Phase I/IIa Dose Escalation Safety and Efficacy Study of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelium Cells Transplanted Subretinally in Patients With Advanced Dry-Form Age-Related Macular Degeneration (Geographic Atrophy)
Phase: PHASE1
Conditions: Age-Related Macular Degeneration
Sponsor: Hoffmann-La Roche

 
Official Title: 
Phase I/IIa Dose Escalation Safety and Efficacy Study of Human 
Embryonic Stem Cell-Derived Retinal Pigment Epithelium Cells 
Transplanted Subretinally in Patients With Advanced Dry-Form Age-
Related Macular Degeneration (Geographic Atrophy) 
NCT Number: 
NCT02286089 
Document Date: 
Protocol Amendment 14: 09-April-2019 
 
 

Study Title: Phase I/IIa Dose Escalation Safety and Efficacy Study of Human 
Embryonic Stem Cell-Derived Retinal Pigment Epithelium Cells Transplanted 
Subretinally in Patients with Advanced Dry-Form Age-Related Macular Degeneration 
(Geographic Atrophy) 
Clinical Phase: 
I/IIa 
Sponsor Details: 
Cell Cure Neurosciences Ltd. / BioTime, Inc. 
Suite 500 Jerusalem BioPark Building 
Hadassah Ein Kerem, Jerusalem 
POB 12247 Jerusalem 91121 Israel 
And 
1010 Atlantic Avenue, Suite 102 
Alameda, CA 94501 USA 
Director of Clinical Trial: 
Medical Monitor: 
, MD 
Jerusalem BioPark Building Suite 500 
Jerusalem Israel 91121 
Tel: 
Cell: 
US Cell: 
Protocol Number: 
CCN_CT02 
Amendment number 
14 
Dated: 
9 April 2019 
Issue: 
FINAL 
This clinical study will be conducted in accordance with the Sponsor's Standard Operating Procedures 
(SOPs), this protocol, current Good Clinical Practice (GCP), the provisions of International Conference on 
Harmonization (ICH) Guidelines and all local applicable laws and regulations. 
CONFIDENTIAL 
The information in this document is considered privileged and confidential and may not be disclosed to others 
except to the extent necessary to obtain Institutional Review Board (IRB)/Ethics Committee (EC) approval, 
written informed consent and the approval of local regulatory authorities as required by local law. 

OpRegen®  
Clinical Protocol No. CCN_CT02 
Cell Cure Neurosciences Ltd./BioTime, Inc. 
Amendment #14 
 
Page 2 of 99 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
CONFIDENTIALITY AND INVESTIGATOR'S AGREEMENT ..................................................... 11 
 
STUDY SYNOPSIS  ....................................................................................................................... 12 
 
STUDY SCHEME  ......................................................................................................................... 21 
 
SCIENTIFIC BACKGROUND  ................................................................................................... 22 
 
Overview ..................................................................................................................................... 22 
 
BACKGROUND ............................................................................................................................ 22 
 
Proposed Indication ................................................................................................................... 22 
 
The Retinal Pigment Epithelium and its Characteristics ....................................................... 22 
 
Treatment Approaches.............................................................................................................. 22 
 
Background on hESC Derived RPE Cells   ............................................................................ 23 
 
Derivation of OpRegen.   ........................................................................................................ 23 
23 
23 
23 
24 
24 
24  
24 
 
RATIONALE FOR CLINICAL STUDY DESIGN AND DOSAGES  ...................................... 24 
 
Study population ........................................................................................................................ 25 
 
Cohort size .................................................................................................................................. 25 
 
Study endpoints ......................................................................................................................... 25 
 
Dosage ......................................................................................................................................... 25 
 
Staggered Enrollment ............................................................................................................... 25 
 
Subretinal routes of administration ......................................................................................... 26 
 
Vitrectomy and Retinotomy   .................................................................................................. 26 
26 
 
STUDY OBJECTIVES, HYPOTHESIS AND STUDY ENDPOINTS  ..................................... 27 
 
Hypothesis .................................................................................................................................. 27 
 
Study objectives ......................................................................................................................... 27 
 
Primary Objectives   ............................................................................................................... 27 
 
Secondary Objectives  ............................................................................................................ 27 
27 
 
Study Endpoints......................................................................................................................... 27 
 
Safety and Tolerability Endpoints  ......................................................................................... 27 
28 
28 
 
Efficacy Endpoints of Clinical Relevance   ............................................................................ 28 
 
STUDY POPULATION  ................................................................................................................ 29 
 
Subjects Characteristics ............................................................................................................ 29 
 
Number of Subjects   .............................................................................................................. 29 
 
Special Populations  ................................................................................................................ 29 
 
Eligibility Criteria for Cohorts 1-3 .......................................................................................... 29 
 
Inclusion Criteria  ................................................................................................................... 29 
 
Exclusion Criteria  .................................................................................................................. 30 
 
Eligibility Criteria for Cohort 4 ............................................................................................... 31 
 
Inclusion Criteria  ................................................................................................................... 31 
 
Exclusion Criteria  .................................................................................................................. 31 
 
CONCOMITANT MEDICATIONS AND SUPPORTIVE CARE  ........................................... 33 
 
Previous Medications ................................................................................................................ 33 

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Adequacy of protection against risks ....................................................................................... 73 
 
Potential Benefits ....................................................................................................................... 74 
 
STUDY MONITORING  ............................................................................................................... 74 
 
Medical monitor, CRO and CRA monitoring visits ............................................................... 74 
 
Data safety monitoring board ................................................................................................... 75 
 
SAFETY REPORTING  ................................................................................................................ 75 
 
Adverse events definition .......................................................................................................... 75 
 
Clinical Laboratory Abnormalities  ........................................................................................ 76 
 
Serious Adverse Events  ......................................................................................................... 77 
 
Suspected Adverse Reaction and Causality  .........................................................................   78 
 
Relationship of Adverse Events and Serious Adverse Events to Study Drug   ....................... 78 
 
Event Expectation  .................................................................................................................. 78 
 
Recording of Adverse Events   ............................................................................................... 79 
 
Toxicity Grading  .................................................................................................................... 79 
 
Severity Grading  ...................................................................................................................  81 
 
Device safety ............................................................................................................................... 81 
 
Device Adverse Events of Special Interest   ........................................................................... 82 
 
Device Adverse Events of Special Interest   ........................................................................... 82 
 
Safety Expedited Reporting ...................................................................................................... 83 
 
Reporting to the IRB/IEC  ...................................................................................................... 83 
 
Reporting to the DSMB  ........................................................................................................  84 
 
Medical Monitoring Review   ................................................................................................. 84 
 
Reporting to Regulatory Authorities  ...................................................................................... 84 
 
Follow-up of the adverse events ............................................................................................... 85 
 
STATISTICAL METHODOLOGY  ............................................................................................ 85 
 
Study Design and Sample Size .................................................................................................. 85 
 
Analysis Sets ............................................................................................................................... 85 
 
Modified Intent-to-Treat (mITT) Analysis Set   ..................................................................... 85 
 
Per Protocol (PP) Analysis Set  .............................................................................................. 86 
 
Significance Level ...................................................................................................................... 86 
 
Interim Reports ......................................................................................................................... 86 
 
Descriptive Statistics ................................................................................................................. 86 
 
Missing Data .............................................................................................................................. 86 
 
Subject Disposition .................................................................................................................... 86 
 
Demographic and Baseline Characteristics ............................................................................. 86 
 
Concomitant Medications Use .................................................................................................. 87 
 
Evaluation of Safety .................................................................................................................. 87 
 Treatment Emergent Adverse Events (TEAEs)  ..................................................................... 87 
 Safety Laboratory Tests  ......................................................................................................... 87 
 Vital Signs   ............................................................................................................................ 88 
 ECG Assessments   ................................................................................................................. 88 
 Physical Examination   ........................................................................................................... 89 
 
Tolerability Assessments ........................................................................................................... 89 
 
Evaluation of Preliminary Efficacy .......................................................................................... 89 
 Efficacy Endpoints of Clinical Relevance   ............................................................................ 89 
89 
 
Hypothesis  ................................................................................................................................. 90 
 
Statistical Methods .................................................................................................................... 90 
 
REFERENCES  ...........................................................................................................................    91 
 
PROTOCOL ATTACHMENTS  .................................................................................................. 99 
 
Laboratory Tests ....................................................................................................................... 99 
 
 

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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Transaminase 
AMD 
Age-Related Macular Degeneration 
AST 
Aspartate Aminotransferase 
BCVA 
Best Corrected Visual Acuity 
BDNF 
Brain-Derived Neurotrophic Factor 
 
 
CA 
Cancer Antigen 
CEA 
Carcinoembryonic Antigen 
CFP 
Color Fundus Photography 
CMV 
Cytomegalovirus 
CNV 
Choroidal Neovascularization 
CNTF 
Ciliary Neurotrophic Factor 
CoA 
Certificate of Analysis 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-Limiting Toxicity  
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ESR 
Erythrocyte Sedimentation Rate 
EBs 
Embryoid Bodies 
EBV 
Epstein–Barr Virus 
ECG 
Electrocardiogram 
ERG  
Electroretinography 
ETDRS 
Early Treatment Diabetic Retinopathy Study 

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Abbreviation 
Definition 
FA 
Fluorescein Angiography 
FAF 
Fundus Autofluorescence (imaging) 
fCNV 
Foveal Choroidal Neovascularization 
FGF 
Fibroblast Growth Factors 
FRI 
Functional Reading Independence (FRI) Index 
G 
Gauge (Needle wire gauge) 
GA 
Geographic Atrophy 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl Transferase 
GMP 
Good Manufacturing Practice 
GTT 
Guttae (Drops) 
Gr 
Gram 
HBsAg 
Hepatitis B Surface Antigen 
HCVAb 
Hepatitis C Virus Antibody 
H&E 
Hematoxylin and Eosin stain 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
hESCs 
Human Embryonic Stem Cells 
HLA 
Human Leukocyte Antigen(s) 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
IFU 
Instructions for Use 
IgM 
Immunoglobulin M 
INR 
International Normalized Ratio (of prothrombin time of blood 
coagulation) 
IOP 
Intraocular Pressure 
iPSCs 
Induced Pluripotent Stem Cells 
IR 
Infrared 
IRB 
Institutional Review Board 
IRF 
Intraretinal Fluid 
LDH 
Lactic Dehydrogenase  

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Abbreviation 
Definition 
 
 
MEF 
Mouse Feeder Cells 
MITF 
Microphthalmia-associated Transcription Factor 
mL 
Milliliter 
MM 
Medical Monitor 
mm 
Millimeter 
MTD 
Maximally Tolerated Dose 
NCI 
National Cancer Institute 
NEI VFQ-25 
National Eye Institute Visual Function Questionnaire-25 
ng 
Nanogram 
 
 
OCT 
Ocular Coherence Tomography 
OD 
Oculus Dexter (the right eye) 
OKR 
Optokinetic Reflex 
 
 
OS 
Oculus Sinister (the left eye) 
OU 
Oculus Utergue (both eyes) 
PD 
Project Director 
PED 
Pigment epithelial detachment 
PEDF 
Pigment Epithelium-Derived Factor 
PMEL17 
Premelanosome protein 
PO 
Per Os (by mouth) 
POS 
Photoreceptor Outer Segments 
PSA 
Prostate Specific Antigen 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
PVR 
Proliferative Vitreo-Retinopathy 
QC 
Quality Control 
QoL 
Quality of Life 
qPCR 
quantitative Polymerase Chain Reaction 

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Abbreviation 
Definition 
 
 
RPE 
Retinal Pigment Epithelium 
SAE 
Serious Adverse Event 
SD-OCT 
Spectral Domain Optical Coherence Tomography 
SRF 
Sub Retinal Fluid 
SLE 
Slit Lamp Examination 
 
 
TGF 
Transforming Growth Factor 
UTCs 
Umbilical Tissue-derived Cells 
VEGF 
Vascular Endothelial Growth Factor 
 
 
 

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Amendment #14 
 
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CONFIDENTIAL 
 
 
Approval of Clinical Research Protocol No. CCN_CT02 – Amendment #14 
 
Phase I/IIa Dose Escalation Safety and Efficacy Study of Human Embryonic Stem 
Cell-Derived Retinal Pigment Epithelium Cells Transplanted Subretinally in Patients 
with Advanced Dry-Form Age-Related Macular Degeneration (Geographic Atrophy) 
 
 
Approved by: 
 
 
 
 
 
 
 
 
Date 
, Clinical 
 
 
 
 
 
 
, MD 
 
Date 
Medical Monitor 
 
 
 
 
 
 
, DVM, MS, PhD 
 
Date 
, Clinical and Medical Affairs 
 
 
 

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Clinical Protocol No. CCN_CT02 
Cell Cure Neurosciences Ltd./BioTime, Inc. 
Amendment #14 
 
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CONFIDENTIAL 
Confidentiality and Investigator's Agreement 
Date: 
09 April 2019 
Sponsor’s details: 
Cell Cure Neurosciences Ltd. 
Jerusalem BioPark Hadassah Ein Kerem 
POB 12247 Jerusalem 91121 Israel 
BioTime, Inc. 
1010 Atlantic Ave.,         
Suite 102 
Alameda, CA, USA 
Protocol number: 
Clinical Protocol No. CCN_CT02 
Protocol title: 
Phase I/IIa Dose Escalation Safety and Efficacy Study of Human 
Embryonic Stem Cell-Derived Retinal Pigment Epithelium Cells 
Transplanted Subretinally in Patients with Advanced Dry-Form Age-
Related Macular Degeneration (Geographic Atrophy) 
 
The information contained in this document and all information provided to you related to 
OpRegen® 
 are confidential and proprietary information to the respective 
companies and except as may be required by federal, state or local laws or regulations, may 
not be disclosed to others without prior written permission of the companies. However, the 
Principal Investigator (PI) may disclose such information to supervised individuals working 
on the study, provided the individuals agree to be bound to maintain the confidentiality of 
such information. 
I have carefully read the foregoing protocol including all appendices and agree that it contains 
all the necessary information for safely conducting the study. I will ensure that all individuals 
assisting me in the conduct of this study have access to the study protocol and any 
amendments and are aware of their obligations. 
I will conduct this study in strict accordance with this protocol and according to the current 
GCP regulations and will attempt to complete the study within the time designated. 
I will provide copies of the protocol and all other information relating to pre-clinical and 
prior clinical experience submitted by the Sponsor to all personnel responsible to me who 
participate in the study. I will discuss this information with them to ensure that they are 
adequately informed regarding the drug and conduct of the study.  
I agree to keep records on all subject information (CRFs, shipment and drug return forms, 
and all other information collected during the study) in accordance with the current GCP and 
local regulations. 
 
 
 
 
 
[Principal Investigator] Signature 
 
Date 
 
 
 
[Print Principal Investigator Name and Title] 
 
 

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Clinical Protocol No. CCN_CT02 
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CONFIDENTIAL 
 STUDY SYNOPSIS 
Protocol Number 
CCN_CT02 
Protocol Title 
Phase I/IIa Dose Escalation Safety and Efficacy Study of Human Embryonic Stem Cell-
Derived Retinal Pigment Epithelium Cells Transplanted Subretinally in Patients with 
Advanced Dry-Form Age-Related Macular Degeneration (Geographic Atrophy) 
Sponsor 
Cell Cure Neurosciences Ltd./BioTime, Inc.  
Study Centers and Planned Geographical Distribution 
Multicenter multinational trial 
Clinical Phase 
Phase I/IIa study 
Investigational Product 
OpRegen® is a cell-based product composed of retinal pigment epithelium (RPE) cells, 
derived from human embryonic stem cells (hESCs) through a process of directed 
differentiation. OpRegen® can be implanted as a single cell suspension to form a targeted 
suspension of 50x103 to 200x103 in a total volume of 50-100 µL in either an ophthalmic 
1 
Study Duration 
• Screening period of up to 
. 
• Part 1: Eligible subjects will be enrolled into Part 1 of the trial for approximately 52 
weeks (up to ±14 days) for a post-implantation follow up assessment. 
• Part 2: Following the successful completion of Part 1 of the study, subjects will 
continue into Part 2 defined as the long term follow up with evaluations at 
, 
 
 
Study Objectives 
Primary Objectives 
To evaluate the safety and tolerability of human embryonic stem cell-derived retinal pigment 
epithelium cells (OpRegen®), transplanted subretinally to subjects with advanced dry age-
related macular degeneration (AMD) with geographic atrophy (GA). 
Secondary Objectives 
To evaluate the preliminary efficacy of OpRegen® treatment by assessing the changes in 
ophthalmological parameters as measured by various methods of primary clinical relevance. 
 
                                                 
1 Refer to Section 2.3 in the Investigator Brochure for more information about the Product Description 

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Clinical Protocol No. CCN_CT02 
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• 
Directional change in the geographic atrophy (GA) lesion area over time 
• 
Overall change in the GA lesion area of the study eye over time using SD-OCT 
and FAF 
• 
Change from baseline over time in BCVA as measured by Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart 
• 
Change from initial assessment over time in retinal sensitivity (as assessed 
by microperimetry) 
• 
Change from baseline over time in Reading Speed Test 
• 
Change from baseline over time in Low Luminance BCVA 
• 
Correlation assessment between quantitative metrics derived from FAF, SD-OCT and 
CFP images 
• 
Correlation assessment between functional and structural changes 
• 
Change over time in National Eye Institute Visual Function Questionnaire-25 
(NEI VFQ-25) Quality of Life (QoL) score 
• 
Change over time in Functional Reading Independence (FRI) Index score 
 
Study Hypothesis 
Implantation of OpRegen® to subjects with advanced dry-form AMD with GA is safe, well-
tolerated and provides preliminary efficacy evidence. 
 
Study Design 
Open-label, dose escalation study of approximately 24 subjects with advanced dry-AMD and 
GA divided into cohorts: 
 
Cohorts 1 – 3 
The first 2 cohorts, each consisting of 3 eyes of 3 legally blind subjects with best corrected 
visual acuity of 20/200 or less in the study eye, will receive a single subretinal implantation 
of OpRegen®. 
 
The third cohort will include up to 6 eyes of 6 subjects with best corrected visual acuity of 
20/200 or less in the study eye, who will receive a single subretinal implantation 
of OpRegen®. 
 
Staggered intervals within and between cohorts will be applied to ensure subjects safety 
and welfare. 
 
 
 

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Clinical Protocol No. CCN_CT02 
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4. Best corrected central visual acuity equal or less than 20/200 in the study eye by ETDRS 
vision testing.  
5. Vision in the non-operated eye must be better than or equal to that in the operated eye.  
6. Subjects with sufficient good health that can participate in all study-related procedures 
and complete the study follow-up period (based on medical records).  
7. Ability to undergo a vitreoretinal surgical procedure under monitored anesthesia care. 
8. Blood 
counts, 
blood 
chemistry, 
coagulation 
and 
urinalysis 
without 
abnormal significance. 
9. Negative for HIV, HBC, and HCV. Negative for CMV IgM and EBV IgM. 
10. Willing to defer donation of blood and tissues. 
11. Able to understand study procedures and willing to sign informed consent. 
Exclusion Criteria: 
1. Evidence of neovascular AMD by history, as well as by clinical exam, fluorescein 
angiography (FA), or ocular coherence tomography (OCT) at baseline in either eye. 
2. History or presence of diabetic retinopathy, vascular occlusions, uveitis, Coat's disease, 
uncontrolled glaucoma, cataract or media opacity preventing posterior pole visualization 
or any significant ocular disease other than AMD that has compromised or could 
compromise vision in the study eye and confound analysis of the primary outcome. 
3. History of retinal detachment repair in the study eye. 
4. Axial myopia greater than -6 diopters. 
5. At least 2 months following cataract removal in the study eye and Yttrium Aluminum 
Garnet (YAG) laser capsulotomy in the study eye in the past 4 weeks and any other 
ocular surgery in the study eye in the past 3 months prior to OpRegen® implantation. 
6. History of cognitive impairment or dementia. 
7. Contraindication for systemic immunosuppression. 
8. History of any condition other than AMD associated with choroidal neovascularization 
in the study eye (e.g. pathologic myopia or presumed ocular histoplasmosis). 
9. Any type of systemic disease or its treatment, in the opinion of the Investigator, including 
any medical condition (controlled or uncontrolled) that could be expected to progress, 
recur, or change to such an extent that it may bias the assessment of the clinical status of 
the patient to a significant degree or put the patient at special risk. 
10. For female subjects; pregnancy or breastfeeding. 
11. Current participation in another clinical study. Past participation (within 6 months) in 
any clinical study of a drug administered systemically or to the eye.  
12. Currently receiving aspirin, aspirin-containing products and/or any other coagulation 
modifying drugs which cannot be discontinued 7 days prior to surgery 
13. History of cancer (other than a non-melanoma skin cancer). For cancers in remission for 
more than five years, enrollment is allowed with concurred documented approval of 
principal investigator and oncologist prior to enrollment.3 
 
Note: “Live” attenuated vaccination prohibited during active systemic immunosuppression.  
                                                 
3 In the case of any suspected malignancies at screening, patient should be referred to appropriate medical specialist.  
 

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progress, recur, or change to such an extent that it may bias the assessment of the clinical 
status of the patient to a significant degree or put the patient at special risk. 
13. For female subjects; pregnancy or breastfeeding 
14. Currently receiving aspirin, aspirin-containing products and/or any other coagulation 
modifying drugs which cannot be discontinued 7 days prior to surgery 
15. History of cancer (other than a non-melanoma skin cancer). For cancers in remission for 
more than five years, enrollment is allowed with concurred documented approval of 
principal investigator and oncologist prior to enrollment.4 
16. Known allergy to any of the study medications or formulations 
17.  Inability to comply with study or follow-up procedures 
18.  Inability to obtain CFP, FAF, OCT/OCTA and microperimetry of sufficient quality to 
be analyzed and graded by the Central Reading Center 
 
Note: “Live” attenuated vaccination prohibited during active systemic immunosuppression.  
 
Final decision for subject eligibility upon confirmation of Central Reading Center and 
the Sponsor. 
 
Statistical Considerations 
As this is an open label, phase I/IIa dose escalation, safety, tolerability and preliminary 
efficacy study, neither power assessment, nor formal hypotheses testing are currently planned 
for study outcome measures. 
 
The planned sample size of approximately 24 treated eyes, 
 
, with targeted doses of 50x103 and up to 200x103 cells, is 
considered clinically appropriate for further characterization of the safety, tolerability and 
preliminary efficacy of OpRegen in the treatment of subjects with advanced dry-form AMD 
with GA. 
Comprehensive interim reports of accumulated safety, tolerability and preliminary available 
efficacy data will be presented to the independent Data Safety Monitoring Board (DSMB) 
prior to escalation to the next to come study dose and to enrolment of the next to come study 
cohort. Between cohorts, and subjects if applicable, the next step to proceed will occur per 
DSMB recommendation, based on accumulated safety data. 
All measured variables and derived parameters will be listed individually and if appropriate, 
presented in summary tables by dose regimen group and overall, providing sample size, 
absolute and relative frequency for categorical variables, or sample size, arithmetic mean, 
standard deviation, median, minimum and maximum for continuous variables. Confidence 
intervals will be presented for the efficacy endpoints for exploratory purposes only. Complete 
analyses to be prospectively performed will be outlined in a separate statistical analysis 
plan (SAP). 
                                                 
4 In the case of any suspected malignancies at screening, patient should be referred to appropriate medical specialist.  

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 SCIENTIFIC BACKGROUND 
 
OVERVIEW 
OpRegen consists of retinal pigment epithelium (RPE) cells that were produced by directed 
differentiation of a human embryonic stem cell (hESC) line and are suspended in injection solution 
to be implanted subretinally. 
The Sponsor intends to carry out a Phase I/IIa study of OpRegen in subjects with GA, the advanced 
form of dry-AMD, to address the safety of this therapeutic cell formulation product and to obtain 
initial indications of any potentially clinically significant efficacy. 
This clinical trial will be conducted in accordance with the standards of Good Clinical Practice 
(GCP) and International Conference on Harmonization guidelines, applicable government 
regulations and the institutional research policies and procedures. This protocol along with the 
Investigators' Brochure, Informed Consent and other supporting documentation will be submitted 
to the Institutional Review Board (IRB) and regulatory authorities, for review and formal approval 
prior to subject enrollment. 
  BACKGROUND 
 
PROPOSED INDICATION 
AMD is a progressive chronic disease of the central retina and a leading cause of vision loss 
worldwide. Most visual loss occurs in the late stages of the disease due to one of two processes: 
neovascular ("wet") AMD and geographic atrophy (GA, "dry"). In GA, progressive atrophy of the 
retinal pigment epithelium, choriocapillaris, and photoreceptors occurs (Lim, et al. 2012). The dry 
form of AMD is more common (85-90% of all cases), but may progress to the "wet" form, which, 
if left untreated, leads to rapid and severe vision loss (Nowak 2006).  
The pathogenesis of the disease involves abnormalities in four functionally interrelated tissues, 
RPE, Bruch’s membrane, choriocapillaris and photoreceptors. However, impairment of RPE cell 
function is an early and crucial event in the molecular pathways leading to clinically relevant AMD 
changes (Nowak 2006). Refer to the Investigator’s Brochure, Section 1.1.1 for more information. 
 
 
THE RETINAL PIGMENT EPITHELIUM AND ITS CHARACTERISTICS 
Description and characteristics of RPE cells are presented in the Investigator’s Brochure in Section 
1.1.2. 
 
 
TREATMENT APPROACHES 
There is currently no effective or approved treatment for dry-AMD. Prophylactic measures include 
vitamin/mineral supplements. These reduce the risk of developing wet AMD but do not affect the 
development of progression of GA. 
There are currently no FDA approved treatments for GA secondary to AMD. GA is a chronic, 
progressive condition that leads to central blind spots and often, permanent loss of vision. 

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6. Subjects with sufficiently good health to allow participation in all study-related 
procedures and complete the study follow-up period (based on medical records).  
7. Ability to undergo a vitreoretinal surgical procedure under monitored anesthesia care. 
8. Blood counts, blood chemistry, coagulation and urinalysis without abnormal 
significance. 
9. Negative for HIV, HBC, and HCV. Negative for CMV IgM and EBV IgM. 
10. Willing to defer donation of blood and tissues. 
11. Able to understand study procedures and willing to sign informed consent 
 
Exclusion Criteria 
1. Evidence of neovascular AMD by history, as well as by clinical exam, fluorescein 
angiography (FA), or ocular coherence tomography (OCT) at baseline in either eye. 
2. History or presence of diabetic retinopathy, vascular occlusions, uveitis, Coat's disease, 
uncontrolled glaucoma, cataract or media opacity preventing posterior pole visualization 
or any significant ocular disease other than AMD that has compromised or could 
compromise vision in the study eye and confound analysis of the primary outcome. 
3. History of retinal detachment repair in the study eye. 
4. Axial myopia greater than -6 diopters. 
5. At least 2 months following cataract removal in the study eye and Yttrium Aluminum 
Garnet (YAG) laser capsulotomy in the study eye in the past 4 weeks and any other 
ocular surgery in the study eye in the past 3 months prior to OpRegen implantation. 
6. History of cognitive impairments or dementia. 
7. Contraindication for systemic immunosuppression. 
8. History of any condition other than AMD associated with choroidal neovascularization 
in the study eye (e.g. pathologic myopia or presumed ocular histoplasmosis). 
9. Any type of systemic disease or its treatment, in the opinion of the Investigator, 
including any medical condition (controlled or uncontrolled) that could be expected to 
progress, recur, or change to such an extent that it may bias the assessment of the clinical 
status of the patient to a significant degree or put the patient at special risk. 
10. For female subjects; pregnancy or breastfeeding. 
11. Current participation in another clinical study. Past participation (within 6 months) in 
any clinical study of a drug administered systemically or to the eye. 
12. Currently receiving aspirin, aspirin-containing products and/or any other coagulation 
modifying drugs which cannot be discontinued 7 days prior to surgery. 
13. History of cancer (other than a non-melanoma skin cancer). For cancers in remission 
more than five years, enrollment is allowed with concurred documented approval of 
principal investigator and oncologist prior to enrollment.5 
Note: “Live” attenuated vaccination is prohibited during active systemic immunosuppression.  
                                                 
5 In the case of any suspected malignancies at screening, patient should be referred to appropriate medical specialist.  

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Clinical Protocol No. CCN_CT02 
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Amendment #14 
 
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11. Contraindication for systemic immunosuppression 
12. Any type of systemic disease or its treatment, in the opinion of the Investigator, 
including any medical condition (controlled or uncontrolled) that could be expected to 
progress, recur, or change to such an extent that it may bias the assessment of the clinical 
status of the patient to a significant degree or put the patient at special risk. 
13. For female subjects; pregnancy or breastfeeding 
14. Currently receiving aspirin, aspirin containing products and/or any other coagulation 
modifying drugs which cannot be discontinued 7 days prior to surgery 
15. History of cancer (other than a non-melanoma skin cancer). For cancers in remission 
more than five years, enrollment is allowed with concurred documented approval of 
principal investigator and oncologist prior to enrollment.6 
16. Known allergy to any of the study medications or formulation. 
17. Inability to comply with study or follow-up procedures 
18. Inability to obtain CFP, FAF, OCT/OCTA and microperimetry of sufficient quality to 
be analyzed and graded by the Central Reading Center 
 
Note: “Live” attenuated vaccination prohibited during active systemic immunosuppression. 
 
Final decision for subject eligibility upon confirmation of Central Reading Center and 
the Sponsor. 
 
 CONCOMITANT MEDICATIONS AND SUPPORTIVE CARE 
 
PREVIOUS MEDICATIONS 
All medications taken by/given to the subject, as a treatment for the primary and concomitant 
diseases within two weeks prior to the subject screening visits, will be recorded in the case report 
form (CRF). Change in these medications should be recorded during each subsequent subject 
evaluation. 
 
DISALLOWED CONCOMITANT MEDICATIONS 
The subjects should be instructed to discontinue medications that may alter coagulation, including 
aspirin and aspirin-containing medications, 7 days prior to the implantation of OpRegen. They 
should be guided to discuss the risks associated with this discontinuation with their primary 
physician. Decisions regarding the timing of restarting these medications will be at the discretion 
of the Principal Investigator. 
Anti VEGF intraocular injections are contraindicated when given as a treatment for Wet AMD. 
However, if subject was treated with Anti VEGF intraocular injections as a short-term therapy for 
an indication other than Wet AMD (or disease which is defined as exclusion criteria) more than 
                                                 
6 In the case of any suspected malignancies at screening, patient should be referred to appropriate medical specialist.  
 

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DOSE ESCALATION AND STAGGERED INTERVALS 
Staggered intervals between subjects within each cohort and between cohorts were designed in 
order to allow monitoring and investigation of adverse events, prior to exposing additional subjects 
to the product. 
The safety data gathered from each cohort will be reviewed by the independent Data Safety 
Monitoring Board (DSMB, see Section 20.2). Depending on the safety data there will be a DSMB 
recommendation to pursue one of the following alternatives: proceed to the next higher dose; stop 
dose escalation; investigate a lower dose; or repeat a dose level.  
The staggered procedure that will be followed in this study is described below. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 DETAILED STUDY PLAN 
 
PRE-SCREENING ACTIVITIES 
A printed version of the IRB approved Informed Consent will be provided to 
potential subjects and their families in order to allow them to review and 
understand all necessary information about the study and the investigational 
product prior to making a decision about their participation in the trial. The 
Principal Investigator and the clinical trial team should provide complete 
explanations and answer all questions raised by the potential participant, including 
explanation that the participation is voluntary, and they will be able to terminate 
their participation at any time, without any prejudice. 
The informed consent must be signed and dated by the subject before the subject 
can undergo any study-related activities. 
The screening period is up to 
 before implantation of the 
investigational product. During this visit the informed consent form is read and 
signed by the subject and screening measurements are taken as detailed in Table 
2. 
The informed consent procedure will ensure that subjects are adequately informed 
about the risks and benefits associated with study procedures and interventions. 
No study related procedures including weaning subjects from medications such 
as aspirin, will be done prior to completion of the informed consent signing 
procedure. A copy of the signed and dated informed consent must be provided to 
the subject. 
A detailed medical history, including “live” attenuated vaccination, should be 
obtained from each subject during the screening period, to ensure that he/she is 
not subject to exclusion. A complete physical examination will be performed, 
including vital signs measurements. A 12-lead ECG will be performed. A 
complete blood count (including differential), serum biochemistry panel, 
coagulation, urinalysis, rheumatology (including ESR and CRP), serology as well 
as malignant hematological transformation and Quantiferon (state of inoculation) 
will be performed at a central laboratory (for detailed list of laboratory parameters 
please refer to Section 24.1). 
In the case of any suspected malignancies at screening, subject should be referred 
to appropriate medical specialist. 
During the 
, the subjects will be asked to complete the NEI-VFQ25 
(interviewer version) questionnaire and Functional Reading Independence (FRI) 
index. 
Immunosuppression assessment will be performed by the study investigator, to 
ensure that the subject's medical condition allows immunosuppression therapy.  

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At screening, a full ocular history will be obtained and an ophthalmic examination 
including the following assessments will be performed, as detailed in Table 2: 
• 
Demographics 
• 
Inclusion/Exclusion Criteria  
• 
BCVA 
• 
Low Luminance BCVA (optional) 
• 
SD-OCT (central reading) 
• 
Microperimetry (central reading) cohort 3 [optional], but is required for all 
 subjects and all cohort 4 US-treated subjects and Cohort 4)  
• 
Fluorescein Angiography (FA) (central reading) 
• 
Fundus Autofluorescence (FAF) (central reading) 
• 
Color Fundus Photography (CFP) (central reading) 
• 
Dilated Fundus Examination 
• 
IOP 
• 
Slit Lamp Exam 
• 
Reading Speed Test (for subject’s proficient in English) 
Final decision for subject eligibility upon confirmation of Central Reading Center 
and the Sponsor. 
Immunosuppression therapy will be prescribed, if subject is eligible for 
enrollment, as detailed in Section 9.3.1. 
 will be measured 
during the 
. 
General Safety Assessment including prior and concomitant medications and 
adverse events will be performed during all visits. 
 
 
• 
LOCS III (baseline 1) 
 
 
 
 
The subjects can be hospitalized (if country specific requirement) 
 
 per investigator discretion. The following 
procedures and assessments will be performed on the 
 
: 
• General safety assessment (AEs and concomitant medication) 
• Vital signs 
• Medical History 
• Physical examination 
• Dilated Fundus Examination 
• IOP 

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• 
Vital Signs 
• 
Dilated Fundus Examination  
• 
IOP  
• 
Slit Lamp Exam  
• 
SD-OCT (central reading) 
• 
Color Fundus Photography (central reading) 
• 
Discharge from the hospital (optional), as per investigator discretion, in 
countries or institutions requiring hospitalization 
• 
Subject will be instructed to take “per protocol medications” and to 
contact the site in case of any general or ophthalmological conditions. 
 
 
The visit and following assessments are optional and will be performed per 
investigator discretion: 
• 
General safety assessments (AEs and concomitant medications) 
• 
Vital Signs 
• 
Dilated Fundus Examination (optional) 
• 
IOP (optional) 
• 
Slit Lamp Exam (optional) 
• 
SD-OCT (central reading) 
 
  
• 
SD-OCT (central reading)   
• 
Discharge from the hospital (optional), as per investigator discretion, in 
countries or institutions requiring hospitalization 
• 
Subject will be instructed to take “per protocol medications” and to 
contact the site in case of any general or ophthalmological conditions.  
 
 
The visit and following assessments are optional and will be performed per 
investigator discretion: 
• 
General safety assessments (AEs and concomitant medications)  
• 
Vital Signs 
• 
Dilated Fundus Examination (optional) 
• 
IOP (optional) 
• 
Slit Lamp Exam (optional) 
• 
SD-OCT (central reading) 
• 
Discharge from the hospital (optional), as per investigator discretion, in 
countries or institutions requiring hospitalization 
• 
Subject will be instructed to take “per protocol medications” and to 
contact the site in case of any general or ophthalmological conditions. 
 

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• 
General safety assessments (AEs and concomitant medications) 
• 
Vital signs 
• 
Physical examination 
• 
Dilated Fundus Examination  
• 
IOP  
• 
Slit Lamp Exam  
• 
Immunosuppression assessment 
 
 
• 
BCVA 
• 
Low Luminance BCVA (optional for cohort 4 subjects with low vision 
who are not able to perform this test and is not applicable for cohorts 1-
3) 
• 
SD-OCT (central reading) 
• 
FAF (central reading) 
• 
CFP (central reading) 
• 
Microperimetry (central reading) cohort 3 [optional], but is required for 
all 
 subjects and all cohort 4 US-treated subjects 
 
 
• 
General safety assessments (AEs and concomitant medications) 
• 
Vital signs 
• 
Physical examination 
• 
Dilated Fundus Examination  
• 
IOP  
• 
Slit Lamp Exam  
• 
Subject will be instructed to take “per protocol medications” and to 
contact the site in case of any general or ophthalmological conditions. 
• 
BCVA 
• 
Low Luminance BCVA (optional for cohort 4 subjects with low vision 
who are not able to perform this test and is not applicable for cohorts 1-
3) 
• 
SD-OCT (central reading) 
• 
FAF (central reading) 
• 
CFP (central reading) – optional, as per investigator discretion. 
• 
CBC (including differential) 
• 
Chemistry (including Serum Electrolytes) 
• 
Coagulation  
• 
Urinalysis  
• 
Rheumatology (including ESR and CRP) 
• 
HLA typing if not done previously 
 

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5.  Protocol Violation of inclusion or exclusion criteria, if, in the opinion of the 
Investigator and the Sponsor, the violation would significantly compromise 
data interpretation  
6. Loss to follow-up/failure to return 
7.  AE/Experience  
8.  Subject requires additional therapy which is prohibited according to 
the protocol 
9.  Disease progression 
10. Death 
12. Termination of the study by the Sponsor 
11. Other  
 
 UNSCHEDULED VISITS 
An unscheduled visit may be performed at any time during the study at the subject's 
request, or as deemed necessary by the study Investigator. The date and reason for the 
unscheduled visit will be recorded. Vital signs, adverse events and concomitant 
medications will be recorded, and the ocular condition will be assessed as per reason 
for unscheduled visit. 
 
 STUDY ASSESSMENTS 
 
SAFETY ASSESSMENTS 
Investigators are responsible for monitoring the safety of subjects who have 
entered this study and for alerting Sponsor or its designee to any event that seems 
unusual, even if this event may be considered an unanticipated benefit to the 
subject. 
 
The investigator is responsible for the appropriate medical care of subjects during 
the study. The investigator remains responsible for following through an 
appropriate health care option, AEs that are serious or that caused the subject to 
discontinue before completing the study. The subject should be followed until the 
event is resolved or becomes chronic or stable. 
 
For the purpose of this study, the safety of the investigational product and surgical 
procedure will be assessed during and after surgery by the investigator observed 
by ocular examinations and imaging techniques. Any observed changes will be 
reported as adverse events. 
 
Ocular toxicity and Systemic toxicity will be reported as per definitions in the 
section 21.1.7. 
 
Imaging assessments will be analyzed by central reading center(s) designated by 
the Sponsor. 
 

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Safety parameters will also be assessed by laboratory tests (e.g., hematology, 
serum chemistry, and urinalysis), ocular examinations, physical examinations. 
Concomitant medications and AEs will be monitored and tracked. 
 
The Study Schedule provides timing of all specimen collections while Protocol 
Attachment 1 defines the clinical laboratory tests to be performed during the 
study. The actual date and timing (24-hour clock time) of each sampling will be 
recorded by site personnel. 
 
Unless otherwise noted in the Protocol Attachment 1 (Section 24.1), laboratory 
tests will be analyzed by a central laboratory designated by Sponsor and will be 
used for data analysis purposes. Investigators must document their review of each 
laboratory report and evaluate out-of-range results to determine if clinically 
significant and record as AEs. 
 
Assessment of Ocular Toxicity 
Routine eye examination will be performed before and after implantation of 
OpRegen®. The Investigator will be alert to possible intra-operative 
complications. Clinical ocular examinations for toxicity will include slit lamp 
examination, applanation tonometry, and gonioscopy (if needed), and 
examination of the vitreous and fundus. The list of potential ocular toxicities 
and grading is shown in Section 21.1.7. 
 
 
Assessment of Systemic Toxicity 
Physical examination at regularly-scheduled time points will be performed by 
the clinical trial medical personnel to allow detection of and response to any 
acute symptoms. Complete blood count with differential, INR, PTT, serum 
chemistry, measures of hepatocellular integrity and renal function (including 
BUN and creatinine) and urinalysis will be performed during the 
 
, serving as a baseline, pre-implantation evaluation, and during post-
treatment evaluations. These tests will allow detection of toxicity in a number 
of organ systems. In addition, safety information will be obtained by specific 
questioning. Systemic toxicity will be graded based on the scale shown in 
Section 21.1.7. 
 
 
ASSESSMENT OF POTENTIAL OPHTHALMOLOGICAL 
CLINICAL EFFECT 
Visual assessments will be performed prior to and after OpRegen® implantation 
in order to determine whether OpRegen® implantation has an effect on visual 
parameters.  
Potential efficacy will be evaluated, but not limited by determining the rate of the 
GA progression, retinal sensitivity to light in the engrafted regions and changes 
in visual acuity. 
 

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 SUBJECT CONFIDENTIALITY AND DISCLOSURE OF DATA 
The Investigator must ensure that each subject’s anonymity is maintained as described 
below. On the CRFs or other documents submitted to the Sponsor and/or its designee, 
subjects must only be identified by study, Subject Identification Number, and 
demographics, subject to restrictions of local regulations. No other personal identifiers 
will be used, and data will be de-identified in a manner compliant with applicable 
privacy laws and regulations. Documents that are not for submission to the Sponsor 
and/or its designee (e.g., signed Informed Consent Forms [ICF]) should be kept in strict 
confidence by the Investigator in compliance with applicable laws and regulations and 
International Conference on Harmonization (ICH) Good Clinical Practice (GCP) 
Guidelines. The Investigator and institution must permit authorized representatives of 
the Sponsor and/or its designee, national and local health authorities, and the IRB direct 
access to review the subject’s original medical records for verification of study-related 
procedures and data. Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are needed for the evaluation of the study. The 
Investigator is obligated to inform the subject in the ICF that his/her study-related 
records will be reviewed by the above-named representatives. 
Subjects will be informed that data will be held on file by the Sponsor and that these 
data may be viewed by staff including the study monitor and by external auditors on 
behalf of the Sponsor and applicable regulatory authorities. All subject data will be 
held in strict confidence, as allowed by law. 
Upon the subject’s permission, medical information may be given to the subject’s 
personal physician or other appropriate medical personnel responsible for the 
subject’s welfare.  
At the time of death, no matter the cause, permission for an autopsy will be requested 
from the subject's family. Subjects will be asked to advise their families of this request 
and of its scientific and medical importance. If an autopsy is performed, a copy of the 
autopsy report should be obtained by the site and provided to the Sponsor and/or designee. 
 
 DATA REPORTING AND MONITORING 
The clinical trial at site will be managed by the Principal Investigator who will ensure 
that systems are in place so that the rights of the subjects are respected and protected 
while quality is implemented in all aspects of the trial. 
Copies of the processing documents, labels, temperature recordings, relevant batch 
certificates-of-analysis, chain-of-custody documents, or other official papers will be 
stored with the clinical trial or subject-specific records. 
All data and observations will be documented in CRF (electronic) using the source 
documentation generated at the clinical site. The CRF will be maintained on each 
subject and will be the primary data collection instrument for this study. CRFs will be 
completed and signed by the study Investigator as information becomes available. 
The procedures outlined in the protocol and the CRFs will be carefully reviewed by the 
study Investigator and clinical staff prior to study initiation to ensure appropriate 
interpretation and implementation. No deviations from the protocol should be made, 

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formulation, in case washing and replacement of the medium is required to 
prepare the dose. 
The release tests and product specifications will appear in the product Certificate 
of Analysis (CoA). Current OpRegen® release criteria are summarized in Table 4, 
below. 
 
 
 
 
 
                                                 
 
 

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ADEQUACY OF PROTECTION AGAINST RISKS 
The following procedures are likely to minimize the potential risks associated 
with study procedures: 
• The medical history and physical examination performed prior to the 
implantation of OpRegen® will identify subjects with medical or ophthalmic 
conditions that would increase the risks associated with the study procedures. 
These subjects will not be enrolled to the study. 
• The surgical procedures and implantation of the investigational product will 
be performed in standard fashion by highly experienced retinal surgeons and 
with strong attention to the risks described above.  
• To minimize the risks associated with systemic immunosuppression, 
assessment of the subjects will be performed by the study-dedicated 
investigator or designee in order to evaluate whether the subject's medical 
condition is appropriate for immunosuppression and in order to follow up 
after potential adverse reactions associated with immunosuppression (see 
Section 10.3).  
• To minimize the risks associated with severe immunological reaction, 
monitoring for the presence of an immune response to the transplanted cells 
will be performed. 
• Topical administration of antibiotics and steroids is planned to minimize the 
risk of local inflammation. 
• To minimize the risk of potential acute adverse events, the subjects may be 
hospitalized for up to three days (per investigator discretion) following 
implantation of OpRegen® and will be examined frequently on an 
ambulatory basis thereafter.  
• Results of all laboratory and safety examinations of each subject will be 
reviewed by the study Investigator throughout the study. In addition, an 
independent medical monitor will evaluate the records. 
• Results of all laboratory and safety examinations of each cohort will be 
periodically reviewed by the independent DSMB. 
 
Informed Consent and supporting study documentation include thorough 
explanation of the study procedures and related risks and benefits. All 
documentation will be approved by the relevant ethical and regulatory authorities, 
to ensure maximal protection of the subjects. 
 
During the enrollment process, and the study itself, the subjects will receive all 
information from the study Investigator and designated Research Coordinators. 
The Investigator and Research Coordinators will be available to address all 
questions and concerns arising regarding possible effects of OpRegen® during 
the enrollment and during the study. The subjects will be provided with contact 
information of the study Investigator and the Research Coordinators and will be 
encouraged to contact them in case of any emergency. 
 

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Participation in this study is completely voluntary and great care will be taken to 
ensure that individuals do not feel coerced to participate. All subjects will be able 
to terminate their participation at any time, without prejudice. 
 
Confidentiality of the study subjects and their medical information will be 
maintained by coding data collection forms. 
 
 
POTENTIAL BENEFITS 
This Phase I/II clinical trial will define the safety and tolerability of OpRegen®, 
implanted into one eye of subjects with advanced dry-AMD. No direct clinical 
benefit to the study subjects is expected. The results of this trial will be helpful in 
understanding of potential clinical benefit of OpRegen® in dry-AMD subjects and 
in planning of the future clinical trials in this and other indications. 
 
 STUDY MONITORING 
Site visits will be conducted by the Sponsor and/or designee to inspect study data, 
subject medical records, and CRFs in accordance with current US GCP and the 
respective local and national government regulations and guidelines, as applicable per 
the study Monitoring Plan. The Investigator will permit authorized representatives of 
the Sponsor, the FDA, the IRB/IEC and appropriate national or local health authorities 
access to all relevant study information. 
SAEs or other safety concerns will be evaluated immediately by the Medical Monitor 
as well as the DSMB (see Section 20.2). 
 
MEDICAL MONITOR, CRO AND CRA MONITORING VISITS 
The safety medical monitoring for this trial will be provided either by the Sponsor 
or its designee. The Medical Monitor (MM) should be adequately qualified, will 
follow the study specific monitoring plan and current guidelines for the safety 
monitoring of clinical investigations.  
The Clinical Research Organization (CRO) will be designated by the Sponsor (if 
applicable) and will be responsible for regular monitoring of study data at the 
clinical site and for ensuring compliance with the regulatory requirements, 
including ICH guidelines and adherence to the study protocol. The clinical site 
will be monitored to verify that enrollment rate, data recording, and protocol 
adherence are satisfactory. The frequency of monitoring individual sites may 
fluctuate depending upon enrollment rate, quantity of data collected and the 
complexity of the study.  
These monitoring visits will be performed for the purposes of verifying adherence 
to the protocol and the completeness and accuracy of data entered in the CRF. 
During these visits, the clinical research associate (CRA) will verify CRF entries 
by comparing them with the primary source documents (hospital/clinic/office 
records), which will be made available for this purpose. The CRA will review the 
maintenance of regulatory documentation and drug accountability. The CRA will 
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a regular basis. CRF sections will be recorded by the site personnel and verified 
by the CRAs during these visits. At the end of the study, a closeout monitoring 
visit will be performed. CRA monitoring visits will be arranged in advance with 
site personnel at a mutually acceptable time. Sufficient time must be allowed by 
the site personnel for the CRA to review CRFs and relevant source documents. 
The Study Coordinator and/or Investigator should be available to answer 
questions or resolve data clarifications. Adequate time and space for these visits 
will be made available by the Investigator. 
 
DATA SAFETY MONITORING BOARD 
The DSMB will be composed of independent physicians with expertise in 
ophthalmology/clinical trials in the targeted population, and a statistician. A 
DSMB Charter specifying role, process, and constitution of the DSMB will be 
prepared and signed by all members. The DSMB will receive safety data of each 
study cohort periodically, carefully review it and forward to the Sponsor its 
recommendations regarding study continuation. It will have the right to 
recommend discontinuation of the trial for safety reasons or for overwhelming 
clinical effect. 
The DSMB members will communicate with the Sponsor with regards to issues 
resulting from the conduct and clinical aspects of the trial. The Sponsor will work 
closely with the board to provide the necessary data for review. 
The justification for lack of sponsor blinding of the data provided to the DSMB is 
based on the fact that the study is an open label and single-arm design; therefore, 
safety monitoring is of major importance. 
 SAFETY REPORTING 
 
ADVERSE EVENTS DEFINITION 
A clinical trial AE is any untoward medical event associated with the use of a drug 
or drug delivery system in humans, whether or not it is considered related to a 
drug or drug delivery system, or due to per protocol medications received. 
A lack of drug effect is not an AE in clinical trials because the purpose of clinical 
trials is to establish whether there is drug effect and the nature of that effect or 
lack thereof. 
AEs may be either spontaneously reported or elicited during questioning and 
examination of the subject. The occurrence of an AE will be determined on the 
basis of observed or volunteered signs and symptoms and changes in the subject’s 
physical examination and laboratory test results. 
During the study, site personnel will record any change in the condition(s) and the 
occurrence and nature of any AEs on the source documents and on the appropriate 
AE CRF. AE is any symptom, sign, illness or experience that develops or worsens 
in severity during the course of the study or through the long-term follow up 
period. Intercurrent illness or injuries will be considered as AEs. Abnormal results 
of diagnostic procedures will be considered as AEs if the abnormality: 
• 
Results in study withdrawal 

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• 
Is associated with SAE 
• 
Is associated with clinical sign or symptom 
• 
Leads to additional treatment or to further diagnostic tests 
• 
Is of clinical significance, as considered by the study Investigator 
Preexisting condition is one that is present at the start of the study. Preexisting 
conditions will be recorded as AEs if their frequency and/or intensity worsens 
during the study period. At baseline evaluations, any clinically significant 
abnormality will be recorded as a preexisting condition at medical history. All 
new signs and symptoms will be reported as AEs. 
The recording period for AEs starts at the time of written informed consent until 
the subject completes the study, unless an unresolved AE is still being followed-
up. For all subjects who took at least one dose of study drug/ per protocol 
medications – whether they completed the treatment period or not – the recording 
period ends 4 weeks/28±4 days after study termination/completion. 
All AEs will be evaluated by the Investigator for seriousness, severity, 
relationship to study drug, and outcome. All AEs with ongoing/unknown 
outcomes require follow-up. Outcome information will be pursued until 
resolution or until the last batch of queries (after the last subject’s last visit). For 
adverse events that are serious or medically relevant, additional follow up will 
continue beyond last batch of queries under the responsibility of the 
Sponsor/Delegate safety department. Such events will be followed until resolution 
or stabilization. 
Any changes in subject condition reported spontaneously or observed during and 
after surgery will be documented as AE, if the condition meets criteria for AE. 
Surgical procedures will not be reported as an outcome of AE if the purpose of 
the surgery was elective or diagnostic and the outcome was uneventful. 
 
Clinical Laboratory Abnormalities 
Clinical laboratory abnormalities will be documented as an AE if one or more of 
the following conditions are met: 
• 
It is associated with a specific medical condition (defined as a diagnosis 
or clinically significant signs or symptoms) 
• 
It required medical intervention (e.g., treatment discontinuation, 
new/change in concomitant medications). 
• 
The laboratory abnormality is clinically significant and confirmed in a 
repeat test 
• 
The abnormality suggests disease and/or organ toxicity 
 
The test will be repeated and the subject will be followed-up until the test value 
has returned to the normal range, or the Investigator has determined that the 
abnormality is chronic or stable. The Investigator will exercise medical judgment 
in deciding whether abnormal values are clinically significant. 
 

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 Serious Adverse Events 
An AE or suspected adverse reaction is considered serious if, in the view of 
either the Investigator or the Sponsor, it is characterized by any of the 
following: 
• Results in death 
• Is life-threatening (i.e., in the view of either the Investigator or 
the Sponsor, its occurrence places the subject at immediate risk 
of death at the time of the event) 
• Requires inpatient hospitalization or prolongation of existing 
hospitalization (i.e., the AE requires at least a 24-hour inpatient 
hospitalization or prolongs a hospitalization beyond the expected 
length of stay.) Hospitalization, prolonged hospitalization or 
surgery will not be reported as SAE if related to diagnostic or 
elective surgical procedures for a preexisting condition. (Note: 
complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious) 
• Results in a persistent or significant disability/incapacity or 
substantial disruption of the ability to conduct normal life 
functions 
• Results in a congenital anomaly or birth defect in a subject's 
offspring (i.e., if it is suspected that exposure to a study drug [in 
male or female subjects] may have resulted in a congenital 
anomaly in the child) 
• Other important medical event (i.e., events may not be 
immediately life-threatening but are clearly of major clinical 
significance. They may jeopardize the subject and may require 
intervention to prevent another serious outcome) 
 
All SAEs (DLTs refer to section 10.2) will be carefully monitored 
throughout the course of the study. Collection of SAE information will 
begin upon the subject’s signing of the informed consent through the end of 
the long-term follow-up period, or for as long as is necessary per the 
Investigator’s discretion (whichever is later). SAEs may be either 
spontaneously reported or elicited during questioning and examination of 
the subject. All identified SAEs must be recorded and described in the 
subject’s source records. If known, the diagnosis of the underlying illness 
or disorder should be recorded, rather than its individual symptoms. All 
SAEs will be classified as related or not related to the study drug. All SAEs 
must be reported to the Sponsor as soon as possible and no later than 24 
hours after the Investigator has knowledge of the event. Serious adverse 
events will be reported by completing the SAE form provided by the 
Sponsor. Refer to the Safety Management Plan for procedures and 
reporting requirements. 
If a subject terminates study participation early after receiving any amount 
of study drug/SAEs will be collected for at least 12 weeks after the last dose 

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of per protocol drug, regardless of the investigator's opinion of causation. 
Thereafter, SAEs are not required to be reported unless the investigator feels 
the events were related to either study drug/per protocol medication, or a 
protocol procedure. 
 
 
Suspected Adverse Reaction and Causality  
Suspected adverse reaction is any adverse event for which there is a 
reasonable possibility that the drug caused the event. “Reasonable 
possibility” means there is evidence to suggest a causal relationship 
between the drugs/per protocol drug and adverse event. 
The Investigator will use the following question when assessing causality 
of an adverse event to study drug: Is there a reasonable possibility that the 
drug caused the event? An affirmative answer designates the event as a 
suspected adverse reaction. 
 
 
Relationship of Adverse Events and Serious Adverse Events 
to Study Drug 
AEs that occur during clinical studies can be significant enough to lead to 
changes in the drug development program (e.g., changes in dose, changes 
in study population, or changes in the information given to subjects in the 
informed consent form.) Such changes are particularly possible with AEs 
that are suspected to be related to the study drug and with AEs that, in 
their most severe form, are life-threatening. It is therefore very important 
for the Investigator to give an opinion on the cause-effect relationship 
between an AE and the study drug. 
 
Causality must be assessed when reporting the AE in the AE CRF and 
SAE forms. Only AEs judged by the Investigator, by the Sponsor, or by 
the Sponsor’s legal representative as having a reasonable, suspected, 
causal relationship to the study drug will be considered to be suspected 
adverse drug reactions. In general, the expression “reasonable, causal 
relationship” means that there is evidence or arguments to suggest a causal 
relationship. 
 
 
Event Expectation 
Unexpected: An event is considered “unexpected” when its nature 
(specificity) or severity is not consistent with the list of potential adverse 
reactions included in the current Investigator’s brochure. 
Expected: An event is considered “expected” when its nature and severity 
are consistent with the list of potential adverse reactions included in the 
current IB. 
 

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Recording of Adverse Events 
At each contact with the subject the study Investigator or his/her designee 
will seek information on AEs by specific questioning and examination. 
Information on all AEs will be immediately recorded in the source 
document and the data will be transferred to the CRF. All clearly related 
signs, symptoms and abnormal results will be recorded in the source 
document. The CRF will include a description, onset and resolution date, 
duration, maximum severity, assessment of causality, other suspected 
agent, subject's preexisting disease, action taken and outcome. 
All AEs occurring during the study and long-term follow up period will be 
recorded and graded as described in Section 21.1.7. The clinical course of 
each event will be followed until resolution, stabilization or until it has been 
reported as non-related to the investigational product. 
 
Toxicity Grading 
The AEs will be graded using NCI’s CTCAE. 
The list of potential ocular toxicities and their grading is shown in Table 6. 
This list is a modification of the Ocular/Visual Adverse events v.3.0 
(CTCAE), considering the specific subject population and the 
circumstances of the intervention. 
The following AEs are defined as ocular toxicity and are to be assessed for 
grading as follows: 

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Table 6. Ocular toxicity scale 
Toxicity 
Grade 1 
Grade 2 
Grade 3 SAE 
Grade 4 SAE 
Keratitis (corneal 
inflammation/cornea 
ulceration) 
Abnormal 
ophthalmologic 
changes only; 
intervention not 
indicated 
Symptomatic; 
Medical 
intervention 
indicated 
 
Symptomatic; 
Surgical 
intervention 
indicated 
Perforation or 
blindness 
(worse than 
baseline 
visual 
function) 
Glaucoma 
Elevated 
intraocular 
pressure (EIOP) 
warranting 
topical agent for 
intervention 
EIOP requiring 
topical agents 
and oral agents 
for intervention 
EIOP requires 
operative 
intervention 
Uncontrolled 
EIOP, 
resulting in 
blindness 
(worse than 
baseline 
visual 
function) 
Cataract 
Mild change 
from baseline, 
detected on 
ophthalmologic 
examination, not 
warranting 
intervention 
Moderate change 
from baseline, 
detected on 
ophthalmologic 
examination, not 
warranting 
intervention 
Severe change 
from baseline, 
detected on 
ophthalmologic 
examination, not 
warranting 
intervention 
 NOT SAE 
Severe change 
warranting 
operative 
intervention 
NOT SAE 
Uveitis 
Mild anterior 
uveitis, not 
warranting 
intervention 
Moderate 
anterior uveitis, 
warranting 
intervention 
Severe posterior 
or pan-uveitis, 
warranting 
medical 
intervention 
Severe uveitis 
warranting 
operative 
intervention 
and threating 
ocular 
integrity 
Vitreous hemorrhage 
Mild 
hemorrhage 
detected on 
ophthalmologic 
examination, not 
warranting 
intervention 
Moderate 
hemorrhage not 
warranting 
intervention  
Severe 
hemorrhage 
warranting 
vitrectomy 
Uncontrolled 
vitreous 
hemorrhage, 
threatening 
ocular 
integrity 
Retinal 
detachments/PVR 
(Proliferative 
vitreoretinopathy) 
Localized, 
peripheral 
intervention not 
indicated 
Not resolving; 
intervention not 
indicated 
Operative 
intervention 
indicated 
Operative 
failure, 
threatening 
ocular 
integrity 

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Device Adverse Events of Special Interest 
When present at the time of surgery the following AESI may be assessed for 
grading as follows: 
 
MILD: Subject is aware of event or symptom but 
event/symptom is easily tolerated. 
 
MODERATE: Subject experiences sufficient discomfort 
to interfere with or reduce his or her usual level 
of activity. 
 
MODERATELY 
SEVERE: 
Subject 
experiences 
impairment (e.g. vision loss up to 3 lines) or a related 
event that may require an additional procedure 
 
SEVERE: Significant impairment of functioning; subject 
is unable to carry out usual activities and/or the subject’s 
life is at risk from the adverse event. 
 
Device Adverse Events of Special Interest 
 
Table 8. Device Adverse Events of Special Interest 
  
Grade 
1 
2 
3  
4 
Event 
Mild 
Moderate 
Moderately 
Severe 
Severe/significant 
• Endophthalmitis  any occurrence 
resolving 
no change in 
vision 
 
any occurrence 
not resolving 
vision loss up to 2 
lines ETDRS 
 
any 
occurrence 
not resolving 
vision loss up 
to 3 lines 
ETDRS 
 
Panophthalmitis 
Or significant >3 lines 
vision loss ETDRS 
• Retinal 
detachment 
Localized, 
peripheral, 
intervention not 
planned 
Not resolving, 
intervention not 
indicated 
Operative 
indication 
indicated 
Operative failure, 
threatening ocular 
integrity 
• Choroidal 
hemorrhage* 
Localized 
subretinal/subRPE 
hemorrhage 
Not resolving, 
localized 
subretinal/subRPE 
hemorrhage 
Operative 
indication 
indicated 
diffuse 
subretinal/sub 
RPE 
hemorrhage 
Choroidal effusion, 
Choroidal rupture, 
Expulsive choroidal 
hemorrhage, and 
Unspecified choroidal 
hemorrhage 
• Perforation of 
retina  
 
 
Yes, any 
occurrence 
Operative 
indication 
indicated 
Yes, any occurrence 
Operative failure 

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Grade 
1 
2 
3  
4 
Event 
Mild 
Moderate 
Moderately 
Severe 
Severe/significant 
• Cell egress 
 
 
Yes, any 
occurrence 
Operative 
indication 
indicated 
Yes, any occurrence 
Operative failure 
Significantly 
decreased vision 
• Failure to 
deliver cells 
•  
•  
Yes, any 
occurrence 
Operative 
indication 
indicated 
Yes, any occurrence 
Operative failure 
Significantly 
decreased vision 
• Unplanned 
vitrectomy  
•  
•  
Yes, any 
occurrence 
 
Yes, any occurrence 
Operative failure 
Significantly 
decreased vision 
*Significant choroidal hemorrhage includes the following medical codes: choroidal 
effusion, choroidal rupture, expulsive choroidal hemorrhage, and unspecified 
choroidal hemorrhage 
 
 
SAFETY EXPEDITED REPORTING 
 
Reporting to the IRB/IEC 
All serious and unexpected AEs including grade 3-4 toxicities based on Table 
6, Table 7 and Table 8 will be reported to the IRB and to the FDA and other 
relevant regulatory authorities. 
It is the responsibility of the study Investigator or his/her designee to comply 
with applicable local regulatory requirements for the reporting of SAEs to the 
IRB/IEC. Investigators should immediately forward to the IRB/IEC any written 
safety report or update provided by the Sponsor in accordance with local 
regulatory requirements (e.g., safety report, IB, safety amendments, and 
updates). 
 
A special SAE report will be created for this purpose and will include the 
following information: 
• Subject number 
• Description of the event 
• Date of onset 
• Current status 
• Whether study treatment was discontinued 
• The reason why the event was classified as serious 
• Investigator's assessment of causality 
 

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All SAEs must be reported to the Sponsor as soon as possible and no later than 
24 hours after study Investigator or his/her designee has knowledge of the event. 
 
When an SAE occurs, the Investigator must do the following: 
• Note in the subject’s medical file the date on which the Investigator or 
site staff first learned of the event by any route (e.g., at a follow-up visit 
with the subject, by telephone with the subject, or from a third party). 
• Immediately complete an AE CRF and an SAE form, without waiting 
for the clinical outcome or for the results of further investigation. 
• Send to the assigned Medical Monitor (MM) de-identified copies of 
pertinent records, as soon as such copies are available, for example: 
o Hospital admission reports 
o Reports of further consultations 
o Laboratory test reports 
o Reports from other examinations aiding diagnosis 
o Results from pre-treatment assessments for comparison with the 
results obtained under treatment 
o Autopsy report, if an autopsy is performed 
• Fulfill regulatory requirements for reporting to the IRB/IEC. 
 
If an AE initially judged non-serious worsens and becomes serious, the 
Investigator must follow the procedure described above. 
 
 
Reporting to the DSMB 
The reporting rule described in Section 21.3.1 should be applied for reporting to 
the DSMB. All serious and unexpected AEs including grade 3-4 toxicities based 
on Table 6 and Table 7 above should be reported to the DSMB. The SAE report 
created for notification of the IRB and regulatory authorities should be sent to the 
DSMB members within 48 hours from the event. 
 
Medical Monitoring Review 
The MM (see Section 20.1), CRA and the Sponsor should be notified about SAE 
by the study Investigator or his/her designee, by email or fax, as soon as possible 
and not later than 24 hours after the event. 
 
The MM is responsible for initial review of these events within two (2) days of 
the notification. The MM review will be documented. If the MM requires 
additional information to make an assessment, the clinical site will have two (2) 
days to respond to the request. Most information should be available within four 
(4) days of the site's knowledge of the event. 
 
 
Reporting to Regulatory Authorities 
The Sponsor or his authorized representative will notify the FDA or any other 
relevant regulatory authorities of any unexpected, serious adverse event or fatal 
or life-threatening experience associated with study procedures as soon as 

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possible, in accordance with regulatory requirements. As per 21 CFR 312.32, 
unexpected fatal or life-threatening suspected adverse reactions are reported by 
telephone or fax no later than seven (7) calendar days after knowledge of the 
event. All serious, unexpected, suspected adverse reactions and Grade 3-4 ocular 
toxicities (except cataract) related to the investigational product, such as 
intraocular infection, inflammation, retinal detachment, tumor/ectopic tissue 
formation will be reported to the FDA via a written report within fifteen (15) days 
of receipt of the information. 
 
 
FOLLOW-UP OF THE ADVERSE EVENTS 
Subjects who experienced AEs will be followed until resolution or stabilization. 
SAEs that are ongoing at the end of the study period will be followed up to 
determine the final outcome. Any SAE that occurs after the study period and is 
considered to be possibly related to study participation will be recorded and reported 
immediately. 
 
 STATISTICAL METHODOLOGY 
 
STUDY DESIGN AND SAMPLE SIZE 
As this is an open-label, phase I/IIa dose escalation, safety, tolerability and 
preliminary efficacy study, neither power assessment, nor formal hypotheses testing 
are currently planned for study outcome measures. 
Detailed methodology for data summary and analyses will be documented in a 
Statistical Analysis Plan (SAP). This document may modify the plans outlined in the 
protocol; however, any major modification of the outcome measures and/or its 
analysis will also be reflected in a protocol amendment. Additional statistical 
analyses other than those described in this section may be performed if deemed 
appropriate and included in the SAP. 
The planned sample size of approximately 24 eyes for 4 study cohorts to be treated 
with targeted OpRegen® doses of 50x103 and up to 200x103 cells, is considered 
clinically appropriate for further characterization of the safety, tolerability and 
preliminary efficacy of OpRegen® in the treatment of subjects with subjects with 
advanced dry-form AMD with GA. 
 
 
ANALYSIS SETS 
 
Modified Intent-to-Treat (mITT) Analysis Set 
The Modified Intent-to-Treat (mITT) analysis set will consist of all subjects who 
have been enrolled to the trial and received the OpRegen® implantation. This 
analysis set, which will include all data captured in database for these subjects, 
will serve as the primary Analysis Set for inference. 

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Per Protocol (PP) Analysis Set 
The Per Protocol (PP) analysis set is a subset of the mITT Analysis Set and will 
consist of all subjects who have been enrolled into the trial, received the 
OpRegen® implantation and violated none of the major protocol guidelines. 
 
 
SIGNIFICANCE LEVEL 
No formal hypothesis testing is planned for this study. However, a significance level 
of 0.05 using two-tailed tests will be utilized in the case that exploratory significance 
testing will be performed. 
 
 
INTERIM REPORTS 
Comprehensive interim reports of accumulated safety, tolerability and preliminary 
available efficacy data will be presented to the independent Data Safety Monitoring 
Board (DSMB). 
Depending on the safety data available, there will be a DSMB recommendation to 
pursue one of the following alternatives: proceed to the next higher dose; stop dose 
escalation; investigate a lower dose; or repeat a dose level. 
 
 
DESCRIPTIVE STATISTICS 
All measured variables and derived parameters will be listed individually and if 
appropriate, presented in summary tables by dose regimen group and overall, 
providing sample size, absolute and relative frequency for categorical variables, or 
sample size, arithmetic mean, standard deviation, median, minimum and maximum 
for continuous variables. Confidence intervals will be presented for the efficacy 
endpoints for exploratory purposes only. 
 
 
MISSING DATA 
Every effort will be made to complete follow-up for all subjects and avoid missing 
data, in particular regarding essential items. For other cases of missing data, the “last 
observed value” (LOV) approach will be used when appropriate. 
 
 
SUBJECT DISPOSITION 
Data from subjects who are screened but not treated, subjects in the mITT and PP 
Analysis Sets, as well as trial withdrawals from study follow-up will be summarized 
using descriptive statistics. 
  
 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demographics, baseline data as well as disease prognostic factors, medical history, 
and prior medications will be summarized for the mITT analysis set using 
descriptive statistics. 
 

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CONCOMITANT MEDICATIONS USE 
The WHO drug dictionary will be used to classify medications verbatim for 
Concomitant Medication and Pre-Trial Medications. 
Analysis of concomitant drug use will be performed in the following manner: 
• 
Pre-Study IP Implantation Medications Use: Analyses will include coded 
medications that were initiated prior to study IP implantation, regardless 
stopping date. An incidence table including patient counts (no. of subjects) 
and percentages broken down by Medication Class and Preferred Term will 
be provided. 
• 
Concomitant Medications Use (Post-Study IP Implantation): Analyses will 
include only coded medications that were consumed following study IP 
implantation, regardless if drug initiation date was before or after it. An 
incidence table including patient counts (no. of subjects) and percentages 
broken down by Medication Class and Preferred Term will be generated. 
 
 
EVALUATION OF SAFETY 
 Treatment Emergent Adverse Events (TEAEs) 
AEs will be recorded from the time a subject has signed the Informed Consent. 
All AEs reported by the investigators will be coded according to the current 
version of the MedDRA dictionary. 
The following will be incorporated into the analysis of AEs: 
• 
All analyses to be provided will include coded AEs. 
• 
AEs analyses will include only the TEAEs, namely, those events which 
started following study IP implantation. Listings of both TEAEs and non-
TEAES will be provided. 
• 
Summary tables of TEAEs will be provided by Study Cohort and overall. 
• 
The incidence (no. of subjects) and frequency (no. of events) of TEAEs 
will be provided when broken down by System Organ Class (SOC) and 
by Preferred Term (PT) according to MedDRA dictionary. 
• 
Breakdowns of TEAEs by all of the AEs attributes (e.g. seriousness, 
severity) will also be provided. 
• 
Breakdowns of TEAEs by age and sex will also be provided. 
• 
The derived dictionary used in the analyses displaying the MedDRA 
System Organ Class (SOC), the Preferred Term (PT), and the AE 
Verbatim Term as specified by the Investigator, will be provided. 
 
 Safety Laboratory Tests 
Analyses of safety laboratory data will be performed in the following manner: 
• 
Summary tables of safety laboratory parameters will be provided by Study 
Cohort and overall. 
• 
Box-Plots of laboratory measurements before study IP administration and 
afterwards by scheduled visit and will be provided. In this analysis 
baseline values are the measurements taken up study IP administration, 

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while “during trial” evaluations are the measurements taken after that time 
point. 
• 
Descriptive statistics of quantitative tests results and changes from 
baseline by scheduled visit will also be provided. The analysis algorithm 
as described for the above Box-Plots assessments will be used for this 
analysis as well. 
• 
Quantitative laboratory measurements will be categorized with reference 
to the normal ranges as Low, Normal, or High. Shift analysis of the 
categorical change from baseline to each scheduled visit and to the last 
observed assessment will also be performed. 
• 
A list of parameters and related cut-off values defining the potentially 
clinically significant (PCS) abnormal values will be outlined by the 
Sponsor. Measurements used in the analysis are those taken following 
study IP administration. The incidence tables of PCS lab values as well as 
the individual patient listing will be provided using the denominator which 
is the number of subjects with at least one post-baseline administration of 
trial medication. Individual subjects’ listings of PCS measurements will 
also be presented. 
 Vital Signs 
Analyses of vital signs (blood pressure, pulse, temperature, and respiration rate) 
will be performed in the following manner: 
• 
Summary tables of vital signs will be provided by Study Cohort 
and overall. 
• 
Box-Plots of vital signs before study IP administration and afterwards by 
scheduled visit and will be provided. In this analysis baseline values are 
the measurements taken up study IP administration, while “during trial” 
evaluations are the measurements taken after that time point. 
• 
Descriptive statistics of quantitative tests results and changes from 
baseline by scheduled visit will also be provided. The analysis algorithm 
as described for the above Box-Plots assessments will be used for this 
analysis as well. 
• 
A list of parameters and related cut-off values defining the potentially 
clinically significant (PCS) abnormal values will be outlined by the 
Sponsor. Measurements used in the analysis are those taken following 
study IP administration. The incidence tables of PCS lab values as well as 
the individual patient listing will be provided using the denominator which 
is the number of subjects with at least one post-baseline administration of 
trial medication. Individual subjects’ listings of PCS measurements will 
also be presented. 
 ECG Assessments 
As only qualitative ECG assessments are planned, any clinically relevant 
changes occurring from screening until the last trial visit will be recorded as an 
adverse event. 

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• 
 
• 
 
• 
 
 
• 
 
 
HYPOTHESIS 
The primary hypothesis is that there will be no dose-limiting toxicity (DLT) and that 
implantation of OpRegen® to subjects with progressive dry-form AMD with GA 
will be safe and well-tolerated. 
 
For the purpose of this study DLT is defined as an SAE determined to be product-
related. 
 
A secondary null hypothesis is that there will be no difference in disease 
progression, as measured by retinal function and structure, between the treated and 
untreated regions in the treated eye and between treated and untreated eye of a 
subject. 
 
 
STATISTICAL METHODS 
For the primary hypothesis the dose will be defined to exceed the maximally 
tolerated dose (MTD) if at least two of the subjects in a cohort have DLT. 
If the dose has not exceeded the MTD in Cohort 1, the study will proceed to Cohort 
2, pending the DSMB review. If the dose has not exceeded the MTD in Cohort 2, 
the study will proceed to Cohort 3, pending the DSMB review of data from Cohorts 
1 and 2. Enrollment of Cohort 4 will proceed only after review of the accumulated 
safety data by the DSMB. 
For the secondary hypothesis concerning changes in retinal structure and function 
following OpRegen® implantation, the small number of subjects (3 per cohort in 
Cohorts 1 and 2, up to 6 in Cohort 3 and approximately 12 in Cohort 4) precludes 
any definitive assessment of change through formal statistical testing. However, the 
following data analytical techniques will be used to describe the retinal structure 
and function results: assessing the changes in treated eyes will involve comparing 
the magnitude of observed changes in retinal structure and function to the 
distribution of changes between visits in a given subject (including historical data, 
when available), and will be also compared to the same measures gathered from 
previously studied populations of similarly affected subjects. 
Measurements of retinal structure and function made on the non-treated eye of each 
subject will also be examined in the same way as for the treated eye to evaluate the 
extent to which placebo effects or unexpected temporal trends may be contributing 
to observed changes in retinal function. The non-treated eyes form a good 
comparison group for the fellow treated eyes in terms of rate of enlargement of GA. 

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