be enrolled.  The expected duration of patient participation in 
the study is approximately 24 weeks (treatment, then 24 weeks of follow-up).  
4.1 
Overview of Study Design 
Sixteen patients will be enrolled in 4 ascending dose groups.   
After signing informed consent and meeting all eligibility criteria, patients will undergo a 
vitreous tap for cytokine and other potential molecular biomarker analysis followed by a 
single intravitreal injection of ONL1204.  This will occur on the day of diagnosis (Day 
1).  Safety visits will be conducted 1 day post-injection and per Investigator’s discretion 
until Visit 3.  At Visit 3 (3+ days post-injection, in accordance with standard of care) 
patients will undergo surgical repair of their retinal detachment with vitrectomy (with or 
without scleral buckling) and gas or oil tamponade. At the time of surgery, an undiluted 
vitreous sample will be collected for pharmacokinetic and pharmacodynamics analyses, 
and an aqueous sample will be collected for pharmacodynamic analysis. Additional 
safety visits will be conducted 1 day post-surgery, 14 (+4 days) days post-surgery, 
Weeks 6, 9 (±7 days each), and Week 24 (±14 days; study exit).   
As this is a first-in-human safety study of ONL1204, the first patient in the first cohort 
will receive the lowest dose of ONL1204. After this patient completes Visit 5 (14 
+4 days post-surgery) and a safety review committee reviews the data, the remainder of 
the patients in that cohort will be enrolled.  After all patients in the cohort have 
completed Visit 5, the SRC will review the available safety data to determine if dose 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 22 of 52 
  
 
 
limiting toxicity exists that prohibits enrolling the next higher dose cohort.  This process 
will be repeated until escalating to the top dose.   
The following doses will be evaluated:  25 µg, 50 µg, 100 µg, and 200 µg ONL1204.  
ONL1204 is available in vials with concentrations of 0.5 mg/mL and 2 mg/mL. 
Therefore, a volume of 0.05 or 0.1 mL will be injected into the study eye. 
Patient participation will be approximately 24 weeks (6 months):  a single injection 
treatment and 24 weeks of follow-up. 
4.1.1 
Treatment Masking 
This is an open-label study and all patients will be receiving study drug.   
4.2 
Dose Limiting Criteria and Maximum Tolerated Dose  
4.2.1 
Dose Limiting Criteria 
Dose limiting toxicity, if observed, will be declared by the SRC, based on their review of 
the relevant clinical information.  
Determination of dose limiting toxicity will include consideration of the following 
events: 
1. Ocular inflammation increases by 2 units from pre-injection on the Standardization of 
Uveitis Nomenclature (SUN) grading scale for aqueous cell or vitreous haze, 
secondary to inflammation and not the drug formulation itself, identified post-
injection of ONL1204 and prior to retinal reattachment surgery; 
2. Sustained elevation of IOP characterized as > 30 mmHg for 3 consecutive days, post-
injection of ONL1204 and prior to retinal reattachment surgery, despite 
pharmacologic therapy; 
3. Reduction in visual acuity from baseline after injection of ONL1204 and prior to 
retinal reattachment surgery, that in the opinion of the investigator is likely due to the 
investigational product and results in a: 
a) Decrease in visual acuity from 20/200 or 20/400 to light perception without 
progression of the underlying retinal detachment; or 
b) Decrease in visual acuity from baseline to no light perception.  
4. Any serious adverse event (SAE) that occurs within the first 14 days following 
ONL1204 injection that, in the opinion of the investigator, is related to ONL1204. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 23 of 52 
  
 
 
4.2.2 
Dose Escalation Decisions 
Dose escalation decisions include the following: 
1. To begin enrolling the next cohort at the planned dose or an adjusted dose. 
2. To delay opening the next cohort in order to collect additional safety on the current 
cohort, or to enrol additional patients in the current cohort if safety concerns are 
identified. 
3. To stop the cohort escalation if unacceptable toxicities are noted. 
If, in the opinion of SRC, dose limiting toxicity is reached, the previous, lower dose will 
be considered the Maximum Tolerated Dose (MTD).  
 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the Safety, Tolerability, PK and Ocular PD of 
Intravitreal ONL1204 in Patients with Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 24 of 52 
 
 
 
4.3 
Schedule of Assessments 
Table 4-1 
Schedule of Study Procedures and Assessments 
 
Study Visit 
Visit 1 
Day 1 
 
Visit 2 
Day 2 (1, 
Visit 3 
(Day 4 +) 
 
Visit 4 
 
Visit 5 
 
Visits 6, 7 
 
 
Visit 8 
 
Unscheduled 
Visit(s) 
Baseline2/ Injection 
 
1 day 
Post-
Injection 
3 + days Post-
Injection) 
Day of 
Surgery 
(Vitrectomy)3 
1 Day Post-
Surgery 
14 Days   
(±4 days) 
Post-
Surgery 
Weeks 6, 9 (±7 
days) 
Week 24    
(±14 days) 
Exit or early 
termination 
Assessment 
Pre-
Injection 
Study 
Drug 
IVT 
Post-
Injection 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
                                                            
Note: Screening procedures are in red. 
Abbreviations:  AE = Adverse event; ETDRS = Early Treatment Diabetic Retinopathy Study; IOP = Intraocular pressure; PK = Pharmacokinetic; 
Post-op = Postoperative; OU = Both eyes; SD OCT = Spectral Domain Optical Coherence Tomography; SE = Study eye; UA = Urine analysis. 
1 IOP > 30 mmHg requires consecutive daily visits until resolved or vitrectomy. Visits between visit 2 and 3 may be added per investigator’s discretion. 
2 All baseline procedures to be done before injection, except blood draw for ONL1204 levels and PK sample (may be drawn with clinical laboratory evaluations, 
and 1 hour [±15 minutes] after injection), and AE reporting, (pre- and post-injection).  If injection is scheduled for early morning, baseline procedures can be 
done the day before surgery. 
3 All Visit 3 procedures are to be performed before vitrectomy. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the Safety, Tolerability, PK and Ocular PD of 
Intravitreal ONL1204 in Patients with Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 25 of 52 
 
 
 
Study Visit 
Visit 1 
Day 1 
 
Visit 2 
Day 2 (1, 
Visit 3 
(Day 4 +) 
 
Visit 4 
 
Visit 5 
 
Visits 6, 7 
 
 
Visit 8 
 
Unscheduled 
Visit(s) 
Baseline2/ Injection 
 
1 day 
Post-
Injection 
3 + days Post-
Injection) 
Day of 
Surgery 
(Vitrectomy)3 
1 Day Post-
Surgery 
14 Days   
(±4 days) 
Post-
Surgery 
Weeks 6, 9 (±7 
days) 
Week 24    
(±14 days) 
Exit or early 
termination 
Assessment 
Pre-
Injection 
Study 
Drug 
IVT 
Post-
Injection 
 
 
 
 
 
 
 
Concomitant 
Medications 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
(UA) (females only) 
X 
 
 
 
 
 
 
 
X 
 
ETDRS Best 
Corrected Visual 
Acuity  
OU 
 
 
OU 
 
 
 
OU 
OU 
SE4 
Clinical Laboratory 
Evaluation 
X 
 
X 
 
X 
 
 
 
X 
 
                                                            
Note: Screening procedures are in red 
Abbreviations:  AE = Adverse event; ETDRS = Early Treatment Diabetic Retinopathy Study; IOP = Intraocular pressure; PK = Pharmacokinetic; 
Post-op = Postoperative; OU = Both eyes; SD OCT = Spectral Domain Optical Coherence Tomography; SE = Study eye; UA = Urine analysis. 
4 OU if clinically indicated. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the Safety, Tolerability, PK and Ocular PD of 
Intravitreal ONL1204 in Patients with Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 26 of 52 
 
 
 
Study Visit 
Visit 1 
Day 1 
 
Visit 2 
Day 2 (1, 
Visit 3 
(Day 4 +) 
 
Visit 4 
 
Visit 5 
 
Visits 6, 7 
 
 
Visit 8 
 
Unscheduled 
Visit(s) 
Baseline2/ Injection 
 
1 day 
Post-
Injection 
3 + days Post-
Injection) 
Day of 
Surgery 
(Vitrectomy)3 
1 Day Post-
Surgery 
14 Days   
(±4 days) 
Post-
Surgery 
Weeks 6, 9 (±7 
days) 
Week 24    
(±14 days) 
Exit or early 
termination 
Assessment 
Pre-
Injection 
Study 
Drug 
IVT 
Post-
Injection 
 
 
 
 
 
 
 
Blood Sampling for 
Plasma ONL1204 
PK 
 
 
X5 
X 
X 
 
X 
X6 
X 
 
Study Drug IVT 
 
X 
 
 
 
 
 
 
 
 
Pin Hole Visual 
Acuity 
 
 
 
 
 
OU 
 
 
 
 
Low Luminance 
ETDRS Best 
Corrected Visual 
Acuity 
 
 
 
 
 
 
 
OU 
OU 
 
Low Contrast 
ETDRS Best 
Corrected Visual 
Acuity 
 
 
 
 
 
 
 
OU 
OU 
 
Contrast Sensitivity 
Testing 
 
 
 
 
 
 
 
OU 
OU 
 
Farnsworth D15 
Color vision test 
 
 
 
 
 
 
 
 
OU 
 
                                                            
5 Post-injection blood sample for plasma PK to be drawn 1 hour (± 15 minutes) after study drug IVT. 
6 Blood sample for plasma PK to be drawn only on Visit 7 (week 9) 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the Safety, Tolerability, PK and Ocular PD of 
Intravitreal ONL1204 in Patients with Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 27 of 52 
 
 
 
Study Visit 
Visit 1 
Day 1 
 
Visit 2 
Day 2 (1, 
Visit 3 
(Day 4 +) 
 
Visit 4 
 
Visit 5 
 
Visits 6, 7 
 
 
Visit 8 
 
Unscheduled 
Visit(s) 
Baseline2/ Injection 
 
1 day 
Post-
Injection 
3 + days Post-
Injection) 
Day of 
Surgery 
(Vitrectomy)3 
1 Day Post-
Surgery 
14 Days   
(±4 days) 
Post-
Surgery 
Weeks 6, 9 (±7 
days) 
Week 24    
(±14 days) 
Exit or early 
termination 
Assessment 
Pre-
Injection 
Study 
Drug 
IVT 
Post-
Injection 
 
 
 
 
 
 
 
Intraocular 
Pressure7 
OU 
 
 
OU 
SE 
OU 
OU 
OU 
OU 
SE4 
Slit Lamp 
Biomicroscopy 
OU 
 
 
OU 
 
OU 
SE 
OU 
OU 
SE4 
Indirect 
Ophthalmoscopy 
OU 
 
 
OU 
 
OU 
SE 
OU 
OU 
SE4 
Fundus 
Photography 
OU 
 
 
 
 
 
 
 
OU 
 
ONL1204 Fundus 
Autofluorescence 
 
 
 
 
 
 
 
 
OU 
 
B Scan 
Ultrasonography 
(optional) 
SE 
 
 
 
 
 
 
 
 
 
SD OCT 
OU 
 
 
 
 
 
 
SE 
OU 
SE 
                                                            
Note: Screening procedures are in red 
Abbreviations:  AE = Adverse event; ETDRS = Early Treatment Diabetic Retinopathy Study; IOP = Intraocular pressure; PK = Pharmacokinetic; 
Post-op = Postoperative; OU = Both eyes; SD OCT = Spectral Domain Optical Coherence Tomography; SE = Study eye; UA = Urine analysis. 
7 iCare Tonometry and Tonopen methods of measurement are acceptable. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the Safety, Tolerability, PK and Ocular PD of 
Intravitreal ONL1204 in Patients with Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 28 of 52 
 
 
 
Study Visit 
Visit 1 
Day 1 
 
Visit 2 
Day 2 (1, 
Visit 3 
(Day 4 +) 
 
Visit 4 
 
Visit 5 
 
Visits 6, 7 
 
 
Visit 8 
 
Unscheduled 
Visit(s) 
Baseline2/ Injection 
 
1 day 
Post-
Injection 
3 + days Post-
Injection) 
Day of 
Surgery 
(Vitrectomy)3 
1 Day Post-
Surgery 
14 Days   
(±4 days) 
Post-
Surgery 
Weeks 6, 9 (±7 
days) 
Week 24    
(±14 days) 
Exit or early 
termination 
Assessment 
Pre-
Injection 
Study 
Drug 
IVT 
Post-
Injection 
 
 
 
 
 
 
 
Vitreous Tap for 
Cytokine / 
Biomarker Analysis 
SE 
 
 
 
 
 
 
 
 
 
Undiluted Vitreous 
Collection for 
Cytokine / 
Biomarker Analysis 
and ONL1204 Drug 
Levels  
 
 
 
 
SE 
 
 
 
 
 
Anterior Chamber 
Tap for Cytokine / 
Biomarker Analysis  
 
 
 
 
SE 
 
 
 
 
 
Adverse Events 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Note: Screening procedures are in red 
Abbreviations:  AE = Adverse event; ETDRS = Early Treatment Diabetic Retinopathy Study; IOP = Intraocular pressure; PK = Pharmacokinetic; Post-op = Postoperative; OU = 
Both eyes; SD OCT = Spectral Domain Optical Coherence Tomography; SE = Study eye; UA = Urine analysis. 
 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 29 of 52 
 
 
 
5 STUDY POPULATION 
5.1 
Number of Patients 
The study population includes approximately 16 patients to be enrolled at 2 primary sites 
in Australia. Additional sites will be available, if enrollment at the primary sites does not 
meet timeline goals. 
5.2 
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Males and females, ≥ 18 to 80 years old   
2. Able to give informed consent and comply with all study visits and procedures 
3. Patients who: 
a) Present between 1 week (7 days) and 4 weeks (28 days) of a macula-off RRD 
(based on patient-reported history of loss of central vision) 
b) For whom standard retinal reattachment surgery by means of a pars plana 
vitrectomy (with or without scleral buckle) and gas or oil tamponade is indicated, 
and 
c) In the opinion of the investigator, can safely undergo all study procedures. 
4. Best corrected Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity of 
20/100 to hand motion in the study eye 
5. Best corrected ETDRS visual acuity in the fellow eye of 20/60 or better 
5.3 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the 
study: 
1. Presence of giant retinal tear defined as greater than 3 clock hours or other type of 
complex retinal detachment in the study eye 
2. Presence of vitreous hemorrhage in the study eye 
3. Presence of ocular or periocular infection or intraocular inflammation in either eye 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 30 of 52 
 
 
 
4. Intraocular Pressure > 22 mmHg in the study eye 
5. Any other significant ocular disease in the study eye including media opacity that, in 
the opinion of the investigator, would preclude a visual acuity of at least 20/25 
following successful vitrectomy or limit adequate visibility of the retina 
6. Any other ocular pathology in the study eye requiring treatment with topical 
ophthalmic drops or intravitreal injection 
7. History of previous ocular surgery in the study eye other than uncomplicated cataract 
surgery with posterior chamber intraocular lens and intact posterior capsule or a 
refractive surgery (surgery must have occurred at least 3 months prior to the baseline 
visit) 
8. Participation in other clinical trials or use of any other investigational drugs or 
devices within 3 months prior to study participation  
9. Females who are pregnant or lactating and women of childbearing potential who are 
not using adequate contraceptive precautions (e.g., intrauterine device, oral 
contraceptives, barrier method, or other contraception deemed adequate by the 
investigator) 
10. Known retinopathy, known hepatic disease (or history of significant chronic liver 
disease), or known renal disease.  Patients with diabetes and no known retinopathy 
may be enrolled  
11. History of uncontrolled hypertension 
12. History of stroke, transient ischemic attack, or major cardiac surgery within 3 months 
prior to study, or current treatment for systemic infection 
13. Any ocular or systemic condition that in the opinion of the investigator could 
compromise the safety of the patient, or may interfere with the safety and tolerability 
assessments or study procedures of the trial 
6 
STUDY CONDUCT 
This trial will be conducted in compliance with the study protocol, Good Clinical Practice 
(GCP), applicable regulatory requirements, and International Conference on 
Harmonisation (ICH) guidelines. 
6.1 
Study Personnel and Organizations 
A full list of investigators is available in the sponsor’s investigator database.  


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 31 of 52 
 
 
 
6.2 
Treatment Assignment 
All patients will receive study drug in 1 of 4 treatment cohorts.   
6.3 
Recruitment of Patients 
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. 
6.4 
Study Procedures and Assessments 
6.4.1 
Study Visits 
There is a minimum of 10 scheduled study visits: 
• Visit 1:  Day 1 (baseline/injection) 
• Visit 2:  Day 2 (1day post-injection)  
• Visit 3:  Day of Vitrectomy (3 + days post-injection in accordance with standard of 
care)  
• Visit 4:  Postoperative visit (1 day post-surgery) 
• Visit 5:  Clearance of sentinel patient/cohort Day 14 (+4 days) post-surgery 
• Visit 6:  Week 6 (±7 days) 
• Visit 7:  Week 9 (±7 days) 
• Visit 8:  Week 24/Exit (±14 days) 
Patients may return for a non-scheduled visit at any time if deemed appropriate by the 
investigator. 
 
 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 32 of 52 
 
 
 
6.4.2 
Study Procedures 
Refer to the Schedule of Assessments (Table 4-1) for the timing of procedures.  
Additional details are provided as necessary in the manual of procedures (MOP), and in 
the sections that follow.  A list of study procedures for this study is below: 
• Vital signs 
• Height and weight 
• Clinical laboratory evaluation 
• ETDRS BCVA at 3 meters 
• Pin Hole Visual Acuity 
• Low Luminance BCVA at 3 meters 
• Low Contrast BCVA (2.5%) 
• Contrast Sensitivity using the Muenster Aging and Retina Study (MARS) system 
• Farnsworth D15 Color Vision Test 
• Intraocular Pressure  
• Slit Lamp Biomicroscopy 
• Indirect Ophthalmoscopy  
• Fundus photography  
• Fundus autofluorescence 
• Spectral Domain Optical Coherence Tomography (SD OCT)  
• B scan ultrasonography of the affected eye with measurement of the height of 
 
detachment at the macula (this assessment is optional) 
• Plasma ONL1204 levels 
• Vitreous tap for inflammatory cytokine and other potential molecular biomarker 
 
analysis at baseline (post-injection) and vitreous sampling (non-diluted) for cytokine 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 33 of 52 
 
 
 
 
and other potential molecular biomarker analysis and ONL 1204 levels at time of 
 
vitrectomy 
• Anterior chamber fluid (tap) for cytokine and other potential molecular biomarker 
 
analysis, and ONL1204 levels at baseline and at the time of vitrectomy 
• Injection of ONL1204  
• Urine pregnancy test (females of childbearing potential only) 
Additional Procedure: 
• Standard of care vitrectomy (with or without scleral buckling) with gas tamponade 
6.4.3 
Informed Consent 
Each patient must provide written informed consent before any study-required procedures 
are conducted, unless those procedures are performed as part of the patient’s standard 
care. 
6.4.4 
Patient Demographics 
The date of birth, race, ethnicity, and sex of the patient are to be recorded at baseline. 
6.4.5 
Medical History and Prior Medications 
During baseline, a complete medical history will be compiled for each patient.  In 
addition, medications taken by the patient 30 days prior to the IVT injection and 
throughout the study will be recorded. 
6.4.6 
Patient Height and Weight 
Height and weights will be measured only during baseline visit.   
6.4.7 
Vital Signs 
Vital signs will be assessed at the times specified in the Schedule of Assessments (Table 
4-1). Vital signs will consist of sitting blood pressure, heart rate, respiratory rate, and 
body temperature. 
6.4.8 
Pregnancy Test 
A urine pregnancy test will be performed for women of childbearing potential at Visit 1, 
pre-injection. Negative results must be available before the study drug is administered. A 
urine pregnancy test will also be repeated at the exit visit.  


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 34 of 52 
 
 
 
6.4.9 
Contraception and Pregnancy Avoidance Measures 
Due to the unknown effects of ONL1204 on sperm and the developing fetus, female 
patients of childbearing potential (i.e., non-sterilized, premenopausal female patients) and 
male patients must agree to use double barrier contraception methods throughout the 
study and for at least 30 days after the dose of study drug. Double barrier contraception is 
defined as a condom and one other form of the following: a) Birth control pills (The Pill), 
b) Depot or injectable birth control, c) IUD (Intrauterine Device), d) Birth control patch 
(e.g. Ortho Evra), e) NuvaRingR, f) Documented evidence of surgical sterilization at least 
6 months prior to the study drug injection, i.e., tubal ligation or hysterectomy for women 
or vasectomy for men. Rhythm methods during the study and for at least 30 days after the 
dose of study drug will not be acceptable. 
 
Male patients must not donate sperm for at least 24 weeks post-dose of the last study 
treatment. Male partners of female patients and female partners of male patients must 
also use contraception, if they are of childbearing potential.  
6.4.10 
Clinical Laboratory Tests 
The following clinical laboratory tests will be performed, according to the Schedule of 
Assessments (Table 4-1): 
• Complete blood count, including:  white blood cell (WBC) count with differential, 
hemoglobin (hgb), hematocrit (hct), and platelet count. 
• Renal function tests, including:  albumin, blood urea nitrogen (BUN), bicarbonate, 
calcium, chloride, creatinine, eGFR, glucose, phosphorus, potassium, and sodium.  
• Hepatic function tests, including:  alanine transaminase (ALT), alkaline phosphatase 
(ALP), albumin and total protein, aspartate transaminase (AST), bilirubin, and 
prothrombin time (PT). 
6.4.11 
Concomitant Medications and Procedures 
Medications used by the patient and therapeutic procedures completed by the patient will 
be recorded in the electronic Case Report Form (eCRF) from 30 days before treatment 
with study drug through the 24-week follow-up period of the study, or study exit. 
6.5 
Pharmacokinetics 
Systemic PK will be evaluated following IVT administration of ONL1204.  ONL1204 
will also be measured in the vitreous samples taken at the time of the vitrectomy.  
Samples will be shipped for PK analysis when available for each dose escalation cohort.  
Refer to the MOP for instructions.  


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 35 of 52 
 
 
 
6.6 
Ocular Pharmacodynamics 
Exploratory ocular PD will be assessed by cytokine and other potential molecular 
biomarker analysis of aqueous and vitreous samples taken at baseline (by vitreous tap) 
and at vitrectomy.  Samples will be shipped for cytokine analysis when available for each 
dose escalation cohort.  Refer to the MOP for instructions.  
6.7 
Protocol Deviations 
Deviations from this protocol, regulatory requirements, and/or GCP must be recorded and 
reported to the sponsor prior to database lock.  If needed, corrective and preventive action 
should be identified, implemented, and documented within the study records. 
6.8 
Premature Discontinuation 
Patients may discontinue the study if they desire at any time.  The primary reason for 
discontinuation should be recorded in the eCRF.  The procedures outlined in the Schedule 
of Assessments (Table 4-1) for exit/early termination should be completed if possible.  
Patients who exit from the study for reasons unrelated to treatment before completing 
Visit 4, may be replaced. 
7 
STUDY DRUG 
7.1 
Description 
ONL1204 is provided as a sterile liquid in single-use vials stored at 2 to 8°C (36 to 46°F) 
and is administered by intravitreal injection.   
7.2 
Formulation  
Study drug is available at concentration of 0.5 mg/mL or 2.0 mg/mL in 4.5% mannitol, 
0.4% poloxamer 407 and 10 mM acetate buffer pH 4.5.  
7.3 
Storage 
Upon receipt at the investigative site, ONL1204 vials should be stored at 2 to 8°C (36 to 
46°F).  All investigational supplies must be stored in a secure area with controlled access.  
All ONL1204 supplies should be used before the expiry date. 
7.4 
Packaging and Shipment 
ONL Therapeutics will provide the study material to the investigative sites.  ONL1204 
single-use vials will be packaged and labeled in accordance with all applicable 
regulations.  


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 36 of 52 
 
 
 
7.5 
Route, Dose and Administration 
ONL1204 is administered via IVT injection, so the drug can be distributed to the retina, 
ICB, and vitreous.   
The following doses will be evaluated:  25 µg, 50 µg, 100 µg and 200 µg. Patients will 
receive one intravitreal injection of ONL1204 to the one affected eye. The study vial 
contains either a 0.5 mg/mL or 2 mg/mL concentration of ONL1204 and a volume of 
0.05 or 0.1 ml is injected into the eye to deliver the desired dose (as described in MOP).   
7.6 
Permitted Concomitant Therapy 
Standard and necessary concomitant medications (such as drops) are permitted as 
indicated.  
7.7 
Prohibited Concomitant Therapy 
None. 
7.8 
Potential for Drug-Drug Interactions 
No pharmacokinetic interaction studies for ONL1204 have been conducted. 
7.9 
Accountability 
A drug dispensing log, including records of drug received from the sponsor and drug 
dispensed to the patients, will be provided and kept at the study sites.  The sponsor CRA 
will reconcile the study drug for that cohort. 
Proper drug accountability includes, but is not limited to: 
• Monitoring expiration dates if expiry date or retest date is provided to the 
Investigator.  
• Verifying that actual inventory matches documented inventory.  
• Verifying that the master drug log is completed for all study medication received at 
the site and that all required fields are complete, accurate, and legible.  
• Review of temperature log, and assure that the study medication is stored under 
locked, access-controlled conditions.  
• Verifying the patient individual drug accountability log is completed for each patient 
and that all required fields (units dispensed, returned, used, etc.) are complete, 
accurate, and legible.  


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 37 of 52 
 
 
 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately.  At the end of the study, the Investigator will retain all the original 
documentation regarding clinical study material accountability, return, and/or destruction, 
and copies will be sent to the sponsor. 
7.10 Compliance 
Study drug will be administered only to eligible patients under the supervision of the 
principal investigator or identified sub-investigator(s).  The appropriate study personnel 
will maintain records of study drug receipt and dispensing. 
7.11 Documenting Adverse Events 
All AEs spontaneously reported by the patient and/or in response to an open question 
from study personnel or revealed by observation or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF.  Any clinically relevant deterioration in 
laboratory assessments or other clinical finding is considered an AE.  This includes 
changes in ocular assessments, such as a decrease in visual acuity or a persistent increase 
in IOP.  When possible, signs and symptoms indicating a common underlying pathology 
should be noted as one comprehensive event. 
8 
ADVERSE EVENTS 
8.1 
Pretreatment Event Definition 
A pretreatment event is any untoward medical occurrence before administration of any 
study medication or study procedure in a patient or subject who has signed informed 
consent to participate in a study; it does not necessarily have to have a causal relationship 
with study participation. 
8.2 
Adverse Event Definition 
AE means any untoward medical occurrence in a patient or subject administered a 
pharmaceutical product or undergoing a study procedure; the untoward medical 
occurrence does not necessarily have a causal relationship with this treatment.  An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product or study procedure whether or not it is related to the medicinal 
product or study procedure.  This includes any newly occurring event, or a previous 
condition that has increased in severity or frequency since the administration of study 
drug or study procedure. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 38 of 52 
 
 
 
8.3 
Assessment of Intensity 
For both serious and non-serious AEs, the investigator must determine both the intensity 
of the event and the relationship of the event to study drug administration.  For serious 
pretreatment events, the investigator must determine both the intensity of the event and 
the relationship of the event to study procedures. 
8.4 
Assessment of Causality 
Relationship to study drug administration will be determined by the investigator with the 
following options to choose from:  Definitely related – Probably related – Possibly 
related – Unlikely/Remotely related – Not related – Unknown.  
8.5 
Clinical Laboratory Changes 
Blood samples for clinical laboratory evaluation, and urine for pregnancy test will be 
obtained as specified in the Schedule of Assessments (Table 4-1).  Any clinically 
significant or concerning laboratory results will be documented as an adverse event.   
8.6 
Adverse Event Follow-up 
All AEs, both non-serious and serious, will be monitored throughout the study until the 
exit visit, or 30 days after use of the study drug, whichever is longer.  Serious AEs will be 
followed to resolution or stabilization or until 30 days after subject completes the study. 
8.7 
Serious Adverse Events 
8.8 
Serious Adverse Event Definition  
A SAE is any event that meets any of the following criteria: 
• Death 
• Life-threatening 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a patient who received ONL1204 
• Other:  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 patient and may require medical or 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 39 of 52 
 
 
 
surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such events are: 
o Intensive treatment in an emergency room or at home for allergic bronchospasm 
o Blood dyscrasias or convulsions that do not result in inpatient hospitalization 
o Development of drug dependency or drug abuse 
o Study specific:  No study specific serious adverse events are expected 
Definition of Terms 
Life-threatening:  An AE is life-threatening if the patient was at immediate risk of death 
from the event as it occurred; i.e., it does not include a reaction that if it had occurred in a 
more serious form might have caused death.  For example, drug induced hepatitis that 
resolved without evidence of hepatic failure would not be considered life-threatening 
even though drug induced hepatitis can be fatal. 
Hospitalization:  AEs requiring overnight hospitalization should be considered SAEs.  
Hospitalization for elective surgery or routine clinical procedures that are not the result of 
AE (e.g., elective surgery for a pre-existing condition that has not worsened) need not be 
considered AEs or SAEs.  If anything untoward is reported during the procedure, that 
occurrence must be reported as an AE, either 'serious' or 'non-serious' according to the 
usual criteria. 
In general, hospitalization signifies that the patient has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or 
treatment that would not have been appropriate in the physician's office or outpatient 
setting.  When in doubt as to whether 'hospitalization' occurred or was necessary, the AE 
should be considered serious. 
Disability/incapacitating:  An AE is incapacitating or disabling if the experience results in 
a substantial and/or permanent disruption of the patient's ability to carry out normal life 
functions. 
8.9 
Reporting Serious Adverse Events 
Regardless of causality, upon signing the ICF, SAEs and serious pretreatment events 
must be reported by the investigator to the medical monitor and contract research 
organization (CRO) (contact information provided below), and if required, the 
investigator’s own Human Research Ethics Committee (HREC).  This should be done by 
faxing the SAE Form within 24 hours after becoming aware of the event.  The SAE Form 
will be provided to each clinical study site.  SAE report information must be consistent 
with the data provided on the eCRF. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 40 of 52 
 
 
 
SAE Reporting Contact Information: 
Novotech Pharmacovigilance Department, 
Email: safety@novotech-cro.com 
8.10 Overdose 
Any instance of overdose (suspected or confirmed of ONL1204, including any study dose 
higher than that which was assigned to the patient) must be reported to the medical 
monitor and CRO, and if required, the Investigator’s own HREC.  This must be done 
within 24 hours and be fully documented as an SAE.  Details of any signs or symptoms 
and their management should be recorded including details of any antidote(s) 
administered. 
9 
STATISTICS 
One database will be created after all patients in all cohorts have either completed the 
study or prematurely discontinued the study. A detailed statistical analysis plan (SAP) 
will be approved prior to database lock.   
9.1 
Statistical Design 
9.1.1 
Statistical Hypotheses 
No hypothesis will be formally tested in this study. 
9.1.2 
Sample Size 
The number of patients to be enrolled has been selected to provide information for this 
Phase 1 study.  No formal sample size calculation is provided given the pilot nature of 
this study.  
9.1.3 
Analysis Populations 
9.1.3.1 
ITT population 
All patients will be included in the intent to treat ITT Population.  
Safety Population: All patients will be included in the Safety Population.  Patient data 
will be summarized according to the dose they received. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 41 of 52 
 
 
 
9.1.3.2 
Ocular PK Population 
The ocular PK Population will comprise all patients in the Safety Population who provide 
adequate ocular PK samples to calculate the PK parameters.  Patients with protocol 
violations will be assessed on a patient-by-patient basis for inclusion in the ocular PK 
Population.  The PK analysis will be conducted using the ocular PK Population. 
For the pharmacokinetic data, per cohort and per protocol analyses will be performed.  
Each cohort population is defined as all patients within a dose cohort who received their 
assigned treatment and includes all those with no major protocol deviations. The per 
protocol population is defined as all patients who received their assigned treatment and 
includes all those with no major protocol deviations.  These populations will be 
determined well before database lock.  If patients withdraw from the study, their plasma 
concentration data may be included in the pharmacokinetic analysis provided there are no 
significant protocol noncompliance issues. 
9.2 
Study Endpoints 
9.2.1 
Primary Endpoints 
The primary endpoints will be the safety profile demonstrated in this study, including: 
• Adverse event reporting.  AEs will be split into study eye, non-study (fellow) eye, 
and systemic events 
• Clinical evaluations including BCVA 
• Clinical laboratory evaluations 
9.2.2 
Exploratory Endpoints 
• Measurement of ONL1204 drug levels in plasma and vitreous for PK analysis 
• Cytokine and other potential molecular biomarker measurement in aqueous and 
vitreous samples, taken by vitreous tap, and at vitrectomy. 
9.3 
Statistical Methods 
A statistical analysis plan will be developed and finalized before database lock and will 
describe the patient populations to be included in the analyses and procedures for 
accounting for missing, unused, and spurious data.  This section is a summary of the 
planned statistical analyses of the primary, secondary, and exploratory endpoints. 
In general, continuous variables will be summarized by descriptive statistics including 
sample size, mean, standard deviation, median, minimum, and maximum.  Geometric 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 42 of 52 
 
 
 
mean and CV% will be presented for PK parameters.  Categorical variables will be 
summarized by frequency and percentage.  Data for ONL1204 treated patients will be 
summarized at each time point by cohort.   
9.3.1 
Safety Analyses 
All safety analyses will be based on the Safety Population.  Safety will be assessed 
through adverse event reporting, clinical evaluations including BCVA, ophthalmic 
imaging, and clinical laboratory evaluation. 
9.3.1.1 
Adverse Events 
Adverse events will be coded to a Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term and system organ classification.  The occurrence of treatment-
emergent AEs will be summarized using MedDRA preferred terms, system organ 
classifications, and severity.  TEAEs are defined as adverse events that occurred or 
worsened following the first administration of study medication.  Separate summaries of 
treatment-emergent SAEs and TEAEs considered related to study treatment and AEs 
leading to study treatment discontinuation will be generated.  All AEs will be listed for 
individual patients showing both verbatim and preferred terms. 
Ocular and systemic AEs will be reported separately.  Ocular AEs will be split into study 
eye and fellow eye events.  Events reported in ‘both’ eyes will be counted in the study 
and fellow analysis.  Separate causality analyses will be performed for the study eye 
events (related to drug and related to procedure); for fellow eye and systemic events, 
causality will be assessed based on study drug alone.   
9.3.1.2 
Clinical Laboratory Results 
The clinical laboratory results (continuous parameters) will be presented by summary 
statistics for each laboratory parameter within the specific test panel.  In addition, 
summaries will include the change from baseline values at each scheduled post-baseline 
visit.  Laboratory values will be compared to normal range of the laboratory and values 
that fall outside of the normal ranges will be flagged as: H (High) and L (Low) in the data 
listings. 
9.3.1.3 
Vital Signs 
All vital signs parameters will be summarized using descriptive statistics for each 
treatment group for all timepoints assessed, including change from baseline for all post-
treatment assessments.   


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 43 of 52 
 
 
 
9.3.1.4 
BCVA 
BCVA will be summarized using descriptive statistics for each treatment group for all 
time points assessed, including change from baseline for all post-treatment assessments.  
BCVA assessment will be split between the study eye and fellow eye. 
9.3.1.5 
Ophthalmic Imaging 
Ophthalmic imaging will be conducted at the last study visit (exit/early termination), and 
these results will be measures of interest.  Parameters will be summarized using 
descriptive statistics by treatment group.  Ophthalmic Imaging assessments will be split 
between the study eye and fellow eye. 
9.3.1.6 
Intraocular Pressure 
IOP will be summarized using descriptive statistics for each treatment group for all time 
points assessed, including change from baseline for all post-treatment assessments.  
BCVA assessment will be split between the study eye and fellow eye. 
9.3.1.7 
Systemic PK  
The amount of study drug present in the patient plasma will be summarized at each time 
point.  ONL1204 concentrations that are below the quantitation limit (BQL) will be set to 
0 if before the first quantifiable concentration and to 0 thereafter for all descriptive 
analyses of ONL1204.  For the calculation of geometric mean and geometric CV%, all 
BQL values will be set to missing.  The number of BQL values at each time point will be 
summarized through frequency counts and percentages. 
9.3.1.8 
Other Parameters 
Other safety data will be listed by treatment group and may be further evaluated through 
descriptive summaries.  Concomitant medications will be coded using the World Health 
Organization drug dictionary and summarized by treatment group. 
9.3.2 
Ocular PK Analyses 
Ocular PK will be analyzed per treatment group as well as per protocol across all 
treatment groups.  Concentration data from the bioanalysis of the ocular fluid samples 
will be reported in summary tables.  Pharmacokinetic parameters (e.g., Tmax, Cmax, 
terminal t1/2, AUC0-last, and AUC0-infinity) may be calculated based on the 
concentration data from the bioanalysis of the collected samples, if appropriate.  


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 44 of 52 
 
 
 
9.3.3 
PD Analyses 
Pharmacodynamic statistical analyses will be conducted based on the proteomic analysis 
of cytokine biomarkers in ocular fluids.  
Vitreous and aqueous humor sample results and changes from baseline will be 
summarized by treatment group. Treatment effect will be assessed within and between 
treatment groups using an appropriate statistical method. The analysis will be based on 
log-transformed data if required. 
Measurements below or above the limits of detection will be censored at the laboratory 
reported lower or upper limit of detection. Analytes will not be included in the analyses if 
more than half of the measurements in a treatment group are below the limit of detection.  
Further exploratory analyses may be performed to evaluate potential dose-related 
measures. 
9.3.4 
Demographic and Baseline Characteristics 
Demographic information (age, sex, ethnicity, race) will be summarized by treatment arm 
based on the ITT population. 
9.4 
Interim Analysis 
There are no plans to conduct an interim analysis for this study. 
10 
ETHICS AND RESPONSIBILITIES 
10.1 Good Clinical Practice 
The study will be conducted in accordance with the ICH GCP and the appropriate 
regulatory requirements.  The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and the IB. 
10.2 Safety Review Committee 
A safety review committee (SRC) comprising of relevant site investigators, the medical 
monitor, and sponsor representative will oversee safety, sentinel patient clearance, cohort 
evaluation, and dose escalation for the study.  A formal charter will be established to 
include the rules, meeting frequency, and scope of responsibilities of the SRC for the 
conduct of the SRC. The respective IRB’s will be informed of the outcome of the SRC 
meetings. 
 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 45 of 52 
 
 
 
The decision to dose-escalate to the next cohort will include evaluation of potential dose 
limiting toxicities as detailed in Section 4.2.1 as well as adverse events, clinical 
laboratory evaluations and ophthalmologic imaging data.  Applicable sections of the 
Common Terminology Criteria for Adverse Events (CTCAE) version 5, 17Nov2017 will 
be used to grade adverse events. 
10.3 Human Research Ethics Committee 
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards.  The HREC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the patients.  The study 
will be conducted only at sites where HREC approval has been obtained.  The protocol, 
IB, informed consent form, advertisements (if applicable), written information given to 
the patients, safety updates, annual progress reports, and any revisions to these 
documents will be provided to the HREC by the investigator or the sponsor, as allowed 
by local regulations. 
10.4 Informed Consent 
After the study has been fully explained, written informed consent will be obtained from 
the patient before study participation.  The method of obtaining and documenting the 
informed consent and the contents of the consent must comply with the ICH GCP and all 
applicable regulatory requirements. 
10.5 Records Management 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient.  Study data will be entered into an eCRF by site personnel using a secure, 
validated, web-based electronic data capture (EDC) application.  ONL Therapeutics will 
have access to all data upon entry in the EDC application. 
Study monitors will discuss instances of missing or uninterpretable data with the 
investigator for resolution.  Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF. 
10.6 Source Documentation 
The study sites will be provided with secure access to and training on the EDC 
application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 46 of 52 
 
 
 
eCRFs will be completed for each patient.  It is the investigator’s responsibility to ensure 
the accuracy, completeness, clarity, and timeliness of the data reported in the patient’s 
eCRF. 
The investigator, or designated representative, should complete the eCRF within 
5 business days of visit. 
10.7 Study Files and Record Retention 
The investigator will maintain all study records according to the ICH GCP and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s).  If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
ONL Therapeutics must be notified. 
11 
AUDITING AND MONITORING 
Monitoring and auditing procedures developed or approved by ONL Therapeutics will be 
followed to comply with GCP guidelines. 
All information recorded on the eCRFs for this study must be consistent with the 
patient’s source documentation.  Study monitors will visit the sites throughout the study 
to review and confirm that information in the eCRF corresponds with source documents 
for the patient.  They will also assess drug accountability and ensure that the study is 
being conducted according to pertinent regulatory requirements.  The review of all 
patient data will be performed in a manner that ensures patient confidentiality is 
maintained.  
12 
AMENDMENTS 
Protocol modifications, except those intended to reduce immediate risk to study patients, 
may be made only by ONL Therapeutics.  A protocol change intended to eliminate an 
apparent immediate hazard to patients may be implemented immediately, provided the 
HREC is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment.  The 
written amendment must be submitted to the HREC and the investigator must await 
approval before implementing the changes.  ONL Therapeutics will submit protocol 
amendments to the appropriate regulatory authorities for approval. 
If in the judgment of the HREC, the investigator, and/or ONL Therapeutics, the 
amendment to the protocol substantially changes the study design and/or increases the 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
Page 47 of 52 
 
 
 
potential risk to the patient and/or has an impact on the patient's involvement as a study 
participant, the currently approved written informed consent form will require similar 
modification.  In such cases, informed consent will be renewed for patients enrolled in 
the study before continued participation. 
13 
STUDY REPORT AND PUBLICATIONS 
ONL Therapeutic is responsible for preparing and providing the appropriate regulatory 
authorities with clinical study reports according to the applicable regulatory 
requirements. 
The publication policy of ONL Therapeutics is discussed in the investigator's Clinical 
Research Agreement. 
14 
STUDY DISCONTINUATION  
Both ONL Therapeutics and the Principal Investigator reserve the right to terminate the 
study at the investigator’s site at any time.  Should this be necessary, ONL Therapeutics 
or a specified designee will inform the appropriate regulatory authorities of the 
termination of the study and the reasons for its termination, and the Principal Investigator 
will inform the HREC of the same.  In terminating the study, ONL Therapeutics and the 
Principal Investigator will assure that adequate consideration is given to the protection of 
the patients’ interests. 
15 
CONFIDENTIALITY 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written 
consent is gained from ONL Therapeutics.  However, authorized regulatory officials, 
HREC personnel, ONL Therapeutics, and its authorized representatives are allowed full 
access to the records. 
Identification of patients and Case Report Forms shall be by initials, screening, and 
treatment numbers only.  If required, the patient's full name may be made known to an 
authorized regulatory agency or other authorized official. 
 
 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
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16 
APPENDICES 
16.1 APPENDIX I – Sponsor Contact Information 
 
Sponsor: 
ONL Therapeutics 
1600 Huron Pkwy 
Building 520, Second Floor 
Ann Arbor, MI 48109 
 
Clinical Research 
Organizations: 
 
Novotech 
Level 3, 325 Pyrmont Street 
Pyrmont, NSW 2009 Australia 
 
16.2 APPENDIX II – Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF 
HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects,  
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended 
by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996, 
and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. 
INTRODUCTION 
The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other participants in medical 
research involving human subjects.  Medical research involving human subjects includes 
research on identifiable human material or identifiable data. 
It is the duty of the physician to promote and safeguard the health of the people.  The 
physician’s knowledge and conscience are dedicated to the fulfillment of this duty. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
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The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my subject will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the subject's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the subject." 
Medical progress is based on research, which ultimately must rest in part on 
experimentation involving human subjects. 
In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the etiology 
and pathogenesis of disease.  Even the best-proven prophylactic, diagnostic, and 
therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
Medical research is subject to ethical standards that promote respect for all human beings 
and protect their health and rights.  Some research populations are vulnerable and need 
special protection.  The particular needs of the economically and medically 
disadvantaged must be recognized.  Special attention is also required for those who 
cannot give or refuse consent for themselves, for those who may be subject to giving 
consent under duress, for those who will not benefit personally from the research, and for 
those for whom the research is combined with care. 
Research investigators should be aware of the ethical, legal, and regulatory requirements 
for research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal, or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this Declaration. 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and on adequate laboratory and, where appropriate, animal 
experimentation. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
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Appropriate caution must be exercised in the conduct of research, which may affect the 
environment, and the welfare of animals used for research must be respected. 
The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol.  This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
investigator, the sponsor or any other kind of undue influence.  This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed.  The committee has the right to monitor ongoing 
trials.  The researcher has the obligation to provide monitoring information to the 
committee, especially any SAEs.  The researcher should also submit to the committee, for 
review, information regarding funding, sponsors, institutional affiliations, other potential 
conflicts of interest and incentives for subjects. 
The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration.  
Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  
The responsibility for the human subject must always rest with a subject of the research, 
even though the subject has given consent. 
Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to 
the subject or to others.  This does not preclude the participation of healthy volunteers in 
medical research.  The design of all studies should be publicly available. 
Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and can 
be satisfactorily managed.  Physicians should cease any investigation if the risks are 
found to outweigh the potential benefits or if there is conclusive proof of positive and 
beneficial results. 
Medical research involving human subjects should only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the subject.  This is 
especially important when the human subjects are healthy volunteers. 
Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research. 
The subjects must be volunteers and informed participants in the research project. 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
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The right of research subjects to safeguard their integrity must always be respected.  
Every precaution should be taken to respect the privacy of the subject, the confidentiality 
of the subject’s information and to minimize the impact of the study on the subject's 
physical and mental integrity and on the personality of the subject. 
In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study, and 
the discomfort it may entail.  The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal.  After ensuring that the subject has understood the information, the physician 
should then obtain the subject's freely-given informed consent, preferably in writing.  If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
When obtaining informed consent for the research project, the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or 
may consent under duress.  In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law.  
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent 
to decisions about participation in research, the investigator must obtain that assent in 
addition to the consent of the legally authorized representative. 
Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population.  The 
specific reasons for involving research subjects with a condition that renders them unable 
to give informed consent should be stated in the experimental protocol for consideration 
and approval of the review committee.  The protocol should state that consent to remain 
in the research should be obtained as soon as possible from the individual or a legally 
authorized surrogate. 
Both authors and publishers have ethical obligations.  In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results.  Negative as 
well as positive results should be published or otherwise publicly available.  Sources of 


16.1.1 Protocol ONL1204-RRD-001 
Confidential 
ONL1204-RRD-001- A Phase 1 Open-Label, Dose Escalation Study to Assess the 
Safety, Tolerability, PK and Ocular PD of Intravitreal ONL1204 in Patients with 
Macula-off, Rhegmatogenous Retinal Detachment. 
 
ONL1204 
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funding, institutional affiliations and any possible conflicts of interest should be declared 
in the publication.  Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication. 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED 
WITH MEDICAL CARE 
The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic, or therapeutic value.  
When medical research is combined with medical care, additional standards apply to 
protect the subjects who are research subjects. 
The benefits, risks, burdens, and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods.  This does not 
exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists. 
At the conclusion of the study, every subject entered into the study should be assured of 
access to the best-proven prophylactic, diagnostic, and therapeutic methods identified by 
the study. 
The physician should fully inform the subject which aspects of the care are related to the 
research.  The refusal of a subject to participate in a study must never interfere with the 
subject-physician relationship. 
In the treatment of a subject, where proven prophylactic, diagnostic, and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the subject, must be free to use unproven or new prophylactic, diagnostic, and therapeutic 
measures, if in the physician’s judgment it offers hope of saving life, re-establishing 
health, or alleviating suffering.  Where possible, these measures should be made the 
object of research, designed to evaluate their safety and efficacy.  In all cases, new 
information should be recorded and, where appropriate, published.  The other relevant 
guidelines of this Declaration should be followed. 

SAP_001.pdf: 
Protocol Number: ONL1204-RRD-001 
 
2022-09-14 
Document status: Final Version 2.0 
 
Novotech – Strictly Confidential 
 
                                                            Page 1 of 39 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
A Phase I Open-Label, Dose Escalation Study to Assess the Safety and 
Tolerability of Intravitreal ONL1204 in Patients with Macula-off, 
Rhegmatogenous Retinal Detachment 
 
PROTOCOL NO.: 
ONL1204-RRD-001 
 
PRODUCT CODE: ONL1204 
 
PREPARED FOR: 
ONL Therapeutics 
 
1600 Huron Pkwy, 
 
Building 520, Second Floor,  
 
Ann Arbor MI, 
                                          48109, 
                                          USA 
 
PREPARED BY: 
Novotech (Australia) Pty Ltd 
 
Level 3, 235 Pyrmont Street 
 
Pyrmont, NSW, 2009  
 
Australia  
 
DATE OF ISSUE: 
2022-09-14 
 
VERSION/STATUS: 
Final Version 2.0 
 
VERSION HISTORY:   Draft Version 0.1 (2021-10-14)  
                                          Draft Version 0.2 (2022-02-10)  
                                          Final Version 1.0 (2022-04-20)  
                                          Draft Version 1.1 (2022-09-06)  
                                          Final Version 2.0 (2022-09-14) 
 
 
AUTHOR: 
 
 
The information in this document is confidential and proprietary to Novotech Pty Ltd and its 
clients. The information may only be used by the entities to which it was disclosed for the purpose 
it was disclosed. To the maximum extent permissible by law, the information must not be 
disclosed to any third parties without the prior written consent of Novotech. 




Protocol Number: ONL1204-RRD-001 
 
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Document status: Final Version 2.0 
 
Novotech – Strictly Confidential 
 
                                                            Page 3 of 39 
 
Table of contents 
 
1. 
INTRODUCTION 
6 
2. 
PROJECT OVERVIEW 
7 
2.1 
Study Design 
7 
2.2 
Objectives 
8 
2.3 
Endpoints 
8 
2.4 
Sample Size 
8 
2.5 
Randomization 
8 
3. 
STATISTICAL CONSIDERATIONS 
9 
3.1 
General Considerations 
9 
3.2 
Key Definitions 
10 
3.3 
Inferential Analyses 
11 
3.4 
Multiple Comparisons and Multiplicity Adjustments. 
11 
3.5 
Handling of Missing Data 
11 
3.6 
Coding of Events and Medications 
12 
3.7 
Treatment Groups 
12 
4. 
ANALYSIS POPULATIONS 
13 
4.1 
Population Descriptions 
13 
5. 
PARTICIPANT DISPOSITION AND ANALYSIS POPULATIONS 
15 
6. 
PROTOCOL DEVIATIONS 
16 
7. 
DEMOGRAPHIC AND BASELINE INFORMATION 
17 
7.1 
Demographics 
17 
7.2 
Medical History 
17 
7.3 
Disease History 
17 
8. 
TREATMENT EXPOSURE 
18 
9. 
PRIOR AND CONCOMITANT MEDICATIONS 
19 
10. 
PHARMACOKINETICS 
20 
10.1 
Plasma PK Analysis 
20 
10.2 
Ocular PK analysis 
23 
11. 
PHARMACODYNAMICS 
24 
12. 
EFFICACY 
25 
13. 
SAFETY 
26 
13.1 
Adverse Events 
26 
13.2 
Safety Laboratory Assessments 
26 
13.3 
Vital Signs 
27 
13.4 
Ophthalmologic Assessments 
28 
13.5 
Pregnancy Test Results 
31 


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14. 
IMMUNOGENICITY 
32 
15. 
CHANGES TO THE PLANNED ANALYSIS 
33 
16. 
Final Analysis (End of Study) 
33 
16.1 
Final Analysis 
33 
17. 
SOFTWARE 
34 
18. 
TABLES 
35 
19. 
LISTINGS 
37 
21. 
REFERENCES 
39 


Protocol Number: ONL1204-RRD-001 
 
2022-09-14 
Document status: Final Version 2.0 
 
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                                                            Page 5 of 39 
 
List of Abbreviations 
 
Abbreviation 
Description 
R2 adj 
Corrected goodness-of-fit 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Class 
AUC 
Area under the curve 
BCVA 
Best Corrected Visual Acuity  
BLQ 
Below limit of quantification 
nBLQ 
Number of participants below limit of quantification 
BMI 
Body Mass Index 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CI 
Confidence Intervals 
CV 
Coefficient of Variation 
DA 
Dark Adaptometry 
DBP 
Diastolic blood pressure 
ECG 
12-Lead Electrocardiogram  
ETDRS 
Early Treatment Diabetic Retinopathy Study  
FSH 
Follicle Stimulating Hormone 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
IOP 
Intra-Ocular Pressure 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
N/A 
Not Applicable 
NCA 
Non-compartmental analysis 
NCS 
Not Clinically Significant 
NK 
Not Known 
PI 
Principal Investigator 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PO 
per oral 
PT 
Preferred Term 
RBP4 
Retinol-Binding Protein 4  
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard Deviation 
S.I. 
International System of Units 
SOC 
System Organ Class 
 
 
 
 


Protocol Number: ONL1204-RRD-001 
 
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1. 
INTRODUCTION 
The following Statistical Analysis Plan (SAP) provides the outline for the statistical analysis of data 
collected from the ONL1204 study (Protocol Version 1.3 dated 3 July 2019, protocol version 1.5 dated 
10th May 2020, protocol version 1.6 dated 27th July 2020). 
Protocol v1.3 and v1.4 had a total of 10 visits and all these visits are captured for patients 111-001, 111-
002, 111-005, 222-002 only. 
Protocol v1.5 had a total of 8 visits and are applicable to the rest of the patients.  
Protocol v1.6 was introduced only for the use of site 444, to allow for the pre-injection B Scan 
Ultrasonography to be optional at Visit 1/Day1. This was brought about as the site did not have access 
to the relevant equipment. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), regulatory 
submissions, or future manuscripts. Also, post hoc exploratory analyses not necessarily identified in this 
SAP may be performed to further examine study data. Any post hoc, or unplanned, exploratory analyses 
performed will be clearly identified as such in the final CSR. 


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2. 
PROJECT OVERVIEW 
Study Design 
This proposed study is a single-injection, open-label, dose escalation study to assess the use of 
intravitreal ONL1204 in patients with macula-off rhegmatogenous retinal detachment (RRD). 
Approximately 16 patients with RRD will be enrolled. The expected duration of patient participation in 
the study is approximately 24 weeks (treatment, then 24 weeks of follow-up). 
Figure 1: 
Study Design 
 
*Patients may be replaced who do not receive an injection of study medication, or from discontinuing 
from the study for reasons unrelated to treatment before completing Visit 4. 
Sixteen patients will be enrolled in 4 ascending dose groups. 
After signing informed consent and meeting all eligibility criteria, patients will undergo a vitreous tap 
for cytokine and other potential molecular biomarker analysis followed by a single intravitreal injection 
of ONL1204. This will occur on the day of diagnosis (Day 1). Safety visits will be conducted 1-day post-
injection and per Investigator’s discretion until Visit 3. At Visit 3 (3+ days post-injection, in accordance 
with standard of care) patients will undergo surgical repair of their retinal detachment with vitrectomy 
(with or without scleral buckling) and gas or oil tamponade. At the time of surgery, an undiluted vitreous 
sample will be collected for pharmacokinetic and pharmacodynamics analyses, and an aqueous sample 
will be collected for pharmacodynamic analysis. Additional safety visits will be conducted 1-day post-
surgery, 14 (+4 days) days post-surgery, Weeks 6, 9 (±7 days each), and Week 24 (±14 days; study exit). 
As this is a first-in-human safety study of ONL1204, the first patient in the first cohort will receive the 
lowest dose of ONL1204. After this patient completes Visit 5 (14 +4 days post-surgery) and a safety 
review committee reviews the data, the remainder of the patients in that cohort will be enrolled. After all 
patients in the cohort have completed Visit 5, the SRC will review the available safety data to determine 
if dose limiting toxicity exists that prohibits enrolling the next higher dose cohort. This process will be 
repeated until escalating to the top dose. 
The following doses will be evaluated: 25 µg, 50 µg, 100 µg, and 200 µg ONL1204. ONL1204 
ophthalmic solution is available in vials with concentrations of 0.5 mg/mL and 2 mg/mL. Therefore, a 
volume of 0.05 or 0.1 mL will be injected into the study eye. 
16 patients to be enrolled*
Cohort 1
4 patients: 1 sentinel patient, 3 patients 
25 μg ONL1204
Cohort 2
4 patients: 1 sentinel patient, 3 patients
50 μg ONL1204
Cohort 3
4 patients: 1 sentinel patient, 3 patients
100 μg ONL1204
Cohort 4
4 patients: 1 sentinel patient, 3 patients
200 μg ONL1204


Protocol Number: ONL1204-RRD-001 
 
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Objectives 
2.1.1 
Primary objective 
The primary objective will be to determine the Maximum Tolerated Dose (MTD) of ONL1204 and select 
doses for Phase 2. Determination of this will be through review of the parameters measured in the 
Schedule of Assessments, as well as adverse event (AE) reports. 
2.1.2 
Secondary objective 
Not Applicable 
2.1.3 
Exploratory objective 
During the study, ocular fluid samples will be collected at the time of study drug injection and at the 
time of vitrectomy. These samples will be used for pharmacokinetic and pharmacodynamic analyses, the 
results of which will help inform the dose selection for the Phase 2 trial(s). 
Endpoints 
2.1.4 
Primary endpoints 
The primary endpoints will be the safety profile demonstrated in this study, including: 
• 
Adverse event reporting 
• 
Clinical evaluations including BCVA 
• 
Clinical laboratory evaluation 
2.1.5 
Secondary endpoint 
Not Applicable. 
2.1.6 
Exploratory endpoints 
The exploratory endpoints will be the pharmacokinetic and pharmacodynamic analyses performed in 
this study, including: 
• 
Measurement of ONL1204 drug levels in plasma and vitreous fluid for PK analysis 
• 
Cytokine and other potential molecular biomarker measurement in aqueous and vitreous 
samples, taken by vitreous tap, and at vitrectomy 
Sample Size 
The number of patients to be enrolled has been selected to provide information for this Phase 1 study. 
No formal sample size calculation is provided given the open-label nature of this study. 
Randomization 
This is an open-label study, and all patients will be receiving study drug. 


Protocol Number: ONL1204-RRD-001 
 
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3. 
STATISTICAL CONSIDERATIONS 
Data will be handled and processed per the sponsor’s representative (Novotech) Standard Operating 
Procedures (SOPs), which are written based on the principles of good clinical practice (GCP). 
General Considerations 
All data collected on the electronic case report form (eCRF) will be presented in the data listings and 
will be listed and sorted by cohort, participant number and visit, where applicable. All descriptive 
summaries will be presented by cohort and nominal visit/time point (where applicable). 
All safety, PD and PK descriptive summaries will be presented by cohort. All disposition and, 
concomitant medication descriptive summaries will be presented by cohort and nominal visit/time point 
(where applicable). 
Unless otherwise stated, the following methods will be applied: 
• 
Continuous variables: Descriptive statistics will include the number of non-missing values (n), 
arithmetic mean, standard deviation (SD), median, minimum, and maximum values. 
The minimum and maximum values will be displayed to the same decimal precision as the source 
data, the arithmetic mean, SD, and median values will be displayed to one more decimal than the 
source data for the specific variable. 
95% Confidence Intervals (CIs), mean differences (among treatments and from baseline) and 
least-square (LS-Means) values will be displayed to one more decimal than the source data for a 
specific variable. P-values will be displayed to 3 decimal places. 
The appropriate precision for derived variables will be determined based on the precision of the 
data on which the derivations are based, and statistics will be presented in accordance with the 
above-mentioned rules. 
• 
PK data: The actual blood sampling dates and times relative to dosing time will be listed by 
participant and nominal sampling time, with time deviation calculated, for all participants with 
available plasma and vitreous concentration data, including participants excluded from the PK 
population. Individual (for each participant) and mean concentrations over time will be displayed 
graphically in linear and semi-logarithmic plots of concentrations versus time. The actual 
collection time will be used for individual plasma concentration curves and the nominal time will 
be used for the plots of mean plasma concentration curves. Similar plot will be provided using 
vitreous concentration. 
For PK concentration data, the number of non-missing values, number of below limit of 
quantification (BLQ) values, arithmetic mean, standard deviation, median, minimum, maximum, 
coefficient of variation (CV%), geometric mean and geometric coefficient of variation (geo CV%) 
values will be presented. For the calculation of summary statistics, unrounded data will be used 
and reported to three significant figures except for n, n BLQ, and CV% which will be presented 
to the nearest integer and one decimal place, respectively. 
For PK parameters data, the number of non-missing values, arithmetic mean, standard deviation, 
median, minimum, and maximum values will be presented. Individual PK parameters will be 
presented to three significant figures except for Tmax which will be presented to two decimal 
places. 
• 
Categorical variables: Descriptive statistics will include counts and percentages per category. The 
denominator in all percentage calculations will be the number of participants in the relevant 
analysis population with non-missing data, unless specifically stated otherwise. Percentages will 
be displayed to one decimal place. Proportions will be displayed to 3 decimal places. 
• 
Unscheduled assessments: Only values collected at scheduled study visits/time points will be 
presented in summary tables. If a repeat assessment was performed, the result from the original 
assessment will be presented as the result at the specific visit/time point. All collected data will be 
included in the data listings. 


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• 
Assessment windows: All assessments will be included in the data listings and no visit windows 
will be applied to exclude assessments that were performed outside of the protocol specified 
procedure windows. 
• 
Result display convention: Results will be center aligned in all summary tables and listings. 
Participant identifiers visit and parameter labels may be left-aligned if required. 
• 
Date and time display conventions: The following display conventions will be applied in all 
outputs where dates and/or times are displayed: 
Date only: YYYY-MM-DD 
Date and time: YYYY-MM-DD HH:MM 
If only partial information is available, unknown components of the date or time will be presented as 
‘NK’ (not known), i.e., ‘2016-NK-NK’. Times will be reported in military time. 
Key Definitions 
The following definitions will be used: 
• 
Baseline: The baseline value is defined as the last available valid (quantifiable continuous or 
categorical value), non-missing observation for each participant prior to first study drug 
administration. Repeat and unscheduled assessments will be included in the derivation of the 
baseline values. 
• 
Change from Baseline: The change from baseline value is defined as the difference between the 
result collected/derived at a post-baseline visit/time point and the baseline value. 
The change from baseline value at each post-baseline visit/time point will be calculated for all 
continuous parameters using the following formula: 
Change from Baseline Value = Result at Visit/Time Point – Baseline Value 
The change from baseline value will only be calculated if the specific post-baseline visit/time point 
result and the baseline value for the parameter are both available and will be treated as missing 
otherwise. 
• 
Study day: The study day of an event is defined as the relative day of the event starting with the 
date of the first study drug administration (reference date) as Day 1 (there will be no Day 0). 
The study day of events occurring before the first study drug administration will be calculated as: 
Study Day = (Date of Event - Date of First Study Drug Administration) 
For events occurring on or after Day 1, study day will be calculated as: 
Study Day = (Date of Event - Date of First Study Drug Administration) + 1 
Study days will only be calculated for events with complete dates and will be undefined for 
events that are ‘Ongoing’ at the end of the study. 
Relative days compared to an alternative reference point will be calculated similarly, but the 
alternative starting reference start date will be used instead of the date of the first study drug 
dosing. 
• 
Prior Medications: Prior medications are defined as any medication where the use was stopped 
prior to the first administration of the study medication. 
• 
Concomitant Medications: Concomitant medications are defined as any medication (other than 
the study drug) that was used at least once after the first administration of the study drug. 
Medications that were stopped on the same date as the first study drug administration will be 
defined as concomitant medications. If a clear determination cannot be made (partial medication 
end dates) the medication will be classified as concomitant. 


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• 
Actual Time from First Dose (hours) = (Date/Time of First Dose PK Sample collection) – 
(Date/Time of First Dose)  
• 
Actual Time Deviation (hours) = (Actual PK Sample Collection Time Post Dose) – (Scheduled 
PK Sample Collection Time Post Dose).  
• 
Treatment Emergent Adverse Events (TEAEs) are defined as adverse events that occurred 
following the first administration of study medication. 
Inferential Analyses 
Descriptive statistics will be used to summarize the safety, PD and PK data. No formal hypothesis testing 
is planned. 
Multiple Comparisons and Multiplicity Adjustments. 
Not applicable for this study. 
Handling of Missing Data 
For the classification of Treatment emergent adverse event (TEAE) and Concomitant medication, the 
following will be applied in the following order: 
a. 
If all dates/times (start and stop) missing, the event/medication will automatically be classified as 
a TEAE/Concomitant medication. 
b. 
For AEs with a missing start date/time, if the event end date/time is prior to first study drug 
administration, the event will not be classified as a TEAE. 
c. 
If only the AE start year/ medication end year is present and is the same or is after the first study 
drug administration year unit, the event/medication will be classified as a TEAE/Concomitant 
medication. 
d. 
If the AE start month and year/medication end month and year are present and are the same or 
after the first study drug administration month and year units, the event/medication will classified 
as a TEAE/Concomitant medication. 
For plasma concentration-time data/profiles and PK analysis the following will be applied: 
a. 
Concentrations that are below limit of quantification (BLQ) prior to the dosing (Pre-dose) will be 
set equal to zero. Post dose BLQ concentrations will be set to zero. 
b. 
Where there are no results, these will be set to missing. 
c. 
If more than 75% of values per nominal timepoint and treatment group are BLQ, then all 
descriptive statistics, except for nBLQ, will be denoted as not calculable (NC). 
d. 
For the purpose of calculating the non-compartmental plasma PK parameters, concentrations that 
are BLQ prior to the first quantifiable value will be set equal to zero and BLQ values after 
measurable concentrations will be set to zero.  
e. 
For the calculation of summary statistics of plasma PK parameters, all NR (not reported) and NC 
(not calculable) values in a data series will be set to missing. 
f. 
The specific reasons for ‘not calculable (NC)’ and ‘not reported (NR)’ for PK parameters will be 
provided as footnotes in the PK results listings and summaries. 
 
For vitreous concentration-time data/profiles the following will be applied: 
a. 
Concentrations that are below limit of quantification (BLQ) prior to the dosing (Pre-dose) will be 
set equal to zero. Post dose BLQ concentrations will be set to zero. 
b. 
Where there are no results, these will be set to missing. 


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c. 
If more than 75% of values per nominal timepoint and treatment group are BLQ, then all 
descriptive statistics, except for nBLQ, will be denoted as not calculable (NC). 
Conversion of categorical values 
In some instances, continuous variables are expressed as a range (i.e., < 10). In such cases, values may 
be converted to the range boundary (upper or lower limit as applicable). As an example, a value of <10 
may be converted to 10. Such substitutions will be clearly documented in the footnotes of relevant 
outputs. 
Coding of Events and Medications 
Medical history and AE verbatim terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) using version 23.0. Terms will be coded to the full MedDRA hierarchy, but the 
system organ class (SOC) and preferred terms (PT) will be of primary interest for the analysis. 
Prior and concomitant medications will be coded using the World Health Organization Drug Dictionary 
using the latest version available at the time of study commencement. Medications will be mapped to 
the full WHO-DD Anatomical Therapeutic Chemical (ATC) class hierarchy, but PTs will be of primary 
interest in this analysis. 
Treatment Groups 
• 
Cohort 1 - ONL1204 25 µg 
• 
Cohort 2: - ONL1204 50 µg 
• 
Cohort 3 - ONL1204 100 µg 
• 
Cohort 4 - ONL1204 200 µg 
• 
Overall 
 
 


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4. 
ANALYSIS POPULATIONS  
In this study five analysis populations are defined: The Intent-to-Treat (ITT), Safety population, Per 
Protocol, Pharmacokinetic (PK) and Pharmacodynamic (PD). 
Furthermore, any additional exploratory analysis not identified in the SAP will be identified in the final 
CSR as exploratory post hoc analyses, including analyses for additional study populations or subgroups 
of interest. 
Population Descriptions 
4.1.1 
ITT Population 
The ITT population will be defined as all patients enrolled for the study.  
All disposition and demographic data analysis will be based on the ITT population. All listings will be 
presented by the ITT population. 
4.1.2 
Safety Population 
The Safety population will be defined as all patients who received the study drug and will be based on 
actual treatment received. 
All safety analyses will be based on the Safety population. 
4.1.3 
Per Protocol Population 
The per protocol formulation is defined as all patients who received their assigned treatment and includes 
all those with no major protocol deviations. 
4.1.4 
Pharmacokinetic Population 
 Ocular PK population 
All patients who are included in the safety population and for whom quantified vitreous (ocular) 
concentration of ONL1204 is available will be included in the ocular PK population. Patients with 
protocol violations will be assessed on a patient-by-patient basis for inclusion in the ocular PK 
Population. Ocular PK Population determination will be made before database lock by the Study 
Pharmacokineticist. This ocular PK population will be used for the summaries and graphical presentation 
of ocular ONL1204 concentration data. 
 Plasma PK population 
For the systemic PK data, per cohort and per protocol analysis will be performed. All patients who are 
included in the safety population with no major protocol deviations, who provide adequate PK samples 
and have a sufficient PK profile that allows the calculation of relevant PK parameters will be included 
in the PK population. 
Plasma PK population is defined as all patients who are included in the safety population and for whom 
an evaluable plasma concentration-time profile of ONL1204 is available for the determination of at least 
one of the PK parameters among Cmax, Tmax and AUC0-t with no major protocol deviations that could 
potentially affect the PK profile. 
Plasma PK population determination will be made before database lock by the Study Pharmacokineticist. 
The plasma PK population will be used for the plasma PK analysis, the summaries and graphical 
presentation of all plasma PK data. 
 
 
 


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4.1.5 
PD Population 
All patients who are included in the safety population and have at least baseline and 1 post-dose PD 
assessment will be included in the PD population.  This population set will be derived from sample 
collection date for Vitreous Humor sample collected at screening and undiluted vitreous/Aqueous humor 
sample at time of surgery.  
All PD analyses will be based on the PD population. 
 
 


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5. 
PARTICIPANT DISPOSITION AND ANALYSIS POPULATIONS 
Participant disposition and analysis population will be based on the ITT population. Participant 
disposition and analysis populations will be summarized descriptively as described in section 3.1 
(categorical descriptive analysis). 
5.1.1 
Participant Disposition 
Participant disposition will include the number and percentage of participants who are screened, treated, 
completed the study as planned, participants withdrawn from the study, as well as the primary reason for 
early termination. Participant disposition will be summarized descriptively. 
5.1.2 
Analysis Populations 
The number of participants included in each study population will be summarized descriptively. 
In addition, the inclusion of each participant into/from each of the defined analysis populations will be 
presented in the by-participant data listing. 
 
 


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6. 
PROTOCOL DEVIATIONS 
Protocol deviations will be presented for each participant in the by-participant data listings. 
Prior to database lock, all protocol deviations will be reviewed by medical monitors and assigned a status 
of Important if qualifying as such. 
Protocol deviations and important protocol deviations will be categorized as noted in the protocol 
deviation management plan as per project and communication plan. 
 


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7. 
DEMOGRAPHIC AND BASELINE INFORMATION 
Demographic and baseline information analysis will be based on the ITT population. Demographic and 
baseline information will be summarized descriptively as described in section 3.1 (Continuous/ 
Categorical) 
Demographics 
The following demographic parameters will be analyzed: 
Continuous descriptive analysis: 
• 
Age (years) 
• 
Height (cm) 
• 
Weight (kg) 
Categorical descriptive analysis: 
• 
Sex 
• 
Childbearing Potential as defined in the protocol 
• 
Race 
• 
Ethnicity 
Medical History 
Medical history will be coded using MedDRA® and will be presented in the by-participant data listings. 
Disease History 
Disease history will be presented in a separate by-participant listing.  
 
 


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8. 
TREATMENT EXPOSURE  
All study drug administration information (cohort, study drug administered <Yes/No>, date of injection, 
time of injection will be presented in the data listings. 
 
 
 
 


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9. 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior and concomitant medications will be coded using the most current version of the WHO-DD 
available at the start of the study. 
Concomitant medications will be summarized for the safety population. by Anatomical Therapeutic 
Chemical (ATC) class Level 3 and Preferred name as noted in section 3.1 (categorical descriptive 
analysis). Participant who used the same medication on multiple occasions will only be counted once in 
the specific category (level and preferred name). ATC level and Preferred name will be presented 
alphabetically. 
In addition to the summaries by the coded terms, the number of participants who used at least one 
concomitant medication during the study will be presented. 
Prior medications will be presented in the by-participant data listings. 


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10. 
PHARMACOKINETICS 
10.1 Plasma PK Analysis 
The plasma PK samples for ONL1204 will be at specified times as follows: 
• 
 
• 
Post-intravitreal injection  
• 
1-day post- intravitreal injection 
• 
3+ days post- intravitreal injection or day of surgery (vitrectomy) 
• 
14 days  post-surgery 
• 
Week 9 
• 
Week 24 exit or early termination 
All PK summary tables will be based on the plasma PK population. All analyses will be summarized as 
described in section 3.1 (PK - continuous descriptive analysis). All listings will be based on the safety 
population. 
The following pharmacokinetic parameters will, where possible, be determined from the plasma 
concentrations of ONL1204 by non-compartmental method using Phoenix WinNonlin® software 
(Version 8.3 or higher): 
Pharmacokinetic Parameters of Plasma ONL1204 Following a Single Dose Administration of ONL1204 
Intravitreal Injection 
Parameter 
Definition 
AUC0 last 
The area under the plasma concentration time curve, from time 0 (time of dosing) 
to the last time point with measurable analyte concentration, calculated by the log 
down, linear up trapezoidal method 
AUC0 inf 
The area under the plasma concentration time curve from time 0 extrapolated to 
infinity. AUC0 inf is calculated as the sum of AUC0 last plus the ratio of the last 
measurable plasma concentration to the elimination rate constant (λz). 
Cmax 
Maximum analyte plasma concentration 
Tmax 
Time to maximum observed analyte concentration. If the maximum value occurs 
at more than one time point, Tmax is defined as the first time point with this 
value. 
t½ 
Apparent plasma terminal elimination half life calculated as ln (2)/λz 
 
Parameter 
Definition 
Cmax 
Maximum concentration which is directly determined from the plasma 
concentration time profiles 
Tmax 
Time to maximum concentration. If the same Cmax concentration occurs at 
different time points, Tmax is assigned to the first occurrence of Cmax. 
AUC0-last 
Area under the drug concentration-time curve, from time zero to the last 
measurable concentration using the ‘Linear Up and Log Down’ method 
AUC0-inf 
Area under the drug concentration-time curve, from time zero to infinity (∞) using 
the following formula 
 
Where, C't is the observed concentration at the time t (last time point with a 
measurable plasma concentration above the quantification limit) at which 
quantification was still possible, the calculation of λz or kel is given below. 


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Parameter 
Definition 
AUC%extrap 
The percentage of the AUC that has been extrapolated beyond the last observed 
data point, using the following formula 
 
λz or kel 
The apparent terminal elimination rate constant, will be estimated from a 
regression of ln(C) versus time over the terminal log-linear drug disposition 
portion of the concentration-time profiles. 
t½ 
Apparent terminal half-life, using the following formula 
 
CL/F 
 
Apparent total plasma clearance, using the following formula 
 
Where D = Administered dose; AUC0-∞ = AUC0-inf 
Vz/F  
 
Apparent terminal volume of distribution, using the following formula 
 
Value for Kel, t½ AUC0-inf, CL/F and Vz/F will not be reported for cases that do not exhibit a terminal 
log-linear phase in the concentration versus time profile. Additional pharmacokinetic parameters may be 
determined where appropriate. 
Pharmacokinetic analysis will be carried out using actual doses, infusion durations, and blood sampling 
times, where possible. If actual times are missing, nominal times may be used with sponsor approval. 
Plasma concentrations of ONL1204 will be used as supplied by the bioanalytical laboratory. The units 
of concentration and resulting PK parameters, with amount or concentration in the unit, will be presented 
as they are received from the bioanalytical laboratory. 
10.1.1 Criteria for the Calculation of an Apparent Terminal Elimination Half-Life and AUC 
The start of the terminal elimination phase for each participant will be defined by visual inspection and 
will generally be the first point at which there is no systematic deviation from the log linear decline in 
plasma concentrations. 
 Number of Data Points 
• 
At least 3 data points will be included in the regression analysis and not including Cmax. 
 Goodness of Fit 
• 
If data permits, the default ‘best fit’ method by Phoenix WinNonlin will be used for the selection 
of slopes to determine ‘λz’. If data do not permit, then the slope selection will be done by visual 
inspection or by a manual method to determine λz considering the best possible the adjusted R2 
value. 
• 
When assessing terminal elimination phases, the adjusted R2 value will be used as a measure of 
the goodness of fit of the data points to the determined line. 
• 
Regression-based parameters (Kel, t½ AUC0-inf, CL/F and Vz/F AUCinf, t1/2, CL, and Vz) will 
only be calculated if the adjusted R2 value of the regression line is greater than or equal to 0.7. If 
regression-based parameters cannot be calculated, they will be set to “NC”, defined as “not 
calculated” in the data listings and summary tables as appropriate. 


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 Period of Estimation 
• 
Time period used for the estimation of t1/2, where possible, will be over at least 2 half lives. 
• 
Where an elimination half life is estimated over a time period of less than 2 half lives, it will be 
flagged in the data listings at the discretion of the pharmacokineticist, and the robustness of the 
half life value and regression based parameters (AUC0 inf, CL, and Vz) should be discussed in 
the study report. 
 Calculation of AUC 
• 
The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive plasma concentrations above the lower limit of quantification (LLOQ), with at least 
one of these concentrations following Cmax. 
• 
All AUC values will be calculated using the ‘linear up / log down’ trapezoidal rule where the 
linear trapezoidal rule will be used for increasing concentrations and the log trapezoidal rule for 
decreasing concentrations. 
Pharmacokinetic Noncompartmental Analysis (NCA) 
10.1.2 General Plasma NCA Pharmacokinetic Settings  
• 
NCA Model Type 
Plasma (200-202)  
• 
Weighting 
Uniform  
• 
AUC Calculation Method: 
Linear Up/Log Down 
• 
Dose Options Type 
Extravascular 
• 
Slopes Setting Fit Method: 
Best Fit. If the data does not permit best fit 
 
selection, the slope selection will be performed by 
 
visual inspection or by a manual method to determine 
 
λz. 
• 
Rsq_Adjusted Criteria for ‘λz’ 
0.70 
• 
AUC% extrapolation Criteria 
20 
10.3 Inferential Analyses 
No formal hypothesis testing is planned 
10.4 Ocular PK analysis 
An undiluted vitreous sample will be collected at the time of vitrectomy to assess ONL1204 drug levels.  
A separate summary and listing will be provided for the same. Considering the sampling limitations, no 
ocular PK analysis will be applicable for this study and hence concentration listings and summaries along 
with figures will be provided based on ocular PK population. 
 


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11. 
PHARMACODYNAMICS 
Pharmacodynamic statistical analyses will be conducted based on the proteomic analysis 
of cytokine biomarkers in ocular fluids. 
The following PD endpoints will be assessed: 
• 
Vitreous Humor sample collected at pre-injection baseline by vitreous tap 
• 
Vitreous Humor sample from the undiluted sample collected at the time of surgery 
• 
Aqueous Humor sample collected at the time of surgery 
Analyte concentrations will be provided for the vitreous humor and aqueous humor samples.  
 
All PD endpoints will be analyzed separately by ONL Therapeutics. 
 


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12. 
EFFICACY 
No formal efficacy analyses are planned for this study, however exploratory endpoints will be evaluated. 
 
 


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13. 
SAFETY  
Safety endpoints (adverse events, clinical laboratory evaluations, vital signs, BCVA, ophthalmic 
imaging, intraocular pressure, and other safety assessments) will be analyzed using the safety population. 
Safety endpoints (continuous and categorical) will be summarized descriptively as described in section 
3.1. 
13.1.1 Adverse Events 
All AEs will be coded using MedDRA. All AE summaries will be restricted to TEAEs only. Summary 
tables will include the number of participants (%) experiencing an event and the number of events. 
Participants will be counted only once for each SOC and PT level (categorical descriptive analysis). 
Ocular and non-ocular AEs will be reported separately.  Ocular AEs will be split into study eye/fellow 
eye/Both eye events.  
The TEAE summaries will include: 
• 
Overall summary of TEAEs. 
• 
TEAE summary by SOC and PT. 
• 
TEAE summary of serious adverse events (SAE) by SOC and PT. 
• 
TEAE summary by SOC, PT and Severity. 
• 
TEAE summary by SOC, PT, and relationship to study drug. 
• 
TEAE summary by SOC, PT, and relationship to procedure. 
• 
TEAE summary of events leading to the study drug removal by SOC and PT. 
All listings will be presented by the safety population. Separate listings will be provided for patients with 
SAEs, AEs leading to withdrawal from the study and AEs resulting in death, if any. 
13.1.2 Safety Laboratory Assessments 
Blood and urine samples will be collected at the time points specified in the Schedule of Events (refer to 
the Protocol) to conduct CBC, renal function, and hepatic function analyses. 
The following tests will be performed within each of the specified test panels: 
Complete blood count (including): 
• 
While Blood Cell (WBC) count with differential 
• 
Hemoglobin (hgb) 
• 
Hematocrit (hct) 
• 
Platelet count 
Renal function test (including): 
• 
Albumin 
• 
Blood Urea Nitrogen (BUN) 
• 
Bicarbonate 
• 
Calcium 
• 
Chloride 
• 
Creatinine 
• 
eGFR 


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• 
Glucose 
• 
Phosphorus 
• 
Potassium 
• 
Sodium 
Hepatic Function tests (including): 
• 
Alanine transaminase (ALT) 
• 
Alkaline phosphatase (ALP) 
• 
Albumin 
• 
Total protein 
• 
Aspartate transaminase (AST) 
• 
Bilirubin 
• 
Prothrombin time (PT) 
All laboratory data collected at scheduled and unscheduled visits will be included in the listings, but only 
results collected at scheduled visits will be included in the summary tables. 
Results for individual parameters may be reported in different units depending on the analyzing 
laboratory. If required, the results (and the corresponding normal range cut-off values) for individual 
parameters may be converted to International System of Units (S.I.) to summarize the data. 
For all the parameters where a unit value has been reported, the parameter names that will be used in the 
outputs will comprise of the test name and the unit of measure, for example, ‘Albumin (g/L)’. For the 
urinalysis parameters, the parameter name will be the reported test name only. Parameters will be sorted 
alphabetically within tables and listings. 
For all parameters where a normal range limit value was reported, the normal range will be derived based 
on the available lower and upper limit values and any reported mathematical symbols. If both a lower 
and upper limit value is available, the normal range will be presented as ‘(Lower, Upper)’. 
The reported results for each parameter with a defined normal range will be classified (‘Low’, ‘Normal’, 
‘High’) in relation to the defined normal range limits. If a result is equal to the normal range cut-off 
value, the result will be considered ‘Normal’. 
The complete blood count, renal function test and hepatic function test result tables will present summary 
statistics for each laboratory parameter. For each parameter, summaries will be presented for the baseline 
and each scheduled post-baseline visit. In addition, summaries will be presented for the change from 
baseline values at each scheduled post-baseline visit (continuous descriptive analysis). 
The decimal precision to which the summary for each parameter is reported will be based on the 
maximum number of decimals to which the reported result or the normal range limits are presented to in 
the raw data. The results and normal ranges will be displayed to the same decimal precision in the listings. 
13.1.3 Vital Signs 
The following vital signs measurements will be taken at the time points specified in the Schedule of 
Events (refer to the Protocol): 
• 
Heart Rate (beats/min) 
• 
Sitting Systolic Blood Pressure (SBP) (mmHg) 
• 
Sitting Diastolic Blood Pressure (DBP) (mmHg) 
• 
Respiratory Rate (breaths/min) 
• 
Temperature (ºC) 


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All vital signs data collected at scheduled and unscheduled visits will be included in the listings, but only 
results collected at scheduled visits will be included in the summary tables. 
The parameter names that will be used in the outputs will comprise of the test name and the unit of 
measure, for example, ‘Systolic Blood Pressure (mmHg)’. Parameters will be sorted in the order that the 
measurements were collected in on the Vital Signs eCRF page within the tables and listings. 
Vital signs measurements will present summary statistics for the results at the baseline and each 
scheduled post-baseline visit for each of the parameters. In addition, summaries will be presented for the 
change from baseline values at each scheduled post-baseline visit (continuous descriptive analysis). 
The decimal precision to which the summary for each parameter is reported will be based on the 
maximum number of decimals to which the results were reported on the eCRF. 
13.1.4 Ophthalmologic Assessments 
The following parameters will be assessed in study eye and contralateral eye for Safety Population. 
13.1.5 Best Corrected Visual Acuity (BCVA) 
BCVA will be performed in the study eye and fellow eye using the logMAR score. The logMAR score 
will be converted from the ETDRS visual acuity measure at time points specified in the Schedule of 
Assessments (refer to protocol) to assess visual acuity.  
LogMAR (Logarithm of the minimal angle of resolution) score will be calculated using the formulae 
logMAR = -0.02 * ETDRS + 1.7  
If the patient cannot read the ETDRS chart at 1 meter, the assessment result reported in counts fingers, 
hand motions, light perception, or no light perception will be utilized and converted to a logMAR score 
(CF = 2.0 logMAR, HM = 3.0 logMAR, LP = 3.9 logMAR, NLP = 4.0 logMAR). BCVA will be 
performed prior to procedures requiring pupil dilation. 
LogMAR BCVA will be assessed and summarized as described in section 3.1 (continuous descriptive 
analysis) in study eye and fellow eye: 
Summary of total letters read for each eye along with change from baseline will be presented by visit for 
both eyes (continuous descriptive analysis). All other assessments will be listed. 
Low Luminance ETDRS BCVA and Low Contrast ETDRS BCVA will also be summarized as 
continuous variables only. 
13.1.6 Color Fundus Photography (CFP) 
CFP will be performed in study eye and contralateral eye at the time points specified in the Schedule of 
Assessments (refer to protocol). 
Separate listing will be presented for the same.  


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13.1.7 Fundus Autofluorescence 
Fundus Autofluorescence will be performed at Visit 8 in both eyes.  Listing will be presented for the 
same.  
13.1.8 Indirect Ophthalmoscopy 
Ophthalmic Exam will be performed via indirect ophthalmoscopy at baseline and at other times 
according to the Schedule of Assessments (please refer to Protocol). 
The following parameters will be assessed and summarized as described in section 3.1 
(continuous/categorical descriptive analysis) in study eye and fellow eye: 
• 
Posterior Vitreous Detachment 
• 
C/D Ratio 
• 
Macula 
• 
Vessels 
• 
Periphery 
All grading assessments of different eye structures will be summarized descriptively by abnormalities, 
cohort and study visit for both eyes (categorical descriptive analysis as mentioned in section 3.1). 
All data recorded on the eCRF page ‘Indirect Ophthalmoscopy (Retinal Exam)’ will be listed. 
In addition, separate by-patients listing will be provided for pre- and post-surgery of the retinal 
examination.  
13.1.9 Slit Lamp Biomicroscopy 
Biomicroscopy will be performed with a slit-lamp to examine the anterior and posterior 
chambers of the eye. The examination will include following assessments as per Schedule of Events 
please refer to the Protocol).  
Ø Anterior Segment 
 
o Anterior Chamber Cell 
o Anterior Chamber Flare 
 
Ø Posterior Segment 
o Optic Disc 
o Vitreous Cell 
o Vitreous Haze 
 
Ø Lens Status 
o Nuclear Sclerosis 
o Cortical Cataract 
o Posterior subcapsular cataract 
All grading assessments of different eye structures will be summarized descriptively by abnormalities, 
cohort and study visit for both eyes (categorical descriptive analysis as mentioned in section 3.1). 
Listing will be provided for the same.  
 
 


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13.1.10 Intraocular Pressure (IOP)  
IOP measurements will be done using applanation tonometry (either Goldmann (standard preferred 
method) or Tonopen® (use only if required)). For any given participant, the same IOP procedures will 
be followed for the entire duration of the study.  Below measurement will be taken for both eyes. 
• 
IOP (mmHg) 
Summary of IOP measured for both eyes will be presented as per visit.  
13.1.11 Pin Hole Visual Acuity 
Pin Hole Visual Acuity measurements (taken at 1 Day Post-Surgery only) will be summarized using 
descriptive statistics described in section 3.1 for continuous data by cohort by LogMAR Score. 
13.1.12 Contrast Sensitivity Testing  
Contrast Sensitivity Testing measurements will be measured at the time points specified in the Schedule 
of Assessments (refer to protocol).  Scores will be summarized for both the eyes.  Results will be reported 
in log values.  
13.1.13 Farnsworth D15 Color vision test 
Farnsworth D15 color vision measurements will be assessed in both study eye and fellow eye.  
Separate listing will be provided.  
13.1.14 Spectral Domain Optical Coherence Tomography (SD-OCT) 
SD-OCT will be performed in study eye and contralateral eye at the time points specified in the Schedule 
of Assessments (refer to protocol). Measurements of retinal thicknesses and volumes based on 
determinations relying on typical retinal layers as identified by SD-OCT will be calculated. Specifically, 
the following results will be presented from all assessments except for the pre-injection baseline 
measurement. The results for the parameters below will be summarized as described in section 3.1 
(continuous descriptive analysis): 
• 
Average thickness central 1 mm (central subfield thickness) 
• 
Average thickness central 3 mm 
• 
Average thickness central 6 mm 
• 
Total centerpoint thickness 
• 
Central subfield volume 
• 
Macular volume 
• 
Subretinal fluid thickness at the foveal center 
The following parameters will be summarized as described in section 3.1 (categorical descriptive 
analysis) for the collected categories with each parameter: 
• 
Vitreomacular traction deforming the fovea 
• 
Intraretinal fluid (cystoid macular edema) 
• 
Epiretinal membrane 
• 
Epiretinal membrane with deformation in the center 1 mm 
• 
Anomaly  
 
The results from the analyses of the parameters listed in this section above will be prepared by ONL 
and presented as an addendum to the tables, listings, and figures report.   
 


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The following parameters with continuous numerical results will also be obtained from all assessments 
except for the Screening measurement. These results may be analyzed and reviewed, with or without 
descriptive statistics, internally. The results for the following parameters will be available for the central 
1 mm, 3 mm, and 6 mm of the scan, as well as the volume of the central 1 mm region. 
• 
Boundaries ILM to inner aspect of ONL 
• 
Boundaries inner aspect of ONL to Bruch’s Membrane 
• 
Boundaries ELM to Bruch’s Membrane 
 
The following parameters with categorical results will also be obtained from all assessments except for 
the Screening measurement. These results may be analyzed and reviewed, with or without categorical 
descriptive statistics, internally.  
 
• 
Intraretinal fluid in the central subfield  
• 
Intraretinal fluid at the foveal center 
• 
Subretinal fluid in the center 3 mm 
• 
Subretinal fluid in the center 1 mm 
• 
Subretinal fluid at the foveal center 
• 
Anomaly details 
o Retinal pigment epithelium (RPE) elevation, RPE atrophy, outer retinal lucency 
o Potential risk management 
o Other 
 
The results from the analyses of the parameters identified in this section above will be included in the 
addendum to the tables, listings, and figures report only if deemed pertinent and potentially 
informative by expert review. 
Pregnancy Test Results 
All information related to pregnancy testing (urine) and contraception status will be presented in the by-
participant data listings. 
 
 


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14. 
IMMUNOGENICITY 
Not Applicable. 


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15. 
CHANGES TO THE PLANNED ANALYSIS 
Not Applicable 
16. 
FINAL ANALYSIS (END OF STUDY) 
Final Analysis 
The final analysis will be conducted after all participants have completed the study, the clinical database 
has been locked and the analysis populations have been approved. 
The final analysis will be based on the final version of the SAP. Any deviations from the planned analysis 
will be documented in the CSR. 
 
 


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17. 
SOFTWARE 
• 
SAS® Version 9.2 or higher (SAS Institute, Cary, North Carolina, USA). 
• 
Phoenix WinNonlin® (Certara, USA) Version 8.3 or higher. 
 
 
 
 
 
 
 
 
 
 
 


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18. 
TABLES 
Table Number 
Table Title 
Population 
 
 
 
14.1 
Demographics and Other Baseline Characteristics 
 
14.1.1 
Summary of Subject Enrolment and Disposition 
ITT 
14.1.2 
Demographics and Baseline Characteristics 
ITT 
14.2 
PK/PD 
 
14.2.1 
Plasma ONL1204 Concentrations (unit) by Treatment and Time 
PK 
14.2.2 
Plasma ONL1204 Pharmacokinetic Parameters by Treatment 
PK 
 
 
PK 
14.3 
Safety 
 
14.3.1 
Concomitant Medication by ATC Classification 
Safety 
14.3.3 
Adverse Events 
 
14.3.3.1 
Summary of Overall Treatment Emergent Adverse Events 
Safety 
14.3.3.2 
Incidence of Ocular Treatment-Emergent Adverse Events by SOC and PT 
Safety 
14.3.3.2a 
Incidence of Non-Ocular Treatment-Emergent Adverse Events by SOC and PT 
Safety 
14.3.3.3 
Incidence of Serious Ocular Treatment-Emergent Adverse Events by SOC and PT 
Safety 
14.3.3.3a 
Incidence of Serious Non- Ocular Treatment-Emergent Adverse Events by SOC and PT 
Safety 
14.3.3.4 
Incidence of Ocular Treatment-Emergent Adverse Events by SOC, PT and Maximum Severity 
Safety 
14.3.3.4a 
Incidence of Non-Ocular Treatment-Emergent Adverse Events by SOC, PT and Maximum Severity 
Safety 
14.3.3.5 
Incidence of Ocular Treatment-Emergent Adverse Events by SOC and PT and relationship to study drug 
Safety 
14.3.3.5a 
Incidence of Non-Ocular Treatment-Emergent Adverse Events by SOC and PT and relationship to study drug 
Safety 
14.3.3.6 
Incidence of Ocular Treatment-Emergent Adverse Events by SOC and PT and relationship to procedure 
Safety 
14.3.3.6a 
Incidence of Non-Ocular Treatment-Emergent Adverse Events by SOC and PT and relationship to procedure 
Safety 
14.3.4 
Laboratory Parameters 
 
14.3.4.1 
Hematology Results - Change of Hematology Values 
Safety 
14.3.4.2 
Hematology Results – Normal/Abnormal Shift Table 
Safety 
14.3.4.3 
Chemistry Results - Change of Chemistry Values 
Safety 
14.3.4.4 
Chemistry Results – Normal/Abnormal Shift Table 
Safety 
14.3.5 
Other Safety 
 
14.3.5.1 
Vital Signs - Values and Change from Baseline 
Safety 
14.3.6.1 
Summary of Best Corrected Visual Acuity (BCVA) (Letters) 
Safety 


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Table Number 
Table Title 
Population 
 
 
 
14.3.6.2 
Summary of Best Corrected Visual Acuity (BCVA) (LogMAR Values) 
Safety 
14.3.6.3 
Summary of Low Luminance and Low Contrast BCVA 
Safety 
14.3.6.4 
Indirect Ophthalmoscopy 
Safety 
14.3.6.5 
Summary of Biomicroscopy Examination 
Safety 
14.3.6.6 
Summary of Intraocular Pressure (mmHg) 
Safety 
14.3.6.7 
Summary of Pin Hole Visual Acuity 
Safety 
14.3.6.8 
Summary of Log Contrast Sensitivity Scores 
Safety 
 
 
 
 
 
 
 
 
 
 
 
 


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19. 
LISTINGS 
Listing Number 
Listing Title 
Population 
 
 
 
16.2.1 
Subject Disposition 
 
16.2.1.1 
Analysis Populations 
ITT 
16.2.1.2 
Subject Disposition 
ITT 
16.2.1.3 
Screen Failures 
SF 
16.2.2 
Protocol Deviations 
 
16.2.2.1 
Protocol Deviations 
ITT 
16.2.4 
Demographic and Other Baseline Data 
 
16.2.4.1 
Demographics and Baseline Characteristics 
ITT 
16.2.4.2 
Medical History 
ITT 
16.2.4.3 
Duration of Macular Detachment 
ITT 
16.2.4.4 
Inclusion/Exclusion Criteria 
ITT 
16.2.4.5 
B Scan Ultrasonography 
ITT 
16.2.5 
Treatment Administration 
 
16.2.5.1 
Study Drug Administration 
ITT 
16.2.6  
PK/PD 
 
16.2.6.1 
Plasma ONL1204 Concentrations 
Safety 
16.2.6.2 
Plasma ONL1204 Pharmacokinetic Parameters 
PK 
 
 
 
16.2.7 
Adverse Events 
 
16.2.7.1 
Adverse Events 
ITT 
16.2.7.2 
Serious Adverse Events 
ITT 
16.2.7.3 
Adverse Events Leading to Study Drug Removal 
ITT 
16.2.7.4 
Adverse Events with Outcome of Death 
ITT 
16.2.8 
Laboratory Parameters 
 
16.2.8.1 
Hematology Results 
ITT 
16.2.8.2 
Chemistry Results 
ITT 
16.2.9 
Other Safety 
 


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Listing Number 
Listing Title 
Population 
 
 
 
16.2.9.1 
Vital Signs 
ITT 
16.2.10 
Prior & Concomitant Medication 
ITT 
16.2.10.1 
Prior and Concomitant Medication 
ITT 
16.2.11 
Ophthalmic Assessments 
ITT 
16.2.11.1 
Best Corrected Visual Acuity (BCVA) (Letters) 
ITT 
16.2.11.2 
LogMAR Values 
ITT 
16.2.11.3 
Low Luminance and Low Contrast (BCVA) 
ITT 
16.2.11.4 
Color Fundus Photography (CFP) 
ITT 
16.2.11.5 
Fundus Autofluorescence 
ITT 
16.2.11.6 
Indirect Ophthalmoscopy Retinal Exam 
ITT 
16.2.11.7 
Pre surgical Retinal Examination 
ITT 
16.2.11.8 
Post Surgery of Retinal Exam (Study Eye) 
ITT 
16.2.11.9 
Biomicroscopy Examination 
ITT 
16.2.11.10 
Intraocular Pressure 
ITT 
16.2.11.11 
Pin Hole Visual Acuity 
ITT 
16.2.11.12 
Contrast Sensitivity Testing 
ITT 
16.2.11.13 
Farnsworth D15 color vision test 
ITT 
 
 
 
 


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21. 
REFERENCES 
Clinical Study Protocol Version 1.6 dated 27 July 2020