Clinical trial NCT02659098
Conditions: Visual Acuity Geographic Atrophy Macular Degeneration
Keywords: Best Corrected Visual Acuity Geographic Atrophy Macular Degeneration CNTO 2476
Sponsor: Janssen Research & Development, LLC
Start date: 2015-12-04; Completion date: 2019-06-05
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety and performance profile of the suprachoroidal surgical approach and the Delivery System.

Detailed description:
This is a multicenter (when more than one hospital or medical school team work on a medical research study) study which includes an initial unmasked safety phase. The duration of participation in the study for each participant is approximately 3 years. Efficacy will be evaluated at 6 months, 12 months and annually thereafter. Participants' safety will be monitored throughout the study.

Arms: arm 1: Participants will receive CNTO 2476 3.0 x 10\^5 cells in 50 microliter (mcL). CNTO 2476 will be delivered using the custom-designed Delivery System.
Interventions: intervention 1: CNTO 2476 3.0 x 10^5 cells intervention 2: Subretinal Delivery System
Intervention descriptions: intervention 1: Participants will receive a single subretinal administration of CNTO 2476 3.0 x 10\^5 cells in 50 microliter (mcL) given by subretinal Delivery System. intervention 2: Participants will receive CNTO 2476 by using the Delivery System.

Protocol documents:
Prot_000.pdf: 
1
Status: Approved, Date: 15 December 2017
Janssen Research & Development, LLC *
Clinical Protocol
A Phase 2b, Multicenter, Double-masked, Randomized Study Evaluating the Safety and 
Clinical Response of Subretinal Administration of CNTO 2476 in Subjects with Visual 
Acuity Impairment Associated with Geographic Atrophy Secondary to Age Related 
Macular Degeneration
Protocol CNTO2476MDG2002; Phase 2b
AMENDMENT 3
CNTO 2476
*Janssen Research & Development is a global organization that operates through different legal entities in 
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development 
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen 
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Ireland UC; or Janssen Research & 
Development, LLC. The term “sponsor” is used throughout the protocol to represent these various legal 
entities; the sponsor is identified on the Contact Information page that accompanies the protocol.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
Status:
Approved
Date:
15 December 2017
Prepared by:
Janssen Research & Development, LLC
EDMS number:
EDMS-ERI-95495761, 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................. 17
TIME AND EVENTS SCHEDULES ............................................................................................................ 25
ABBREVIATIONS ...................................................................................................................................... 28
1.
INTRODUCTION................................................................................................................................ 30
1.1.
Background .................................................................................................................................... 31
1.1.1.
Nonclinical Studies ..................................................................................................................... 31
1.1.1.1.
Mechanism of Action ............................................................................................................... 31
1.1.1.2.
Pharmacokinetic Profile........................................................................................................... 31
1.1.1.3.
Immunogenicity ....................................................................................................................... 32
1.1.1.4.
Toxicology................................................................................................................................ 32
1.1.2.
Clinical Studies ........................................................................................................................... 33
1.1.2.1.
Human Pharmacokinetics........................................................................................................ 33
1.1.2.2.
Efficacy .................................................................................................................................... 33
1.1.2.3.
Safety....................................................................................................................................... 34
1.2.
Overall Rationale for hUTC Development and Delivery System Innovation.................................. 36
1.3.
The Cell Delivery System............................................................................................................... 37
2.
OBJECTIVES AND HYPOTHESES.................................................................................................. 37
2.1.
Objectives ...................................................................................................................................... 37
2.2.
Hypothesis ..................................................................................................................................... 38
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 38
3.1.
Overview of Study Design.............................................................................................................. 38
3.2.
Study Design Rationale.................................................................................................................. 40
3.2.1.
Control ........................................................................................................................................ 41
3.2.2.
Masking....................................................................................................................................... 41
3.2.3.
Randomization............................................................................................................................ 41
3.2.4.
Primary Outcome Measure......................................................................................................... 41
4.
SUBJECT POPULATION.................................................................................................................. 41
4.1.
Inclusion Criteria ............................................................................................................................ 41
4.2.
Exclusion Criteria ........................................................................................................................... 43
4.3.
Prohibitions and Restrictions ......................................................................................................... 46
5.
TREATMENT ALLOCATION AND MASKING ................................................................................. 46
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 46
6.1.
Open-label Safety Run-in Phase ................................................................................................... 46
7.
TREATMENT COMPLIANCE............................................................................................................ 47
8.
PRESTUDY AND CONCOMITANT THERAPY ................................................................................ 47
9.
STUDY EVALUATIONS .................................................................................................................... 48
9.1.
Study Procedures........................................................................................................................... 48
9.1.1.
Overview..................................................................................................................................... 48
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Clinical Protocol CNTO2476MDG2002 Amendment 3
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9.1.1.1.
Screening Phase ..................................................................................................................... 49
9.1.1.2.
Open-label Safety Run-in Phase............................................................................................. 51
9.1.1.3.
End of Treatment or Early Withdrawal .................................................................................... 51
9.1.1.4.
Long-term Follow-up Phase .................................................................................................... 51
9.2.
Efficacy........................................................................................................................................... 51
9.2.1.
Evaluations ................................................................................................................................. 51
9.2.1.1.
Primary Efficacy Measure........................................................................................................ 51
9.2.1.2.
Secondary Efficacy Measures................................................................................................. 52
9.2.2.
Endpoints.................................................................................................................................... 52
9.3.
Immunogenicity.............................................................................................................................. 52
9.3.1.
Evaluations ................................................................................................................................. 52
9.3.2.
Analytical Procedures................................................................................................................. 53
9.3.3.
Immunogenicity Assessments .................................................................................................... 53
9.4.
Intraoperative Delivery System and Procedure Evaluations.......................................................... 53
9.5.
Safety Evaluations ......................................................................................................................... 53
9.5.1.
Adverse Events........................................................................................................................... 53
9.5.2.
Clinical Laboratory Tests ............................................................................................................ 54
9.5.3.
Vital Signs................................................................................................................................... 55
9.5.4.
Physical Examination.................................................................................................................. 55
9.6.
Sample Collection and Handling.................................................................................................... 55
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 55
10.1.
Completion ..................................................................................................................................... 55
10.2.
Discontinuation/Withdrawal from the Study ................................................................................... 55
11.
STATISTICAL METHODS................................................................................................................. 56
11.1.
Subject Information ........................................................................................................................ 56
11.2.
Sample Size Determination ........................................................................................................... 57
11.3.
Efficacy Analyses ........................................................................................................................... 57
11.4.
Immunogenicity Analyses .............................................................................................................. 57
11.5.
Safety Analyses ............................................................................................................................. 57
11.6.
Data and Safety Monitoring Board................................................................................................. 58
12.
ADVERSE EVENT REPORTING ...................................................................................................... 59
12.1.
Definitions ...................................................................................................................................... 59
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 59
12.1.2.
Attribution Definitions.................................................................................................................. 60
12.1.3.
Severity Criteria .......................................................................................................................... 61
12.2.
Special Reporting Situations.......................................................................................................... 61
12.3.
Procedures..................................................................................................................................... 62
12.3.1.
All Adverse Events...................................................................................................................... 62
12.3.2.
Serious Adverse Events ............................................................................................................. 63
12.4.
Contacting Sponsor Regarding Safety........................................................................................... 63
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 64
13.1.
Procedures..................................................................................................................................... 64
13.2.
Contacting Sponsor Regarding Product Quality ............................................................................ 64
14.
TREATMENT INFORMATION .......................................................................................................... 64
14.1.
Physical Description of CNTO 2476 .............................................................................................. 64
14.2.
Packaging ...................................................................................................................................... 64
14.3.
Labeling.......................................................................................................................................... 65
14.4.
Preparation, Handling and Storage................................................................................................ 65
14.5.
Investigational Product and Device Accountability ........................................................................ 65
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 65
16.
ETHICAL ASPECTS ......................................................................................................................... 66
16.1.
Study-Specific Design Considerations........................................................................................... 66
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16.2.
Regulatory Ethics Compliance....................................................................................................... 66
16.2.1.
Investigator Responsibilities ....................................................................................................... 66
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 67
16.2.3.
Informed Consent ....................................................................................................................... 68
16.2.4.
Privacy of Personal Data ............................................................................................................ 69
16.2.5.
Long-Term Retention of Samples for Additional Future Research ............................................ 70
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 70
17.1.
Protocol Amendments.................................................................................................................... 70
17.2.
Regulatory Documentation ............................................................................................................ 71
17.2.1.
Regulatory Approval/Notification ................................................................................................ 71
17.2.2.
Required Prestudy Documentation............................................................................................. 71
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 72
17.4.
Source Documentation................................................................................................................... 72
17.5.
Case Report Form Completion ...................................................................................................... 73
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 73
17.7.
Record Retention ........................................................................................................................... 74
17.8.
Monitoring ...................................................................................................................................... 74
17.9.
Study Completion/Termination....................................................................................................... 75
17.9.1.
Study Completion ....................................................................................................................... 75
17.9.2.
Study Termination....................................................................................................................... 75
17.10.
On-Site Audits ................................................................................................................................ 75
17.11.
Use of Information and Publication................................................................................................ 76
REFERENCES............................................................................................................................................ 78
INVESTIGATOR AGREEMENT ................................................................................................................. 80
LIST OF ATTACHMENTS
Attachment 1:
Anticipated Events ......................................................................................................... 79
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Status: Approved, Date: 15 December 2017
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Schedule of Study Assessments for the Safety Run-in Phase and the Randomized 
Double-masked Treatment Phase from Screening through the Month 12 
Postoperative Visit .................................................................................................................... 25
Table 2
Schedule of Study Assessments During the Long-term Follow-up Phase*.............................. 27
Table 3:
Study CNTO2476MDG1002: Number (%) of Subjects with 1 or More Treatment-
emergent Serious Adverse Events by Preferred Term (Subjects Treated in Phases 1 
and 2a Combined) .................................................................................................................... 35
Table 4:
Volume of Blood to be Collected From Each Subject............................................................... 49
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Status: Approved, Date: 15 December 2017
PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
1 July 2015
Amendment 1
21 December 2015
Amendment 2
29 September 2016
Amendment 3
15 December 2017
Amendments below are listed beginning with the most recent amendment.
Amendment 3 (15 December 2017)
The overall reason for the amendment: The palucorcel development program is discontinued for strategic 
business reasons. For this reason, this study protocol is amended to eliminate the 2nd Safety Cohort and the 
randomized masked portion of the study; to reduce the study sample size; to reduce the length of total follow-up 
period from 60 months to 36 months; and to eliminate most secondary and exploratory efficacy assessments.
Applicable Section(s)
Description of Change(s)
Rationale: To allow elimination of the 2nd Safety Cohort and randomized masked portion of the study.
Synopsis, Objectives and 
Hypothesis; Efficacy 
evaluations/endpoints;
2. Objectives and 
Hypothesis
9.2.2 Endpoints
Primary objectives and endpoints: “The randomized Double-masked Treatment 
Phase of the study to assess the effects on visual acuity of a single subretinal 
administration of CNTO 2476 at 1 of 2 doses, compared with the control.” was 
removed.
The primary efficacy endpoint “The proportion of subjects in the randomized 
Double-masked Treatment Phase showing improvement from baseline of ≥15 letters 
in best corrected visual acuity (BCVA) at the 6-month visit following treatment with 
1 of 2 doses of CNTO 2476 compared to the control arm” was removed.
Secondary objectives and endpoints: Updated the major secondary objectives and 
secondary efficacy endpoints to reflect elimination of the Double-Masked Treatment 
phase.
Exploratory objectives and endpoints: The exploratory objectives and endpoints 
related to the Double-masked Treatment phase were removed.
Hypothesis: Added a statement about termination of the Double-masked Treatment 
phase.
Synopsis, Overview of 
study design, subject 
population;
3.1 Overview of Study 
Design;
3.2 Study Design Rationale
4 Subject Population;
Synopsis, Safety Run-in 
Phase
Synopsis, Randomized 
Double-masked Treatment 
Phase
3.2 Study Design Rationale
The total subjects to be screened was decreased from 400 to 100 subjects to limit the 
total number of subjects in the open-label phase to 21 subjects. A sentence “This 
represents a significant reduction in scope and duration based on a decision to 
discontinue the palucorcel development program.” was added.
The Figure 1 representing the study design with the Double-masked treatment phase 
was removed.
Updated the text to reflect the elimination of the Randomized Double-masked 
treatment phase.
Updated the target number of subjects to be enrolled in the safety run-in phase from 
“approximately 75” to “approximately 21”.
Updated the text to reflect that this planned phase of the study was eliminated.
Updates made to the study design rationale to reflect that changes were made to 
minimize the visit burden on subjects and investigators.
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Status: Approved, Date: 15 December 2017
Applicable Section(s)
Description of Change(s)
5. Treatment Allocation and 
Masking
Synopsis; Long-term 
follow-up phase
3.1 Overview of Study 
Design
8. Prestudy and 
Concomitant medications
16.1 Study specific design 
considerations
9.1.1.4 Long-term Follow-
up Phase
Patient Reported Outcomes planned for the Double-Masked Treatment phase of the 
study were removed.
Updated the control, masking, and randomization details to reflect that the open-label 
phase of the study do not require control, masking, or randomization.
Procedures for randomization and stratification were removed and all subjects were 
planned to receive the same dose of 3.0 x 105 cells.
Table 4 and Table 5 with masking procedures for subjects, site personnel, and team 
members were deleted.
The frequency of Long-term Follow-up Phase was updated from every 6 months for 
4 years to every 6 months for 2 years.
The total study duration was update to 3 years from 5 years.
Synopsis, Dosage and 
administration;
6.2 Randomized Double-
masked Treatment Phase
Updated the dosing details to eliminate dosing information for the Randomized 
Double-masked treatment phase.
The details of sham surgical procedure for the control group were removed.
Rationale: Updates were made to align the protocol with the decision to eliminate the randomized masked portion 
of the study.
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Applicable Section(s)
Description of Change(s)
Synopsis, Efficacy 
evaluations;
9. Study Evaluations
10.1. Completion
10.2 
Discontinuation/Withdrawal
Synopsis, Secondary 
efficacy measures; 9.2.1.2 
Secondary efficacy 
measures
14.4. Preparation, Handling 
and Storage
Time and Events Schedule 
(Table 2)
Footnotes for Time and 
Events Schedule (Table 1)
Footnotes for Time and 
Events Schedule (Table 2)
Open-label Safety Run-in Phase: Updated to remove the 2nd Safety Cohort and 
safety review by DSMB before the initiation of Randomized Double-masked 
treatment phase.
Randomized Double-masked treatment phase: Text updated to remove this phase.
End of Treatment or Early withdrawal: Updated to reflect that the final visit will 
be conducted on Month 36.
The pharmacogenomic evaluations were eliminated.
The additional assessments of contrast sensitivity, low luminescence BCVA (best 
corrected visual acuity), health related quality of life, and MN read were removed.
Exploratory efficacy measures were removed.
The use of software prediction tool to predict the treatment of dry AMD was 
eliminated.
The sentence “To support the masking of the trial, a vapor-phase shipper containing 
no CNTO 2476 vials will be shipped for subjects assigned to the sham surgery arm” 
was removed.
The ‘DNA blood samples for genetic testing’ was removed.
The columns for Months 42, 48, 54, and 60 (End of Study) visit were deleted. 
The assessments of low luminescence visual acuity, contrast sensitivity, MN read, 
microperimetry, and NEI-VFQ-25, and 3-item Near Vision Subscale, and SF-36, FRI
were removed.
The phrase “the Double-masked Treatment Phase” was removed from the Note 2 in 
the footnote.
Bullet ‘g)’ was updated to reflect that the double-blind masked phase was eliminated 
from the study
The follow-up phase was updated to 2 years
The abbreviations and expanded forms of NEI-VFQ-25 and SF-36 were removed.
Synopsis, Statistical 
methods;
11. Statistical Methods
Updated to reflect that descriptive statistics will be used instead of previously 
planned formal statistical testing.
The statistical methods planned for primary, secondary, exploratory endpoint 
analyses were removed.
Updates were made to depict that all the subjects receiving treatment will be 
considered for safety analyses.
11.2 Sample size 
determination
11.5 Pharmacogenomic 
analyses
11.6 Data and Safety 
Monitoring Board
Updated the text to reflect that 21 subjects will be included in the study for an 
adequate clinical assessment of safety and usability of the novel delivery system 
instead of using the BCVA response rates between the control group and 
CNTO 2476 group for sample size determination.
The pharmacogenomic analyses were eliminated.
Updated the text to reflect that no further DSMB meetings will be held and DSMB 
will be disbanded until further decision from Janssen’s to reform the DSMB.
Rationale: The first Safety Cohort having already been done and the efficacy portion of the study no longer 
planned, there is no need to describe the rationale for the sham surgical procedure.
Synopsis;
3.2 Study Design Rationale
5. Treatment allocation and 
masking
16 Ethical Aspects
The rationale for performing the sham surgical procedure was removed.
Rationale: Minor errors were noted.
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Applicable Section(s)
Description of Change(s)
Throughout the protocol
Minor grammatical, formatting, or spelling changes were made.
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Amendment 2 (29 Sept 2016)
The overall reason for the amendment: to include modifications to inclusion and exclusion criteria taken from 
learning acquired through the first 21 subjects (the initial Safety Cohort), to include a 2nd Safety Cohort of 
21 additional subjects agreed upon by the DSMB, to expand the screening to treatment window to 45 days and to 
include additional baseline assessments (axial length). Other modifications are in included to provide clarity to 
study sites where there was ambiguity, or the protocol was silent on logistical issues that have arisen. Editorial 
changes were made to improve the overall clarity of the Protocol.
Applicable Section(s)
Description of Change(s)
Overview of Study 
Design
Screening Phase
Safety Run-in Phase
Subject Population
Inclusion Criteria
Exclusion Criteria
Updated the target number of subjects to be enrolled in the study to “approximately 
285 subjects”. Specified the screening period of up to 45 days before initial randomization 
that subjects must be confirmed with a diagnosis of GA of the macular secondary to age-
related macular degeneration with associated vision loss. Clarified vision between the 
patient’s eyes as “not clinically equal” or “clinically equal” for the relevant disease state 
of the eyes. Updated the approximate number of subjects to 75 in the Safety Run-in Phase 
of the study. Specified the addition of the 2nd Safety Cohort. Also updated the number of 
sites for this phase of the study to 20.
Clarified that subjects may have the option to donate their eyes for histological evaluation 
post mortem. Specified the screening period of up to 45 days between a subject giving 
written informed consent and occurrence of treatment. Also clarified that screening 
activities need not take place in one visit. Clarified that the BCVA examination to 
determine eligibility should be performed prior to any other ocular study procedures that 
might interfere with vision assessments (dilation, bright light examination, etc). Also 
specified that axial length will be recorded at baseline. Indocyanin green angiography will 
be performed for all subjects unless discussed with the Sponsor
Clarified that a minimum of the first 3 eligible subjects at each center will receive active 
treatment in an uncontrolled, open-label Safety Run-in Phase. Clarified that the first 
21 subjects at 8 (not 7) study sites will comprise the initial Safety Cohort, and specified the 
addition of the 2nd Safety Cohort
Updated protocol to specify that approximately 400 subjects will be screened to provide
approximately 285 subjects enrolled. The change reflects the additional safety run-in 
subjects resulting from an increase in the number of sites, the 2nd Safety Cohort and an 
estimated increase in the percentage of screen failures. Also updated the protocol to 
specify that screening for eligible subjects will be performed within 45 days before 
administration of the treatment.
Criterion 2 (renumbered to 2.2) was updated to indicate AMD confirmed within 45 days 
prior to initial randomization. Diagnosis to be verified by the central reading center.
Macular Photocoagulation Study (MPS) disc areas (DA) of 0.5 for all subjects. In the 
Safety Run-in Phase only there is no maximum DA as long as the criteria for photography 
can be met and the surgeon determines that the GA size will not impede cell delivery. 
Criterion 3 (renumbered to 3.2) was updated to indicate that the treatment eye will be 
that with the worse BCVA at screening. If BCVA is clinically equivalent, the eye with the 
larger GA determines the study eye.
Criterion 1 (renumbered to 1.2) was updated to state “subjects with a history of 
neovacular (“wet”) AMD …… or fluid. In cases where imaging is inconclusive, review of 
the case with the study site, considering history and imaging will determine eligibility”
Criterion 7 (renumbered to 7.2) was extended to include “Subjects who have received 
anti-VEGF treatment without a confirmed diagnosis of wet AMD or who have participated 
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
Applicable Section(s)
Description of Change(s)
Time and Events 
Schedule (Table 1)
Footnotes for Time 
and Events Schedule
Time and Events 
Schedule (Table 2)
in previous studies for AMD may be considered eligible if these treatments/study 
participation were given at least one year prior to enrollment”
Criterion 8 (renumbered to 8.2) was updated to “previous intraocular surgery within 3
months prior to screening in either eye. Previous treatment with Visudyne®, external-beam 
radiation therapy, or transpupillary thermotherapy in the study eye at any previous time 
point”
“Visual Acuity” was replaced with “Best Corrected Visual Acuity” (BCVA)
Low Luminance Visual Acuity was added as a separate Study Assessment at Screening, 
Week 4, and at Months 2, 3, 6 and 12. Axial Length was added as a Study Assessment at 
Screening. Footnotes for several items on Table 1 were re-numbered to accurately reflect 
the new assessments added to the table.
Note 1 was updated to reflect that screening procedures could occur 45 days prior to 
treatment and over multiple days. Also it states that BCVA will be performed twice and 
the best value (lowest logMAR value) will be used as the subject’s baseline BCVA value. 
Footnote (b) was updated. A new footnote (c) “Axial length should be recorded once at 
screening as a baseline measure. Any instrument may be used OR measurement taken 
from the subjects medical records may be utilized. Measurement, instrument and date of 
recording will be noted in the CRF. Indocyanin green angiography will be performed for 
all subjects unless discussed with the Sponsor” was added. Added footnote (l) to indicate 
that SD-OCT may optionally be performed at Day 1 post-operatively or Day 2
A separate line to detail “Low Luminance Visual Acuity: was added for Months 18, 24, 
30, 36, 42, 48, 54 and 60 as it had previously been ambiguous when this assessment took 
place.
Section 1.3 The Cell 
Delivery System
Section 3.1 Overview 
of Study Design
This section was rewritten to be more general. Reference is made to the Investigational 
Product Manual for detailed Delivery System information.
Updated the target number of subjects to be enrolled in the study to “approximately 
285 subjects”. Specify the screening period of up to 45 days before treatment that subjects 
must be confirmed with a diagnosis of GA of the macular secondary to age-related 
macular degeneration with associated vision loss. Clarified vision between the patient’s 
eyes as “not clinically equal” or “clinically equal” for the relevant disease state of the 
eyes. Updated the approximate number of subjects to 75 in the Safety Run-in Phase of the 
study. Also updated the number of sites for this phase of the study to 20. Also specified 
that a minimum of 7 different surgeons would be required during the safety run-in phase.
Specified the addition of the 2nd Safety Cohort.
Screening Phase: updated the protocol to specify that subjects may be screened over a 
period of 45 days prior to treatment, and that BCVA examinations would be done prior to 
any other ocular study procedures that would interfere with vision assessments such as 
dilation or bright light assessments. Also specified that at baseline, dilated fundus 
examination readings will be carried out on all subjects. In addition, axial length will be 
recorded in the CRF. Indocyanin green angiography will be performed on all subjects 
unless discussed with the Sponsor.
Safety Run-in Phase: Updated the protocol to reflect that a minimum of the first 3 eligible 
subjects at each center will receive active treatment in an uncontrolled, open-label Safety 
Run-in Phase to assess the safety of the surgical procedure and Delivery System, and to 
ensure the familiarity of the surgeons with the device and the procedure. Also specified that 
the first 21 subjects at the first approximately 7 sites would comprise the initial Safety 
Cohort. Specified the addition of the 2nd Safety Cohort.
Double-masked Treatment Phase: Included the sham surgical procedure among the 
treatments to be administered at the clinical site on Day 1.
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Status: Approved, Date: 15 December 2017
Applicable Section(s)
Description of Change(s)
Section 3.2
Study Design 
Rationale
Section 3.2.2
Section 3.2.6 
Patient-Reported 
Outcomes
Section 4 Subject 
Population
Section 4.1 Inclusion 
Criteria
Section 4.2 Exclusion
Criteria
Table 4
Section 9.1.1 
Overview
Section 9.1.1.1 
Screening Phase
Section 9.1.1.2 
Open-Label Safety 
Run-in Phase
Figure 6 Schematic Representation of Study CNTO2476MDG2002 was updated and now 
becomes Figure 1 as the original Figures 1-5 in Section 3.1 were removed from the 
protocol and are now located in the Investigational Product Manual.
Specified the addition of the 2nd Safety Cohort.
Replaced “suture” with “conjunctival incision, a scleral mark and a masking stitch”
Corrected a typographical error, replacing “retinal” with “retinal experts”
Updated the subject population to indicate that “Approximately 400 subjects will be 
screened to provide approximately 285 subjects enrolled. Screening for eligible subjects 
will be performed within 45 days before administration of the treatment.
Changes to the Inclusion Criteria are described in the Summary of Changes in the 
Synopsis (see Page 6).
Changes to the Inclusion Criteria are described in the Summary of Changes in the 
Synopsis (see Page 7).
A correction was made in footnote “a” to indicate that potential to become unmasked upon 
ophthalmic examination and/or review of AEs, SAEs and ocular procedure results
The following was added to the protocol “New technology assessments, eg, Optical 
Coherence Tomography Angiography (OCT-A) and intraoperative Optical Coherence 
Tomography, may be performed at the surgeon or investigator’s discretion but do not 
substitute for any of the mandatory evaluations listed in this protocol”
Text was added to specify that a subject failing screening for a reason determined to be 
temporary could be re-screened per the following criteria:

Elevated IOP, uncontrolled blood pressure, elevated liver enzymes , decreased 
platelets and decreased renal function, if correctable with treatment or time

Acute infections, after successful treatment

Time-bound restrictions (eg, Exclusions 8, 9, 12, 20, 21 and 25) after an appropriate 
waiting period such that the exclusion no longer applies

Use of prohibited prior medications, after an appropriate waiting period.
In addition, Potential patients who fail screening for visual acuity, retinal anatomy or other 
ocular findings should not be rescreened. Any rescreening request not mentioned here 
should be discussed with the study Medical Monitor. For rescreened subjects, imaging 
studies do not have to be repeated if performed in the 60 days prior to start of new 
screening. For rescreened subjects, clinical laboratory exams (bloodwork) do not have to 
be repeated if performed in the 45 days prior to start of the new screening. Furthermore, 
Axial length will be recorded at baseline. Indocyanin green angiography will be performed 
for all subjects unless discussed with the Sponsor. Changes in concomitant medications 
will be recorded on Day 1
Clarified that the study will begin with a minimum of 7 surgeons performing
approximately 3 open-label procedures to complete an initial Safety Cohort of 21 subjects. 
A minimum of 7 surgeons were chosen for the Safety Cohort based on the amount of 
device users needed to identify complications with a surgical procedure and device. Added 
“significant loss of vision defined as loss of ≥15 letters compared to baseline in the first 
month post-surgery,” as an event of special interest. Specified the addition of the 2nd Safety 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
13
Status: Approved, Date: 15 December 2017
Applicable Section(s)
Description of Change(s)
Section 9.1.1.3 
Randomized Double-
Masked Treatment 
Phase
Section 9.2.1.2 
Secondary Measures
Section 9.2.2 
Endpoints
Section 9.3.3 
Immunogenicity 
Assessments
Section 9.7.1 Adverse 
Events
Section 9.7.2 Clinical 
Laboratory Tests
Section 11 Statistical 
Methods
Section 11.7 Data 
Safety Monitoring 
Board
Section 12.1.1 
Adverse Event 
Definitions and 
Classifications
Section 14.2 
Packaging
Section 14.4 
Preparation, Handling 
and Storage
Section 14.5 
Investigational 
Cohort.
Clarified that a sham surgical procedure will take place on Day 1 (pre-operative visit on 
the treatment day). 
Included “visual assessment” among assessments to be performed. 
Major Secondary Endpoints: specified that “RS plateau” was being measured
Clarified that Blood samples will only be collected during study assessments for the safety 
run-in phase and the randomized double-masked treatment phase from screening through 
the Month 12 postoperative visit
Updated the text of the protocol to indicate that adverse events will be reported by the 
investigator or the subject (or, when appropriate, by a caregiver, surrogate, or the subject's 
legally acceptable representative) for the duration of the study
Aligned the text of the penultimate paragraph with the Inclusion Criteria, ie, “Female 
subjects must be post-menopausal with last menses 12 months prior, or longer, OR a 
measured follicle stimulating hormone ≥26 mIU/mL”
Updated the text of the protocol to state that data from approximately 75 subjects 
participating in the open-label safety run-in, after have completed 1 month of follow-up, 
will be analyzed for simple descriptive statistics for key safety and efficacy measures. Also 
specified the analysis of data after the 21 subjects of the 2nd Safety Cohort have completed 
1 month of follow-up.
Specified the addition of the 2nd Safety Cohort.
Under Adverse Event Associated With the Use of the Drug, the following was added to the 
text of the protocol “The surgical procedure and delivery of CNTO 2476 result in a small 
retinal detachment per procedure guidelines. This in itself should not be listed as an 
adverse event”. 
It was clarified in the protocol that each vial of product is for single us. In addition, the 
following text was added “Each vial is enclosed in a paperboard carton with appropriate
labeling on the carton”.
The text in the protocol was updated to exclude temperature deviations that were 
applicable to manufacturing only. In addition, the following was added to the protocol 
“CNTO 2476 is shipped to the clinical site in a liquid nitrogen vapor-phase shipper that is 
also used for short-term storage up to 7 calendar days after shipment. The distribution is on 
a just-in-time basis for each treatment in the trial. The shipment for a subject will be 
triggered when enrolled or randomized through the IWRS. To support the masking of the 
trial, a vapor-phase shipper containing no CNTO 2476 vials will be shipped for subjects 
assigned to the sham surgery arm”
The text in the protocol was updated to the following “The investigator is responsible for 
ensuring that all CNTO 2476, Delivery System devices received at the site are inventoried 
and accounted for throughout the study, per the requirements in the Investigational Product 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
14
Status: Approved, Date: 15 December 2017
Applicable Section(s)
Description of Change(s)
Product and Device 
Accountability
Section 16.1 Study-
Specific Design 
Considerations
Section 17.8 
Monitoring
Manual. All CNTO 2476 will be stored and disposed of according to the sponsor's 
instructions, per the Investigational Product Manual. Study-site personnel must not 
combine contents of the CNTO 2476 containers”
Clarified there are 2 Safety Cohorts.
The following text was added to the protocol “Representatives from the sponsor company, 
Janssen and/or its’ designees may be present at the clinical facility, in the operating room 
during surgery or observing remotely. This is to ensure oversight of aspects of the surgical 
procedure and protocol”
Throughout the 
Protocol
“Maximum Reading Speed, MRS” has been replaced with “Reading Speed, RS”
“Discontinue from the study”, “Drop out of the study” replaced with “Withdrawal ….” 
Withdrawal from the study”
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
15
Status: Approved, Date: 15 December 2017
Amendment 1 (21 Dec 2015)
The overall reason for the amendment: Include the Functional Reading Index (FRI) as a major secondary 
objective, update the Time and Events Schedule to reflect tests no longer to be done, update some Exclusion 
Criteria, correct the stratification data and clarify how informed consent is to be obtained. Editorial changes were
made to improve the overall clarity of the Protocol. 
Applicable Section(s)
Description of Change(s)
Synopsis, Objectives
and Hypotheses;
Synopsis, Overview 
of Study Design
Synopsis, Subject 
Population
Synopsis Exclusion 
Criteria
Synopsis, Secondary 
Efficacy Endpoints
Synopsis, Statistical 
Methods
Time and Events 
Schedule
Introduction
Section 1.1.1.1 
Mechanism of Action
Section 1.1.1.2
Section 2.1 
Objectives
Section 3.1 Overview 
of Study Design
Section 3.2.4
Section 3.2.6 Patient-
Reported Outcomes
Section 4 Subject 
Added Functional Reading Index (FRI) to the list of major secondary objectives
Updated target number of subjects to 255. Also update the subjects in the safety run-in 
phase to 45, and the number of sites to 15.
Described the screening process including BCVA examinations performed to determine 
patient eligibility
Updated the total number of subjects to be screened, and also update the number of 
subjects to be enrolled (open-label safety phase and subjects randomized in 1:1:1 ratio)
Modified Criteria 7.1 and 20.1 (Details in Section 4.2 Exclusion Criteria, below)
Added FRI as a secondary efficacy endpoint
Updated the baseline BCVA stratification criteria
Removed Visual Acuity Tests on Day 2, and on Days 7 & 15
NEI-VFQ-25, SF-36, Near Vision Subscale (3-item) and FRI will no longer be done on 
Treatment Day 1 (pre-op)
Clarified that an additional optional pre-screening visit may be performed to determine 
potential subject BCVA for eligibility purposes this was already noted in the original 
protocol
Clarified that Pharmacodynamic Marker Testing will not be done. Clarified that no 
samples will be collected for immunogenicity testing after the Month 12 visit
Removed reference to blood sample volume after Month 12 (no samples will be collected)
Editorial changes to capture additional files names previously listed as “data on file”
Re-wrote for clarity
Re-wrote for clarity
Added the Functional Reading Index as a Secondary Objective
Updated the number of subjects in run-in phase and the number of sites. Updated Figure 6 
to capture the number of subjects and sites
Specified how stratification would be done
Re-wrote the description of the NEI-VFQ-25 for clarity
Updated the section with a description of the Functional Reading Index
Updated the number of subjects enrolled into the study, including those from the 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
16
Status: Approved, Date: 15 December 2017
Applicable Section(s)
Description of Change(s)
Population
Section 4.2 Exclusion 
Criteria
open-label safety run-in phase
Bullet point 7 was renumbered 7.1, and “AMD” changed to “AMD (dry or wet)”
Bullet point 20 was renumbered to 20.1 and the text “… has participated in other 
ophthalmic investigational drug studies within 6 months of Day 1, or is currently enrolled 
in an investigational study” deleted
Section 5. Treatment 
Allocation and 
Masking
Section 8 Prestudy 
and Concomitant 
Therapy
Section 9.1.1 
Overview
Section 9.2.2
Section 11. Statistical 
Methods
Section 11.3.2 Major 
Secondary Endpoint 
Analyses
Section 16.2.3. 
Informed Consent
Definition of BCVA was added
Text describing the stratification used was clarified and corrected to the below:

0.6 log MAR (20/80) to 1.3 logMAR (20/400) inclusive (i.e. the moderate loss 
stratum)

1.32 logMAR (20/400-1 letter) to 1.6 logMAR (20/800) inclusive, ie, the low vision 
stratum
The use of peri-operative and post-operative medications was clarified
Table 6 was simplified and updated with corrected volumes of blood to be collected from 
each subject during the course of the study
Text was introduced to describe how patient eligibility would be determined based on the 
results of BCVA examinations done at the screening visit
The Functional Reading Index was added as a major secondary endpoint
The major secondary endpoint of LL BCVA was re-written as the following to provide 
clarification and additional detail
Mean change from baseline at 6 and 12 months in low luminance BCVA (LL 
BCVA) letters following treatment with CNTO 2476 compared to the control arm.
Proportion of subjects with gain of >=15 letters from baseline at 6 and 12 months in 
LL BCVA following treatment with CNTO 2476 compared to the control arm.
BCVA was defined and the stratification re-written as below:
0.6 log MAR (20/80) to 1.3 logMAR (20/400) inclusive (i.e. the moderate loss 
stratum), and 
32 logMAR (20/400-1 letter) to 1.6 logMAR (20/800) inclusive (i.e the low vision 
stratum)
A description was provided for how data analysis would be performed after the first 
21 subjects, and after all subjects participating in the open-label safety run-in phase had 
completed 1 month of follow-up.
Text was clarified to include subjects gaining 15 LLBCVA letters. The sensitivity 
analyses were also clarified to include LLBCVA letters
Clarified that all study sites will be asked by the Sponsor to obtain informed consent using 
a validated electronic system instead of a paper-based process. An additional description of 
the process of obtaining informed consent is provided
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
17
Status: Approved, Date: 15 December 2017
SYNOPSIS
A Phase 2b, Multicenter, Double-masked, Randomized Study Evaluating the Safety and Clinical 
Response of Subretinal Administration of CNTO 2476 in Subjects with Visual Acuity Impairment 
Associated with Geographic Atrophy Secondary to Age Related Macular Degeneration
CNTO 2476 is an allogeneic somatic cell therapy medicinal product derived from the isolation and 
ex-vivo expansion of human umbilical tissue-derived cells (hUTC) that is to be injected in the subretinal 
space of the eye of subjects with retinal degeneration. In addition to impacting retinal pigment epithelium 
(RPE) cells, CNTO 2476 appears to preserve photoreceptors, and inner retinal cells.
Study CNTO2476MDG2002 is a Phase 2b study to evaluate the safety and usability profile of the 
procedure and the Delivery System, as well as to assess the clinical efficacy, safety, and tolerability of a 
single subretinal administration of CNTO 2476 at 1 of 2 doses, compared with the control.
OBJECTIVES AND HYPOTHESIS
Primary Objectives
The primary objective of the open-label Safety Run-in Phase is to evaluate the safety and performance
profile of the suprachoroidal surgical approach and the Delivery System. 
Major Secondary Objectives
The major secondary objectives of this study are the following: 

to assess the safety and performance profile of the Delivery System, the safety and tolerability of the 
suprachoroidal surgical approach, and the safety and tolerability of CNTO 2476 cells in the open-
label Safety Run-in Phase

to assess the effects of CNTO 2476 on anatomic correlates of treatment, including change in the area 
of geographic atrophy (GA)

to assess the effects of CNTO 2476 on additional and alternative efficacy outcomes including 
duration of clinical response.
Hypothesis
The primary hypothesis of the open label safety phase of this study is that the novel subretinal delivery 
system is sufficiently safe and usable to deliver cells to the subretinal space. An additional hypothesis is 
that palucorcel is safe and well tolerated when delivered as a single dose to the subretinal space. 
OVERVIEW OF STUDY DESIGN
This is a multicenter Phase 2b study. A target of approximately 21 subjects will be enrolled in this study.
This protocol amendment represents a significant reduction in scope and duration of the study based on a 
decision to discontinue the palucorcel development program.
The target population will be subjects at least 55 years of age and no older than 90 years, inclusive with a 
confirmed diagnosis of GA of the macula secondary to age-related macular degeneration, with associated 
vision loss, confirmed within 45 days prior to initial randomization by the central reading center using 
fundus and/or autofluorescence, fluorescein angiography, and fundus photography. In subjects with
neovascular AMD in 1 eye, the eye with GA must be the worse eye. In subjects with bilateral GA and the 
vision between both eyes not clinically equal, the eye with the worse vision will be treated in order to 
minimize risk to the subject’s vision. In cases where the BCVA of the 2 eyes is clinically equal, the eye 
with more extensive GA as demonstrated on the imaging studies will become the study eye.
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
18
Status: Approved, Date: 15 December 2017
The Safety Run-in Phase consists of approximately 21 subjects (the first 3 subjects at each of 
approximately 8 sites) who will first be enrolled in an open-label assessment of the safety profile of the 
procedure and the Delivery System. During the Safety Run-in Phase, subjects will receive a CNTO 2476 
dose of 3.0 x 105 cells in 50 µL. The first 21 subjects in the Safety Run-in Phase will be the initial Safety 
Cohort. 
The safety profile of the procedure and the Delivery System will be assessed after the first 21 subjects
(the initial Safety Cohort) have been treated and followed for a minimum period of 1 month. An external 
Data and Safety Monitoring Board (DSMB) will be commissioned for this study. 
The Randomized Double-masked Treatment Phase of the study was planned to follow the DSMB’s 
evaluation of the safety phase data and its supportive recommendation to advance to the randomized 
Double-masked Treatment Phase. This cohort was to consist of approximately 210 subjects for evaluation 
of both efficacy and safety. However, the Double-masked Treatment Phase has been eliminated from this 
study protocol.
The study will consist of a 12-month acute phase, followed by a 2-year maximum duration follow-up 
period (3 years total) for all subjects. 
Screening Phase
Prior to the full study screening phase, optional BCVA pre-screening may be done to evaluate subjects for 
BCVA eligibility. In this case, subjects must sign an optional pre-screening informed consent form (ICF)
prior to testing. The site will determine results of local testing and indicate if the subject is eligible for full 
study screening. If the BCVA test indicates the subject meets the necessary eligibility criteria, he or she 
will enter the full screening phase after signing the full study ICF for determination of full study 
eligibility.
All subjects will be required to give written informed consent to participate in the trial. 
After giving written informed consent, subjects may be screened over a period of up to 45 days prior to 
treatment to assess their eligibility for the study according to the inclusion and exclusion criteria defined 
for this study. The screening process may occur over a period of days and need not take place in one visit. 
Patient eligibility will be determined based on the results of 2 BCVA examinations performed at the 
screening visit. These examinations can occur on the same day or subsequent days. The better of the 2 
logMAR BCVA scores will be used for eligibility and randomization. These examinations should be 
performed prior to any other ocular study procedures that might interfere with vision assessments 
(dilation, bright light examination etc). 
Visual acuity tests, contrast sensitivity, MN Read, intraocular pressure (IOP), slit lamp examinations 
(including lens mobility examination), microperimetry, fundus photography, spectral domain optical 
coherence tomography (SD-OCT), fundus autofluorescence, and fluorescein angiography, will be 
performed for all subjects. Axial length will be recorded at baseline. Indocyanin green angiography will 
be performed for all subjects unless discussed with the Sponsor.
Other assessments will include medical history, genomic material from consented subjects, demographics, 
a targeted physical examination, vital signs, routine laboratory and routine urinalysis In addition blood 
samples for immunogenicity, medication history, concomitant medications, the NEI-VFQ-25 and Near 
Vision subscale, the SF-36 and FRI will be collected.
Safety Run-in Phase
The first 3 eligible subjects at each center will receive active treatment in an uncontrolled, open-label 
Safety Run-in Phase to assess the safety of the surgical procedure and Delivery System, and to ensure the 
familiarity of the surgeons with the Delivery System and the procedure. The first 21 subjects at the first 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
19
Status: Approved, Date: 15 December 2017
8 study sites will comprise the initial Safety Cohort. Enrollment into the Safety Run-in Phase will be 
staggered across sites to ensure that the outcomes and learnings from earlier procedures can be transferred 
to all participating surgeons who will perform subsequent procedures. A 1-week interval for information 
sharing is appropriate since most procedure-related adverse events (AEs) are expected to be apparent 
within hours of surgery.
Long-Term Follow-up Phase
Following the 12-month acute phase of the study, subjects will be followed every 6 months for 2 years in 
the Long-term Follow-up Phase. 
SUBJECT POPULATION
Approximately 100 subjects will be screened to provide approximately 21 subjects enrolled.
Screening for eligible subjects will be performed within 45 days before administration of the treatment.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Subject must be a man or woman at least 55 years to 90 years of age, inclusive.
2.2
Diagnosis of GA secondary to AMD confirmed within 45 days prior to initial randomization. 
Diagnosis verified by the central reading center using fundus photographs and including the 
following;

The study eye must have at least 1 GA lesion that involves the fovea, and a Macular 
Photocoagulation Study (MPS) disc areas (DA) of 0.5 and 7 (1 MPS disc area equivalent 
to 2.54 mm2 on the retina) determined by screening images of fundus autofluorescence 
photographs as calculated by the reading center. If GA is multifocal, at least one lesion 
must be 0.5 DA.
o
In the Safety Run-in Phase only, DA of 0.5 is allowed with no maximum
specified area, as long as the criteria below for photography can be met and the 
surgeon determines that the GA size will not impede cell delivery.

Geographic atrophy must be able to be photographed in its entirety and may be contiguous 
with peripapillary atrophy. 

Retinal photographs, fundus autofluorescence images, and angiography of sufficient 
quality, allowing assessment of the macular area according to standard clinical practice, 
can be obtained. 

The imaging center must be able to delineate and confirm peripapillary atrophy with 
fundus photography and fundus autofluorescence. 

Images must include the central field 1, 2, and 3 field images as defined by the University 
of Wisconsin standards as well as a supero-temporal image to capture the subretinal 
injection area if possible. 
3.2
Study eyes will have a BCVA of 20/80 to 20/800 (Early Treatment Diabetic Retinopathy Study 
[ETDRS] log of the minimal angle of resolution (logMAR) value 0.6-1.6). The treatment eye 
will be that with the worse BCVA at screening. If BCVA is clinically equivalent, the eye with 
the larger GA determines the study eye.
4.
Subject is a suitable candidate for ophthalmologic surgery, is willing and able to comply with the 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
20
Status: Approved, Date: 15 December 2017
surgical procedure, scheduled visits, treatment plan, laboratory tests and other study procedures. 
Subject has met criteria of the surgery center anti-coagulation protocol, if applicable.
5.
Female subjects must be post-menopausal with last menses 12 months prior, or longer, OR a 
measured follicle stimulating hormone 26 mIU/mL.
6.
Male subjects must be sterile or willing to use 2 approved methods of contraception from first 
day post-operatively to 3 months post-operatively (approved methods of contraception include 
condom with spermicide, a sterile sexual partner, a sexual partner using oral or implantable 
contraceptive or an intrauterine device with spermicide, a diaphragm with spermicide, or 
cervical cap with spermicide).
7.
Each subject must sign an ICF indicating that he or she understands the purpose of and 
procedures required for the study and are willing to participate in the study. 
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating in the 
study
1.2
Subject has a history of neovascular (“wet”) AMD in the treatment eye, including evidence of 
retinal pigment epithelium rips or evidence of subretinal or choroidal neovascularization or 
fluid. In cases where imaging is inconclusive, review of the case with the study site, considering 
history and imaging will determine eligibility. History or evidence of neovascular AMD in the 
fellow eye is allowed, if anti-vascular endothelial growth factor (VEGF) therapy has not been 
required for at least 8 weeks prior to screening.
2.
Geographic atrophy secondary to any causes other than AMD in either eye
3.
A diagnosis of glaucoma with an IOP 25 mmHg while being treated with an ocular 
hypotensive drug. Treatment should be no more than 1 drug preparation/combination, which can 
contain 1 or 2 ocular hypotensive active ingredients; subjects receiving more than 2 ocular 
hypotensive active ingredients are excluded. Note: subjects with a diagnosis of ocular 
hypertension (not glaucoma) are eligible to participate whether or not they are being medically 
treated.
4.
Nuclear sclerotic cataract, cortical spoking, posterior subcapsular cataract above Grade 2 per 
Age-Related Eye Disease Study (AREDS) scale or any other ophthalmologic condition that 
reduces the clarity of the media that, in the opinion of the investigator or reading center,
interferes with ophthalmologic examination (eg, corneal abnormalities, inadequate pupillary 
dilation), surgery or imaging in the study eye
5.
Myopia >-8 diopters and subjects with >4 diopters of astigmatism, and >+10 diopters of 
hyperopia. Note: clinical evidence of retinal degeneration secondary to pathological myopia will 
exclude the subject as will a scleral ectasia with or without high myopia.
6.
Evidence of other significant ophthalmologic disease (eg, intraocular inflammatory disease, 
diabetic retinopathy, Stage II, III, or IV macular hole, clinically evident vitreoretinal traction, 
choroidal or retinovascular disease, cystoid macular edema, significant epiretinal membrane, 
significant blepharitis, keratitis, conjunctivitis or staphyloma) in the study eye
7.2
Previous treatment for confirmed AMD (dry or wet) in the study eye with treatments other than
antioxidant or zinc supplements (eg, AREDS1 or AREDS2 formula) or other oral vitamin 
supplements. Subjects who have received anti-VEGF treatment without a confirmed diagnosis 
of wet AMD or who have participated in previous studies for AMD may be considered eligible 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
21
Status: Approved, Date: 15 December 2017
if these treatments/study participation were given at least one year prior to enrollment.
8.2
Previous intraocular surgery within 3 months prior to screening in either eye. Previous treatment 
with Visudyne®, external-beam radiation therapy, or transpupillary thermotherapy in the study 
eye at any previous time point.
9.
Previous laser photocoagulation in the study eye (peripheral laser for treatment of a tear is 
allowed if more than 6 months prior to screening except when, in the opinion of the surgeon, 
this would hamper the suprachoroidal cannulation procedure in the study eye)
10.
Previous vitrectomy, retinal detachment repair, submacular surgery, other surgical interventions 
targeting AMD, scleral buckling or glaucoma filtration surgery or any other extraocular or 
orbital procedure in the study eye that, in the opinion of the surgeon, would hamper the 
suprachoroidal cannulation procedure in the study eye
11.
History of choroidal or scleral rupture in either study or fellow eye due to uveitis (previous 
trauma in the study eye or fellow eye in the case of good vision in that eye is not an exclusion 
criterion)
12.
Uveitis or other intraocular inflammatory disease within past 3 months
13
Active infections of the anterior segment
14.
Keratoconus, penetrating keratoplasty, Descemet's stripping endothelial keratoplasty (DSEK), 
radial keratotomy (RK), laser-assisted in situ keratomileusis (LASIK) in the study eye
15.
Monocular subjects
16.
Subject has known allergies, hypersensitivity, or intolerance to CNTO 2476 or its excipients 
(refer to Investigator's Brochure)
17.
Medically not qualified for monitored anesthesia care intravenous sedation
18.
Previous cell therapy other than standard blood and platelet transfusions
19.
Subject has taken any disallowed therapies as noted in Section 8, (Prestudy and Concomitant 
Therapy) before the planned first dose of treatment
20.1
Subject has received an investigational drug (including investigational vaccines) within 30 days 
before the planned first dose of treatment 
21.
Active malignancy (requiring therapy) or history of malignancy requiring therapy within 2 years 
prior to Day 1 (with exception of cases of basal cell and squamous cell carcinoma of the skin)
22.
History of human immunodeficiency virus (HIV) disease
23.
Significant cognitive impairment that interferes with a subject’s ability to participate with the 
testing regimen
24.
History of organ or bone marrow transplants
25.
History of alcohol or drug abuse within past 2 years
26.
Significant hepatic dysfunction (aspartate aminotransferase [AST] or alanine aminotransferase 
[ALT] >3x upper limit of normal [ULN]), or significant renal dysfunction (estimated creatinine 
clearance 30mL/min), or on renal dialysis
27.
Significant uncorrectable coagulopathy, thrombocytopenia (platelets <100 x 103/µL) or other 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
22
Status: Approved, Date: 15 December 2017
significant bleeding risk. Note: subjects on an anticoagulant therapy should be considered at low 
risk for new thromboembolic events, and must agree to stop all anticoagulation therapy prior to 
surgery, as follows:

Warfarin 5 days

Aspirin 7 days

Oral Factor Xa inhibitors 3 days (or longer, depending on renal function)

Dabagatran 3 days

Low molecular weight heparin 1 day

Clopidogrel and ticagrelor 5 days

Prasugrel 7 days

Ticlopidine 10 days
28
Uncontrolled systemic hypertension on the day of surgery, defined as a systolic blood pressure
180 mm Hg. Note: if the subject’s systolic blood pressure can be controlled later by the 
subject’s medical doctor, eligibility for surgery can be re-assessed.
29.
Subject has any condition for which, in the opinion of the investigator, participation would not 
be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, 
or confound the protocol-specified assessments
30.
Subject is an employee of the investigator or study site, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study site, as well as family 
members of the employees or the investigator
31.
Known allergy to iodinated contrast dyes
DOSAGE AND ADMINISTRATION
During the Safety Run-in Phase, subjects will receive a CNTO 2476 dose of 3.0 x 105 cells in 50 µL.
CNTO 2476 will be delivered using the custom-designed Delivery System and surgical procedure.
Each subject in each target dose group will receive a single subretinal administration of CNTO 2476. 
EFFICACY EVALUATIONS/ENDPOINTS
Primary Efficacy Endpoint
The primary efficacy measure will be the BCVA testing performed after refraction and under 
standardized photopic lighting conditions and distance using an ETDRS logMAR chart.
The endpoints of the open-label Safety Run-in Phase are all related to the objective of evaluating the 
safety profile of the procedure, Delivery System, and of the implanted hUTC cells.
Secondary Efficacy Endpoints
Assessments will be performed at the 6- and 12-month visits to evaluate:

Proportion of subjects losing 15 BCVA letters from baseline at 12 months following treatment with 
CNTO 2476

Change in mean number of BCVA letters from baseline at the 6- and 12-month visits following 
treatment with CNTO 2476
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
23
Status: Approved, Date: 15 December 2017

Growth rate of GA lesion documented at baseline to 6 and 12 months following treatment with 
CNTO 2476 compared to the control arm. The area of GA is determined based primarily on fundus 
autofluorescence as well as fluorescein angiography and fundus photos
Safety Endpoint

Treatment-related ocular AEs and SAEs and other safety outcomes including markers of 
immunogenicity, safety of the surgical procedure and performance of the Delivery System
IMMUNOGENICITY EVALUATIONS
Serum antibody levels pre- and post-administration of CNTO 2476 will be assessed. The titer of 
confirmed positive samples will be reported.
SURGICAL EVALUATIONS
Data on the conduct of the procedure, including the success of individual elements of the surgical 
procedure and Delivery System performance will be collected and tabulated, as well as any complications 
of the procedure or any product quality defects.
SAFETY EVALUATIONS
Any clinically relevant changes occurring during the study must be recorded on the Adverse Event 
section of the CRF. Any clinically significant abnormalities persisting at the end of the study/early 
withdrawal will be followed by the investigator until resolution or until a clinically stable endpoint is 
reached. In addition to AEs, clinical laboratory tests for hematology, serum chemistry, and urinalysis will 
be performed and reported. In addition, vital signs and physical examination will be measured and 
reported. 
STATISTICAL METHODS

All outcome assessments will be tabulated using descriptive statistics; no formal statistical testing is 
planned for outcome in the Safety Cohort.
Sample Size Determination
The sample size of 21 subjects is based on the number of subjects required for an adequate clinical 
assessment of the safety and usability of the novel delivery system. 
Efficacy Analyses
The BCVA response is defined as an increase of 15 letters or more from baseline in ETDRS letters, a 
magnitude of change that is determined to be clinically important. 
The BCVA, LL BCVA, LLD, contrast sensitivity and growth rate of GA lesion will be summarized with 
descriptive statistics as specified in the SAP.
Other Analyses
Safety analyses will be performed and reported for AEs, the Delivery System and surgical procedure, 
clinical laboratory tests, immunogenicity, vital signs, and physical examination.
Specifically, the number and percentage of subjects who experienced at least 1 treatment-emergent 
serious ocular AE will be presented in summary tables by treatment group and preferred term according 
to terminology from the Medical Dictionary for Regulatory Activities (MedDRA) as well as by affected 
eyes (events occurring in the treated eye only, in the fellow eye only, and in both eyes). 
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Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
Ocular TEAEs will be summarized by treatment group and preferred term according to MedDRA 
terminology, as well as by affected eyes (events occurring in the treated eye only, in the fellow eye only, 
and in both eyes). 
The number and percentage of subjects who experienced at least 1 treatment-emergent serious AE (SAE)
will be presented in summary tables by treatment group and preferred term, as well as by preferred term 
within system-organ class according to MedDRA terminology. 
The number and percentage of subjects who experienced at least 1 treatment-emergent AE will be 
presented in summary tables by treatment group and preferred term, as well as by preferred term within 
system-organ class according to MedDRA terminology.
Data regarding the Delivery System and surgical procedure will be tabulated by treatment group. A listing 
of all data pertaining to the Delivery System and surgical procedure, as well as any surgical deviations 
and surgical medications, will be provided. Adverse events for subjects who receive surgery but not 
CNTO 2476 cells will be listed. 
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
TIME AND EVENTS SCHEDULES
Table 1:
Schedule of Study Assessments for the Safety Run-in Phase and the Randomized Double-masked Treatment Phase from Screening through the 
Month 12 Postoperative Visit
Optional Pre-
Screening
Screen
(see note)
Treatment Day
1 (pre-op)
Day 2
Days 7 & 15
(±3d)
Week 4
(±3d)
Month 2
(±3d)
Month 3
(±3d)
Month 6
(±3d)
Month 12
(±7d)
Visit number
1
2
3
4, 5
6
7
8
9
10
Informed consent
xa
x
Inclusion/Exclusion criteria
x
Medical History and demographics
x
Vital signs
x
x
x
x
x
x
x
x
x
Physical exam
x
x
Best Corrected Visual Acuity (BCVA)
x
xb
x
x
x
x
x
Low Luminance Visual Acuity
x
x
x
x
x
x
Axial Length
xc
Contrast sensitivity 
x
x
x
x
MN Read
x
x
x
x
IOP
x
x
x
x
x
x
x
x
Slit lamp biomicroscopy/ophthalmoscopy
x
x
x
x
x
x
x
x
Microperimetry assessments
x
x
x
x
Fundus photography
x
x
x
x
x
x
x
SD-OCTl
x
x
x
x
x
x
x
Fundus autofluorescence
x
x
x
x
x
x
x
Fluorescein angiography
x
x
x
Indocyanin green angiography
x
Routine laboratoryd
x
x
x
Routine urinalysis
x
x
x
Blood samples for immunogenicityf
x
x
x
x
x
x
x
Medication History
x
x
NEI-VFQ-25, SF-36i, and Near Vision Subscale 
(3-item), FRI
x
x
x
Randomization (for the Double-masked Treatment 
Phase only)g
CNTO 2476 Administration
xh
PGIC-S
x
x
PGIC-Q
x
x
CGIC
x
x
Change in concomitant medications
<---------------------------------------------------Continuous--------------------------------------------------->
Adverse events
<----------------------------------------------------------Continuous---------------------------------------------------------->
Blood samples volumej
16.3 mL
0
0
20 mLk
16.3mL
10 mL
10 mL
10 mL
16.3 mL
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
BCVA=Best Corrected Visual Acuity; CGIC=Clinician Global Impression of Change; ETDRS=Early Treatment Diabetic Retinopathy Study; IOP=intraocular pressure; 
MN Read=Minnesota reading test; NEI-VFQ-25=National Eye Institute Visual Functioning Questionnaire; PGIC-Q=Patient Global Impression of Change – Quality of Life; PGIC-
S=Patient Global Impression of Change – Symptoms; SD-OCT=spectral domain optical coherence tomography; SF-36=Short Form (36) Health Survey, FRI= Functional Reading Index 
questionnaire
Note 1:
Screening procedures must occur within 45 days prior to treatment and may occur over multiple days. An additional optional pre-screening visit may be performed to determine 
potential subject BCVA for eligibility purposes. At the next screening visits, BCVA will be performed twice and the best value (lowest logMAR value) will be used as the 
subjects’ baseline BCVA value. 
Note 2:
If a subject withdraws early from the Safety Run-in Phase, the end-of-study assessments (described in Table 2) should be performed.
a)
Subjects will be presented with an optional pre-screening ICF to allow the determination of their BCVA results prior to full study screening. The subjects who meet the BCVA
eligibility criteria will be further screened to determine the full study eligibility. For the full study eligibility assessments, the subject will be presented a separate ICF within 45 days
prior to treatment. The pre-screening visit is optional
b) Best Corrected Visual Acuity testing includes BCVA using the ETDRS chart under high illumination and standardized conditions at 4 meters and 1 meter (as needed). .
c)
Axial length should be recorded once at screening as a baseline measure. Any instrument may be used OR measurement taken from the subjects medical records may be utilized. 
Measurement, instrument and date of recording will be noted in the CRF.
d) Includes routine hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, platelet count, prothrombin time, and partial thromboplastin time) 
and serum chemistry (sodium, potassium, chloride, blood urea nitrogen, creatinine, glucose, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, total 
bilirubin, alkaline phosphatase, lactic acid dehydrogenase, uric acid, calcium, albumin, and total protein) and urinalysis (dipstick).
e)
Optional blood draw (ie, for subjects who provide consent for this blood draw)
f)
Includes samples for antibody assay testing.
g) Enrollment and randomization of subjects in the Double-masked Treatment Phase was to follow the DSMB’s evaluation of the Safety Run-in Phase and its supportive recommendation 
to advance the study to the Double-masked Treatment Phase. However, the Double-masked Treatment Phase has been eliminated from this study protocol.
h) Includes assessment of Delivery System.
i)
SF-36 is included to assess the measurement properties of the NEI-VFQ-25 and Near Vision subscale.
j)
Blood sample estimates based upon the following volumes per sample: Screening=16.3 mL, DNA=8.5 mL, Day 7=10 mL, Day 15=10 mL, Week 4=16.3 mL, Month 2=10 mL, 
Month 3=10 mL, Month 6=10 mL, Month 12=16.3 mL Total volume of blood through Month 12 = approximately 107.4 mL.
k) Includes 10 mL samples each for Day 7 and Day 15
l)
Optional SD-OCT at day 1 (post-operatively) and day 2 may be performed
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
Table 2
Schedule of Study Assessments During the Long-term Follow-up Phase*
Time Post-treatment
Month 18 (±2 wk)
Month 24 (±2 wk)
Month 30 (±2 wk)
Month 36 (±2 wk)
Visit number
11
12
13
14
Best Corrected Visual Acuity testing
x
x
x
x
IOP
x
x
x
x
Slit lamp biomicroscopy / ophthalmoscopy
x
x
x
x
SD-OCT
x
x
x
x
Fundus photography
x
x
x
x
Fundus autofluorescence
x
x
x
x
Concomitant medications
<------------------------------------------------Continuous----------------------------------------------->
Adverse eventsb
<------------------------------------------------Continuous----------------------------------------------->
Footnotes
*
After the 12-month acute phase of the study subjects will be followed for 2 years. Subjects will come in for a follow-up visit every 6 months.
AE=adverse event; IOP=intraocular pressure; SAE=serious adverse event; SD-OCT=spectral-domain optical coherence tomography.
a) If a subject is withdrawn from the study, he/she will be asked to have the End-Of-Study Visit assessments performed.
b) Only SAEs, ophthalmologic AEs, ongoing AEs from acute phase or any AEs designated as related to treatment or surgical procedure are recorded.
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
ABBREVIATIONS
ABCA4
ATP-binding cassettes A4
AE
adverse event
AMD
age-related macular degeneration
AMD-GA
age-related macular degeneration with geographic atrophy
AREDS
Age Related Eye Disease Study 
ALT
alanine aminotransferase
AST
aspartate aminotransferase 
BCVA
best corrected visual acuity 
BSS
balanced salt solution
CFR
Code of Federal Regulations
CGIC
Clinician Global Impression of Change
CPS
critical print size
CRO
Contract Research Organization
DA
disc area
DARC
Digital Angiography Reading Center
DSMB
Data and Safety Monitoring Board
eCRF
electronic case report form
eDC
electronic data capture
ETDRS
Early Treatment Diabetic Retinopathy Study
FDA
Food and Drug Administration
FRI
Functional Reading Index questionnaire
GA
geographic atrophy
GCP
Good Clinical Practice
GTP
Good Tissue Practice
HIV
human immunodeficiency virus
hUTC
human umbilical tissue-derived cells
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IOP
intraocular pressure 
IRB
Institutional Review Board
ITT
intent-to-treat
IWRS
interactive web response system
LASIK
laser-assisted in situ keratomileusis
LL BCVA
low luminance best corrected visual acuity 
LLD
low luminance difference
logMAR
log of the minimum angle of resolution
MAIA2
Macular Integrity Assessment 
MCID
minimal clinical important difference
MDS
microcatheter delivery system 
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat 
MN Read
Minnesota reading test
MertK
Mer tyrosine kinase 
MPS
Macular Photocoagulation Study
NEI-VFQ-25
National Eye Institute Visual Function Questionnaire
NOAEL
no-observed-adverse-effect level
PGIC-Q
Patient Clinician Global Impression of Change – Quality of Life
PGIC-S
Patient Clinician Global Impression of Change – Symptoms
PQC
Product Quality Complaint
PRO
patient-reported outcome(s)
pUTC
pig umbilical tissue-derived cells
RA
reading acuity
RCS
Royal College of Surgeons
RGC
retinal ganglion cell
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
RK
Radial keratotomy 
ROS
rod outer segments 
RPE
retinal pigment epithelium
RS
reading speed
SAE
serious adverse event
SAP
statistical analysis plan
SD-OCT
spectral domain optical coherence tomography 
SF-36
Short Form (36) Health Survey
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
VEGF
vascular endothelial growth factor
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
1.
INTRODUCTION
CNTO 2476, BB-IND 13198, is an allogeneic somatic cell therapy medicinal product derived 
from the isolation and ex vivo expansion of human umbilical tissue-derived cells (hUTC) that is 
to be injected in the subretinal space of the eyes of subjects with retinal degeneration. In addition 
to impacting retinal pigment epithelium (RPE) cells, CNTO 2476 appears to preserve 
photoreceptors, and inner retinal cells. As a result, treatment with CNTO 2476 may have a 
positive impact on visual function. The putative mechanisms of action of CNTO 2476 relevant to 
age-related macular degeneration (AMD) are stimulating RPE phagocytosis of rod outer 
segments, promoting RPE survival and promoting synaptogenesis and neuron survival.
Age-related macular degeneration with geographic atrophy (AMD-GA) is a retinal degenerative
disease involving the macula. The pathogenesis of AMD, though not conclusively defined, 
involves the loss of photoreceptors and RPE cells. This loss is thought to be induced by toxic 
agents such as lipofuscin in RPE. The accumulation and deposition of lipofuscin and the 
formation of drusen has been associated with dysfunction and subsequent loss of RPE, resulting 
in degeneration of the overlying photoreceptors1,6,9,4,13, and synaptic loss and mislocalization.8,15
Biological functions of RPE cells include phagocytosis of rod outer segments (ROS) and 
recycling of visual cycle products. Genetic mutations that affect the normal phagocytosis and 
visual cycle functions of the RPE cells result in significant deficiencies, underscoring their 
importance maintaining retinal homeostasis.12 In particular, mutations in RPE Mer tyrosine 
kinase (MertK) and ATP-binding cassettes A4 (ABCA4) induce AMD-like retinal degeneration. 
The MertK mutation interferes with Mer receptor mediated phagocytosis in RPE cells and causes 
retinitis pigmentosa, another degenerative disease of the retina in human.5 Mutation of lipid 
visual cycle transporter—ABCA4 in the eye increases a toxic byproduct of the visual cycle, 
A2E, a component in lipofuscin, and results in early onset macular degeneration in children.1
Both of these mutations lead to the loss or dysfunction of RPE cells and consequently in the 
accumulation of lipofuscin, the formation of drusen, and loss of overlying photoreceptors.9,11,6
Therefore, overcoming RPE deficiencies could have a significant impact on photoreceptor 
function.
Animal models of AMD-GA presenting all clinical and histological signs of the human disease 
are lacking. Nevertheless, several key elements of AMD-GA pathogenesis can be identified in 
the Royal College of Surgeons (RCS) rat model, such as phagocytosis and visual cycle lipid 
metabolism. The RCS rat carries the MertK mutation resulting in diminished phagocytosis of 
ROS and leading to photoreceptor cell death.14 The RPE cells from dystrophic RCS rats showed 
reduced phagocytosis in vitro. Furthermore, deterioration of the visual cycle associated with 
disease progression was identified by gene profiling in dystrophic RCS rats. The visual cycle 
transporter (ABCA4) was down-regulated with disease progression over time, potentially leading 
to an accumulation of A2E. This is supported by the finding that A2PE, a precursor of A2E, is 
increased in the RCS retina.11 Therefore, the RCS rat RPE cells have functional deficits in 
phagocytosis and visual cycle functions, which are similar to deficiencies that may lead to 
AMD-GA in humans. Finally, RCS rats exhibit early changes in synaptic connectivity that lead 
to mislocalization and loss of synapses.2
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
Data from preclinical studies with CNTO 2476 support the hypothesis that CNTO 2476 can 
improve the phagocytic function of dystrophic RCS RPE cells. In vitro, CNTO 2476 restored 
dystrophic RPE phagocytosis function to the level of normal RPE cells (SCIV-DR14). In vivo, 
subretinal injections of CNTO 2476 into dystrophic RCS rats led to preservation of visual 
function and photoreceptors (SCIV-DR1, SCIV-DR2). Moreover, the presence of CNTO 2476 
resulted in an increase of phagosomes in the RPE and a reduced layer of debris between the 
photoreceptor and RPE (SCO-TD-2009-0035). This increase in phagocytosis may lead to a 
reduction of photoreceptor apoptosis. Additionally, in vitro studies utilizing a purified rat retinal 
ganglion cell (RGC) culture system, further confirmed CNTO 2476 secrete factors that enhanced 
neuronal survival, supported neurite outgrowth and strongly promoted excitatory synaptic 
connectivity (SCO-DR-2015-0001). In addition, CNTO 2476 also promoted survival reduced 
apoptosis of RPE cells exposed to oxidative stress (SCO-DR-2009-0004 and SCO-DR-2015-
0002). Finally, subretinal injections of CNTO 2476 to the RCS rat also preserved the gene 
expression of ABCA4, a visual cycle transporter (SCO-DR-2009-0005).
For the most comprehensive nonclinical and clinical information regarding CNTO 2476, refer to 
the latest version of the Investigator's Brochure for CNTO 2476.7
The term "sponsor" used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
1.1.1.
Nonclinical Studies
1.1.1.1.
Mechanism of Action
Mechanism of action studies indicated that CNTO 2476 can affect phagocytic function of 
dystrophic RCS retinal pigment epithelial (RPE) cells, both in vitro and in vivo. Additionally, 
studies performed in human RPE cells demonstrated hUTC promoted survival and reduced 
apoptosis of RPE cells exposed to oxidative stress. Finally, in vitro studies utilizing a purified rat 
retinal ganglion cell (RGC) culture system further confirmed CNTO 2476 secrete factors that 
enhanced neuronal survival, supported neurite outgrowth and strongly promoted excitatory 
synaptic connectivity. Together, these data suggest that CNTO 2476 can potentially improve 
vision by enhancing the phagocytic function of dysfunctional RPE cells, promoting RPE survival 
and enhancing neuronal survival and function.
1.1.1.2.
Pharmacokinetic Profile
The disposition of hUTC were characterized with respect to persistence and systemic 
biodistribution in xenogeneic settings. These studies have indicated that following subretinal 
administration, hUTC persist for approximately 2 to 3 months. In non-target organs in RCS rats 
treated with immunosuppressants, human cell equivalents were detected by polymerase chain 
reaction in the peripheral blood, kidney, liver, and testis up to 14 days following subretinal 
administration of hUTC. However, in a study conducted in nude rats designed to evaluate 
systemic distribution of hUTC to the ovaries, testes, and seminal fluid, no human cells could be 
detected. Taken together, these results indicate that following subretinal administration, 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
umbilical tissue-derived cells do not engraft and that in contrast to subretinal persistence, 
systemic exposure is limited over time for CNTO 2476.
1.1.1.3.
Immunogenicity
The in vivo immunogenicity of umbilical tissue-derived cells was characterized following 
subretinal administration to pigs. No antibodies to pUTC or cellular immune responses were 
observed in the allogeneic setting following single or repeated subretinal administration of pUTC 
to pigs. In the xenogeneic setting, following single or repeated subretinal administration of 
hUTC to pigs, antibodies to hUTC developed when surgical methods used for cell administration 
caused an intentional or inadvertent retinal perforation. No antibody responses were observed 
when targeted subretinal delivery of hUTC was achieved without retinal perforation. Following 
repeated subretinal delivery, focal mononuclear cell infiltrates and subretinal granulomas were 
observed at the cell administration site. In all animals with subretinal granulomas antibodies to 
hUTC were detected consistent with the premise that they were a manifestion of a xenogeneic 
immune response intended to wall off foreign antigens that were too large to phagocytose. This 
finding was monitorable by spectral domain optical coherence tomography (SD-OCT), which 
revealed resolution into small focal areas of fibrosis over time suggesting the finding was 
reversible. 
1.1.1.4.
Toxicology
The toxicology program was conducted in rats and mini-pigs. No tumorigenicity of CNTO 2476 
was observed in nude rats following subretinal administration at a maximum feasible dose which 
corresponded to approximately a 5-fold multiple of an efficacious dose in the RCS rat model. No 
systemic toxicity of CNTO 2476 was observed in rats following a single intravenous dose of up 
to 1.5 x 106 cells (corresponding to approximately a 5-fold multiple of an efficacious dose in the 
RCS rat model) when intravenous injection rates were limited to approximately 
1 x 106 cells/minute. 
Toxicology studies conducted in the Göttingen mini-pigs allowed development and evaluation of 
surgical techniques based on the similar size and anatomy of the pig eye relative to human eyes. 
Both CNTO 2476 and pUTC were employed to characterize safety following single and repeated 
dosing in the xenogeneic and allogeneic setting. No evidence of systemic toxicity was observed 
in these studies. Vitreoretinal reaction characterized by traction, tractional retinal detachments 
and formation of membranes were identified as the major adverse effects in these pig toxicology 
studies following subretinal administration of cells using the initial surgical procedure. This 
procedure was used in the initial pig toxicology studies, and clinical Study CNTO2476RPG1001
employed full or partial 3-port pars plana vitrectomy, retinotomy, and creation of bleb to provide 
a subretinal space for subretinal injection of cells. A new surgical procedure was subsequently 
developed that used a microcatheter to achieve targeted subretinal delivery of cells that mitigated 
vitreoretinal adverse effects observed in nonclinical studies with the initial surgical procedure. 
Based on these preclinical observations, the microcatheter delivery method was implemented in 
clinical Study CNTO2476RPG1002. Following a single subretinal injection of CNTO 2476 in 
pigs the no-observed-adverse-effect level (NOAEL) was considered to be 3 x 105 cells and 
1.5 x 106 cells using the initial surgical procedure and microcatheter procedure, respectively. 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
Following repeated subretinal administration 6 x 104 and 1.5 x 106 cells were considered the 
NOAELs following repeated subretinal dosing with a microcatheter for CNTO 2476 and pUTC, 
respectively based on the observation of subretinal granulomas.
1.1.2.
Clinical Studies
Study CNTO2476RPG1001 was a Phase 1 open-label, noncomparative study to evaluate the 
safety of a single, unilateral, subretinal administration of CNTO 2476 (using a transvitreal 
approach) in subjects with advanced retinitis pigmentosa. Seven subjects were enrolled in the 
study and completed 5-year follow-up. Study CNTO2476MDG1002 is a Phase 1/2a, multicenter, 
randomized, dose escalation, fellow-eye controlled study to evaluate the safety and clinical 
response of a single, subretinal administration of CNTO 2476 in subjects with visual acuity 
impairment associated with geographic atrophy (GA) secondary to AMD. In September 2014, 
enrollment in this study was discontinued but long-term follow-up is ongoing. Per the interim 
report, dated 22 January 2015, 35 subjects enrolled in the study; 33 were evaluable for efficacy 
and safety. Among the 33 subjects, 29 were in the Phase 1 portion of the study and 4 were in the 
Phase 2a portion of the study.
1.1.2.1.
Human Pharmacokinetics
No data on pharmacology, pharmacokinetics, and metabolism of CNTO 2476 in humans are 
available.
1.1.2.2.
Efficacy
Although Study CNTO2476RPG1001 was not designed as an efficacy study, secondary 
objectives included preliminary evaluations of changes from baseline in retinal structure and 
visual function. Overall, changes from baseline in visual acuity and retinal thickness were mixed. 
At the Month 3 visit, 3 subjects had measurable increases in retinal thickness in the treated eye, 
3 subjects had decreases in retinal thickness, and 1 subject had no change from baseline values. 
The data were insufficient to make any meaningful conclusions. No durable changes in visual 
acuity were evident and data were variable. At 12 months post-treatment, no subject had any 
worsening of visual acuity. At the end of the study (Month 60), 3 subjects reported lower visual 
acuity (ie, no light perception or a shift from hand motion to light perception) at Month 12.
Study CNTO2476MDG1002, as described above, is currently ongoing and the efficacy results 
reflect combined data from both the Phase 1 and 2a portions of the study. At baseline, the 
median best corrected visual acuity (BCVA) for the 33 treated subjects was log of the minimum 
angle of resolution (logMAR) 1.2 (20/320) and logMAR 0.6 (20/80) in the treated eye and fellow 
eye, respectively. At 12 months post-treatment, median BCVA for 26 subjects was logMAR 1.1 
(20/250) and logMAR0.6 (20/80) in the treated eye and fellow eye, respectively, suggesting an 
improvement in BCVA in the treated eye compared with no change in the fellow eye. The mean 
change from baseline was 5 letters between fellow and treated eye at 6 months and 6.8 letters at 
12 months. 
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
BCVA gains and losses at 6 and 12 months post-treatment were as follows:

At the 6-month assessment of BCVA gain, 10 subjects out of 27 (37%) had their treated 
eyes showing a 3-line gain in BCVA. At the same time, 1 subject out of 27 (4%) had their 
fellow eyes showing a 3-line gain in BCVA. 

At the 6-month assessment of BCVA loss, 6 subjects out of 27 (22%) had their treated eyes 
showing a 3-line loss in BCVA. At the same time, 1 subject out of 27 (4%) had the fellow 
eye showing a 3-line loss in BCVA.

At the 12-month assessment of BCVA gain, 10 subjects out of 26 (39%) had their treated 
eyes showing a 3-line gain in BCVA. At the same time, 1 subject out of 26 (4%) had their 
fellow eyes showing a 3-line gain in BCVA.

At the 12-month assessment of BCVA loss, 6 subjects out of 26 (23%) had their treated eyes 
showing a 3-line loss in BCVA. At the same time, 3 subjects out of 26 (12%) had their 
fellow eyes showing a 3-line loss in BCVA.
Recognizing the study was designed for safety, interim efficacy data suggest that subretinal 
administration of CNTO 2476 may result in BCVA letter gain in some subjects with vision loss 
secondary to GA. 
1.1.2.3.
Safety
Study CNTO2476RPG1001
This was a Phase 1 open-label, noncomparative study to evaluate the safety of a single, 
unilateral, subretinal administration of CNTO 2476 in 7 subjects with advanced retinitis 
pigmentosa. 
Adverse events (AEs) observed during the study were consistent with the postoperative course 
for the surgical procedure. 

There were no adverse clinical observations suggesting an immune response in the treated 
eye. These observations suggest that a single, subretinal injection of CNTO 2476 was not 
immunogenic and did not cause an adverse immune response through 60 months after
treatment. 

Two subjects who received the targeted doses of 3.0 x 105 or 5.6 x 105 CNTO 2476 cells had 
serious AEs (SAEs) of retinal detachment. In these cases, the mechanism of retinal 
detachment was traction due to proliferation of RPE cells in the vitreous after retinotomy. 
This suggests that transvitreal delivery of CNTO 2476 is not appropriate. 
Ocular and visual assessments during the 4-year safety surveillance period remained similar to 
those noted at Month 12.
Study CNTO2476MDG1002
This was a Phase 1/2a study a to evaluate the safety and tolerability of CNTO 2476, administered 
subretinally using the iScience microcatheter delivery system (MDS), in subjects with visual 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
acuity impairment associated with GA secondary to AMD. The study was limited by the inability 
to deliver cells to the subretinal space without a retinal tear.
Thirty-three subjects received CNTO 2476 (29 subjects in the Phase 1 portion of the study and 
4 subjects in the Phase 2a portion of the study) and were evaluable for safety. Of the 29 subjects 
treated in Phase 1, 28 (96.6%) had at least 1 treatment-emergent AE (TEAE). The most common 
TEAEs by preferred term were retinal tear (9 subjects, 31.0%), conjunctival haemorrhage 
(7 subjects, 24.1%), and hypertension (7 subjects, 24.1%). Of the 4 subjects treated in Phase 2a, 
3 (75.0%) had at least 1 TEAE, the most common of which were conjunctival haemorrhage and 
retinal tear (reported for 3 subjects [75.0%] each). Most AEs were considered related to the 
surgical delivery procedure, or to various co-morbidities. Serious AEs reported for subjects from 
both the Phase 1 and 2a portions of the study combined are summarized in Table 3. The most 
commonly reported SAE was retinal detachment (5 of 33 subjects, 15.2%). The incidence of AEs 
and SAEs did not appear to be dose related.
Table 3:
Study CNTO2476MDG1002: Number (%) of Subjects with 1 or More Treatment-emergent 
Serious Adverse Events by Preferred Term (Subjects Treated in Phases 1 and 2a Combined)
6.0 x 104 cells
1.2 x 105 cells
3.0 x 105 cells
5.6 x 105 cells
Total
Subjects Treated
12
3
15
3
33
Subjects with 1 or more 
Treatment-emergent SAEs
6 (50.0%)
2 (66.7%)
3 (20.0%)
2 (66.7%)
13 (39.4%)
Preferred Term
Appendicitis
1 (8.3%)
0
0
0
1 (3.0%)
Atrial Flutter
0
0
1 (6.7%)
0
1 (3.0%)
Chronic Obstructive Pulmonary 
Disease
1 (8.3%)
0
1 (6.7%)
0
2 (6.1%)
Device Dislocation
0
0
1 (6.7%)
0
1 (3.0%)
Grand Mal Convulsion
1 (8.3%)
0
0
0
1 (3.0%)
Intestinal Obstruction
1 (8.3%)
0
0
0
1 (3.0%)
Metastatic Squamous Cell 
Carcinoma
0
0
1 (6.7%)
0
1 (3.0%)
Nephrolithiasis
0
0
0
1 (33.3%)
1 (3.0%)
Osteoarthritis
1 (8.3%)
0
0
0
1 (3.0%)
Pneumonia
0
1 (33.3%)
0
0
1 (3.0%)
Pneumonia Aspiration
1 (8.3%)
0
0
0
1 (3.0%)
Retinal Detachment
2 (16.7%)
1 (33.3%)
1 (6.7%)
1 (33.3%)
5 (15.2%)
Retinopathy Proliferative
1 (8.3%)
0
0
1 (33.3%)
2 (6.1%)
Suicide Attempt
1 (8.3%)
0
0
0
1 (3.0%)
Thoracic Vertebral Fracture
0
1 (33.3%)
0
0
1 (3.0%)
Urinary Tract Infection
0
1 (33.3%)
0
0
1 (3.0%)
Urosepsis
0
1 (33.3%)
0
0
1 (3.0%)
Note: A treatment-emergent AE was defined as any event that started during or after the administration of study 
treatment. A subject experiencing the same AE multiple times is counted once within the corresponding preferred 
term. Percentages are based on the number of treated subjects. 
There were no clinically significant changes in vital signs, physical examination, or clinical 
laboratory parameters.
Safety data available from this study suggest that CNTO 2476 is without substantial toxicity 
when subretinal administration occurs without a retinal break. However, the iScience MDS is not 
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
suitable for further development, and an alternative approach to subretinal delivery will be 
required.
A single administration of CNTO 2476 did not appear to elicit an immune response. No relevant 
treatment group differences in shift changes were noted for positive antibody titers. There were 
no clinically meaningful changes in median values from baseline for antibody titers within the 
treatment groups. One subject appeared to have pre-existing antibody to CNTO 2476, and 
1 subject had a de novo immunologic response to treatment with CNTO 2476. The presence of 
serum antibodies directed against CNTO 2476 was not associated with ocular adverse or 
inflammatory events. 
There have been 3 deaths among the 33 treated subjects, 1 each of depression/suicide, cancer of 
the lung and chronic obstructive pulmonary disease/pneumonia. None was considered to be 
treatment related.
1.2.
Overall Rationale for hUTC Development and Delivery System Innovation
Geographic atrophy related to AMD is the most common cause of blindness in the developed 
world among persons over age 60; in the United States (US) alone, approximately 8 million 
persons age 55 or older have intermediate or advanced AMD, and the prevalence of GA
specifically in person over age 40 is 0.8%, or approximately 970,000 individuals.10 The 
prevalence of AMD and GA is similar in other developed nations and will increase with the 
aging of the population. There are currently no approved therapies for the treatment of the dry 
form of AMD, including GA. 
Human umbilical tissue cells are easily available without the need to obtain or manage 
differentiation of stem cells; they are fully differentiated and have low potential for uncontrolled 
proliferation or teratoma formation; and they are readily expanded in vitro. Potency and viability 
assays are available to ensure quality and consistency of scaled up manufacturing. 
Both in vitro and in vivo data indicate that hUTCs have beneficial effects on RPE cells. As 
described above, hUTCs improve RPE phagocytic function in vitro and in vivo, with 
corresponding improvement in vision the RSC rat model. HUTCs also appear to modulate 
oxidative stress and neuroplasticity, factors which are disordered in GA. 
Furthermore, Phase 1 human data suggest that subretinal delivery of CNTO 2476 improve vision 
by at least 15 letters in BCVA, as compared to a fellow-eye control, and this benefit appears to 
be maintained through Month 12. CNTO cells appear to be safe when delivered as intended. 
These findings strongly support the further development of the therapy.
The safe delivery of CNTO 2476 to the appropriate location is currently the most important 
factor in the development of this program, and delivery of viable cells in the subretinal space 
requires some type of surgical procedure. Experience in the clinic has shown that leakage or 
reflux of cells into the vitreous may lead to proliferation of cells with membrane formation with 
to traction and retinal detachment. Thus, delivery of CNTO 2476 to the subretinal space without 
a break to the retina is of paramount importance. In the Phase 1 study, the iScience microcatheter 
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Status: Approved, Date: 15 December 2017
delivery system was used with an ab externo surgical approach. That approach was found to be 
challenging, requiring 2 operators, and resulting in an unacceptable rate of retinal tears and 
retinal detachments. That surgical approach is inadequate for further development.
Given the limitations of the iScience MDS, a newly developed Delivery System will be utilized 
in this Phase 2b study. The Delivery System was developed to facilitate delivery of CNTO 2476 
cells to the targeted perimacular subretinal delivery site via a suprachoroidal approach. The 
suprachoroidal surgical procedure was selected and the new Delivery System was developed 
with the goal of improving the delivery device and procedure usability and facilitating the safe 
targeted delivery of CNTO 2476.
The Delivery System is being developed in accordance with 21 Code of Federal Regulations 
(CFR) Part 4, Current Good Manufacturing Practice regulations for Combination Products, 
including 21 CFR Part 820.30, Medical Device Design Controls. Verification and validation 
testing for the device portion of the combination product will be performed prior to this clinical 
study to demonstrate that the devices perform safely according to the intended use of infusing cells.
The Delivery System is investigational in this clinical study for the intended use of delivery of 
CNTO 2476 cells. This is a first-in-human clinical use of an innovative Delivery System. As such,
the proposed Phase 2b study will employ a Safety Run-in Phase as a Delivery System pilot study, 
prior to randomization of subjects into the controlled Double-masked Treatment Phase of the 
study.
1.3.
The Cell Delivery System
The Delivery System is investigational for the intended use of delivering CNTO 2476 cells in 
this study. The Delivery System was developed to facilitate delivery of CNTO 2476 cells to the 
targeted perimacular subretinal delivery site via a suprachoroidal approach. The devices that 
comprise the Delivery System are described in the Investigational Product Manual.
2.
OBJECTIVES AND HYPOTHESES
2.1.
Objectives
Primary Objectives
The primary objective of the open-label Safety Phase is to evaluate the safety and performance
profile of the suprachoroidal surgical approach and the Delivery System. 
Major Secondary Objectives
The major secondary objectives of this study are the following: 

to assess the safety and performance profile of the Delivery System, the safety and 
tolerability of the suprachoroidal surgical approach, and the safety and tolerability of 
CNTO 2476 cells in the open-label Safety Run-in Phase.

to assess the effects of CNTO 2476 on anatomic correlates of treatment, including change in 
the area of GA
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Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017

to assess the effects of CNTO 2476 on additional and alternative efficacy outcomes 
including duration of clinical response.
2.2.
Hypothesis
The primary hypothesis of the open label safety phase of this study is that the novel subretinal 
delivery system is sufficiently safe and usable to deliver cells to the subretinal space. An 
additional hypothesis is that palucorcel is safe and well tolerated when delivered as a single dose 
to the subretinal space.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a multicenter Phase 2b study. A target of approximately 21 subjects will be enrolled in 
this study. This protocol amendment represents a significant reduction in scope and duration of 
the study based on the sponsor’s decision to discontinue the palucorcel development program.
The study includes only an initial open-label safety phase. 
The target population will be subjects at least 55 years of age and no older than 90 years with a 
confirmed diagnosis of bilateral GA of the macula secondary to age-related macular 
degeneration, with associated vision loss, confirmed within 45 days prior to initial randomization 
by the central reading center using fundus and/or autofluorescence photography. In subjects with 
neovascular AMD in 1 eye, the eye with GA must be the worse eye. In subjects with bilateral 
GA and the vision between both eyes is not clinically equal, the eye with the worse vision will be 
treated in order to minimize risk to the subject’s vision. In cases where the BCVA of the 2 eyes 
is clinically equal, the eye with the larger GA as demonstrated on the imaging studies will 
become the study eye.
The Safety Run-in Phase consists of approximately 21 subjects (the first 3 subjects at each of 
approximately 8 sites) who will first be enrolled in an open-label assessment of the safety profile 
of the procedure and the Delivery System. The first 3 subjects at the first 8 sites (approximately 
21 subjects in total) will be the initial Safety Cohort. A minimum of seven different surgeons are 
required to ensure most of the possible failure modes will be identified.16 Enrollment will be 
actively managed to ensure that experience and learning from earlier procedures are promptly 
transferred to the subsequent procedures, and to ensure that an appropriate number of subjects 
are enrolled at the time of the planned safety assessments.
The safety profile of the procedure and the Delivery System will be assessed after the first 
21 subjects (the initial Safety Cohort) have been treated and followed for a minimum period of 1
month. An external Data and Safety Monitoring Board (DSMB) will be commissioned for this 
study. The 2nd Safety Cohort and the double blind portion of this study have been eliminated 
from this study protocol.
The study will consist of a 12-month acute phase, followed by a 2-year maximum duration 
follow-up period (3 years total) for all subjects. 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
Screening Phase
All subjects will be required to give a written informed consent to participate in the trial. In a 
separate consent, subjects will have the option of providing a DNA sample for genotyping. 
Subjects may also have the option of donating their eyes for histological evaluation post mortem, 
using a supplemental informed consent.
Subjects may be screened over a period of up to 45 days prior to treatment to assess their 
eligibility for the study based on the inclusion and exclusion criteria defined for this study. 
Patient eligibility will be determined based on the results of 2 BCVA examinations performed at 
the screening visits. These examinations can occur on the same day or subsequent days. The 
better of the 2 logMAR BCVA scores will be used for eligibility and randomization. These 
examinations should be performed prior to any other ocular study procedures that would 
interfere with vision assessments such as dilation or bright light assessments.
Visual acuity tests, contrast sensitivity, MN Read, intraocular pressure (IOP), slit lamp 
examinations, microperimetry, fundus photography, SD-OCT, fundus autofluorescence, 
fluorescein angiography and dilated fundus examination readings will be carried out on all 
subjects. At baseline, axial length will be recorded in the CRF. Indocyanin green angiography
will be performed on all subjects unless discussed with the Sponsor. 
Other assessments will include medical history, genomic material from consented subjects, 
demographics, a targeted physical examination, vital signs, routine laboratory and routine 
urinalysis In addition blood samples for immunogenicity, medication history, concomitant 
medications, and the NEI-VFQ-25 and the Near Vision subscale, and the SF-36 and FRI, will be 
collected.
Additional details of the screening phase are provided in Section 9.1.1.1 (Screening Phase). 
Open-label Safety Run-in Phase
A minimum of the first 3 eligible subjects at each center will receive active treatment in an 
uncontrolled, open-label Safety Run-in Phase to assess the safety of the surgical procedure and 
Delivery System, and to ensure the familiarity of the surgeons with the Delivery System and the 
procedure. The first 21 subjects from the designated Safety Cohort study sites will comprise the 
initial Safety Cohort. Enrollment into the safety Run-in Phase will be staggered across sites to 
ensure that the outcomes and learnings from earlier procedures can be transferred to all 
participating surgeons who will perform subsequent procedures. A 1-week interval for 
information sharing between the first few subjects is appropriate since most procedure-related 
AEs are expected to be apparent within hours of surgery. 
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
Long-term Follow-Up Phase
After the 12-month acute phase of the study, subjects will be followed every 6 months for 
2 years in the Long-term Follow-up Phase of the study, as shown in the Time and Events 
Schedule (see Table 2).
A DSMB will be established to monitor study data on an ongoing basis to ensure the continuing
safety of the subjects enrolled in this study. Refer to Section 11.6, Data and Safety Monitoring 
Board, for details. The committee will meet periodically to review interim study data. After the 
review, the DSMB will make recommendations regarding the safety and continuation of the 
study. The details will be provided in a separate DSMB charter.
3.2.
Study Design Rationale
This protocol amendment represents a significant reduction in the scope and duration of the 
planned trial, based on the sponsor’s decision to discontinue the palucorcel development 
program. The intent of the current study design is to ensure adequate long-term safety follow-up 
of the subjects previously enrolled, while minimizing the visit burden on subjects and 
investigators.
The target population for this study is adult subjects (at least 55 years of age and no older than 
90 years) with GA of the retina secondary to age related macular degeneration, with a baseline 
visual acuity of approximately logMAR 0.6 (20/80) to logMAR 1.6 (20/800). The best visual 
acuity of logMAR 0.6 (20/80) was selected because in this range, vision is compromised to a 
degree that restricts certain activities of daily living, and the potential benefit to the subjects 
justifies risks associated with the procedure and treatment. 
A critical requirement of the program is the ability to deliver viable cells safely and efficiently to 
the subretinal space, without damaging the retina, and without leakage of cells into the vitreous. 
Currently, there is no alternative to surgical delivery. Previous studies using a transvitreal 
approach or an ab externo surgical approach have led to an unacceptable rate of retinal tears and 
detachments. The new suprachoroidal surgical procedure was selected and the new Delivery 
System designed with the goal of simplifying the procedure and facilitating the safe targeted 
delivery of CNTO 2476.
The use of the Delivery System in the Safety Cohort is a first-in-man study and AEs and device 
quality will be assessed by an independent DSMB after the first 21 subjects have been treated (or 
sooner, if a stopping threshold is reached).
Dose Selection
The breadth of the dose range is constrained by the cell density during cryopreservation and the 
minimal volumes that can be accurately administered to minimize the detachment at the 
subretinal injection site; the feasible doses were all studied in the Phase 1/2a study. The greatest 
experience to date is with the 3.0 x 105 cell dose (15 subjects). Although that dose was 
administered in a 27 µL volume in the prior study, there is no reason to believe that the volume 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
of administration is relevant to either safety or efficacy; the AE profile for this dose/volume 
combination is comparable to a smaller dose (6.0 x 104 cells) given in a 50 µL volume.
3.2.1.
Control
The open-label phase of this study does not require a control group. 
3.2.2.
Masking
The open-label phase of this study does not require masking.
3.2.3.
Randomization
The open-label phase of this study does not require randomization.
3.2.4.
Primary Outcome Measure
Change in BCVA is considered meaningful to patients and has been accepted by the US Food 
and Drug Administration (FDA) as an approvable endpoint in trials of therapeutic agents for 
AMD. In addition, BCVA reflects holistically both the potential benefits (gain in visual acuity 
from therapy) and harms (loss of visual acuity due to AEs). Assessment of BCVA is known to be 
partly effort-dependent, and every effort will be made to standardize these assessments. The 
Early Treatment Diabetic Retinopathy Study (ETDRS) chart at 4 meters is considered the ‘gold 
standard’ for visual acuity testing in clinical research for its physical and statistical properties.
4.
SUBJECT POPULATION
Approximately 100 subjects will be screened to enroll approximately 21 subjects in the 
open-label safety phase of this study.
Screening for eligible subjects will be performed within 45 days before administration of the 
treatment.
The inclusion and exclusion criteria for enrolling subjects in this study are described in the following 
2 subsections. If there is a question about the inclusion or exclusion criteria below, the investigator 
should consult with the appropriate sponsor representative before enrolling a subject in the study. 
For a discussion of the statistical considerations of subject selection, refer to Section 11.2, 
Sample Size Determination.
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study. 
1.
Subject must be a man or woman at least 55 years to 90 years of age, inclusive.
2.2
Diagnosis of GA secondary to AMD confirmed within 45 days prior to initial 
randomization. Diagnosis verified by the central reading center using fundus 
photographs and including the following;
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017

The study eyes must have at least 1 GA lesion that involves the fovea, and a 
Macular Photocoagulation Study (MPS) disc areas (DA) of 0.5 and 7 (1 MPS 
disc area equivalent to 2.54 mm2 on the retina) determined by screening images of 
fundus autofluorescence photographs as calculated by the reading center. If GA is 
multifocal, at least 1 lesion must be 0.5 DA.
o
In the Safety Run-in Phase only, DA of 0.5 with no maximum specified 
area, as long as the criteria below for photography can be met and the 
surgeon determines that the GA size will not impede cell delivery.

Geographic atrophy must be able to be photographed in its entirety and may be 
contiguous with peripapillary atrophy. 

Retinal photographs, fundus autofluorescence images,
and
angiography of 
sufficient quality, allowing assessment of the macular area according to standard 
clinical practice, can be obtained.

The imaging center must be able to delineate and confirm peripapillary atrophy 
with fundus photography and fundus autofluorescence. 

Images must include the central field 1, 2, and 3 field images as defined by the 
University of Wisconsin standards as well as a supero-temporal image to capture 
the subretinal injection area if possible.
3.2
Study eyes will have a BCVA of 20/80 to 20/800 (ETDRS logMAR value 0.6-1.6). The 
treatment eye will be that with the worse BCVA at screening. If BCVA is clinically 
equivalent, the eye with the larger GA determines the study eye. 
4.
Subject is a suitable candidate for ophthalmologic surgery, is willing and able to comply 
with the surgical procedure, scheduled visits, treatment plan, laboratory tests and other 
study procedures. Subject has met criteria of the surgery center anti-coagulation 
protocol, if applicable.
5.
Female subjects must be post-menopausal with last menses 12 months prior, or longer, 
OR a measured follicle stimulating hormone 26 mIU/mL.
6.
Male subjects must be sterile or willing to use 2 approved methods of contraception 
from first day post-operatively to 3 months post-operatively (approved methods of 
contraception include condom with spermicide, a sterile sexual partner, a sexual partner 
using oral or implantable contraceptive or an intrauterine device with spermicide, a 
diaphragm with spermicide, or cervical cap with spermicide).
7.
Each subject must sign an informed consent form (ICF) indicating that he or she
understands the purpose of and procedures required for the study and are willing to 
participate in the study.
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study.
1.2
Subject has a history of neovascular (“wet”) AMD in the treatment eye, including any 
evidence of retinal pigment epithelium rips or evidence of subretinal or choroidal 
neovascularization or fluid. In cases where imaging is inconclusive, review of the case 
with the study site, considering history and imaging will determine eligibility. History 
or evidence of neovascular AMD in the fellow eye is allowed, if anti-vascular 
endothelial growth factor (VEGF) therapy has not been required for at least 8 weeks 
prior to screening.
2.
Geographic atrophy secondary to any causes other than AMD in either eye
3
A diagnosis of glaucoma with an IOP 25 mmHg while being treated with an ocular 
hypotensive drug. Treatment should be no more than 1 drug preparation/combination, 
which can contain 1 or 2 ocular hypotensive active ingredients; subjects receiving more 
than 2 ocular hypotensive active ingredients are excluded. Note: subjects with a diagnosis 
of ocular hypertension (not glaucoma) are eligible to participate whether or not they are 
being medically treated.
4.
Nuclear sclerotic cataract, cortical spoking, posterior subcapsular cataract above 
Grade 2 per Age-Related Eye Disease Study (AREDS) scale or any other 
ophthalmologic condition that reduces the clarity of the media that, in the opinion of the 
investigator or reading center, interferes with ophthalmologic examination (eg, corneal 
abnormalities, inadequate pupillary dilation), surgery or imaging in the study eye
5.
Myopia >-8 diopters and subjects with >4 diopters of astigmatism, and >+10 diopters of 
hyperopia. Note: clinical evidence of retinal degeneration secondary to pathological 
myopia will exclude the subject as will a scleral ectasia with or without high myopia.
6.
Evidence of other significant ophthalmologic disease (eg, glaucoma, intraocular 
inflammatory disease, diabetic retinopathy, Stage II, III, or IV macular hole, clinically 
evident vitreoretinal traction, choroidal or retinovascular disease, cystoid macular 
edema, significant epiretinal membrane, significant blepharitis, keratitis, conjunctivitis,
or staphyloma) in the study eye
7.2
Previous treatment for confirmed AMD (dry or wet) in the study eye with treatments
other than antioxidant or zinc supplements (eg, AREDS1 or AREDS2 formula) or other 
oral vitamin supplements. Subjects who have received anti-VEGF treatment without a 
confirmed diagnosis of wet AMD or who have participated in previous studies for AMD 
may be considered eligible if these treatments/study participation were given at least 
one year prior to enrollment.
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
8.2
Previous intraocular surgery within 3 months prior to screening in either eye. Previous 
treatment with Visudyne®, external-beam radiation therapy, or transpupillary 
thermotherapy in the study eye at any previous time point.
9.
Previous laser photocoagulation in the study eye (peripheral laser for treatment of a tear 
is allowed if more than 6 months prior to screening except when, in the opinion of the 
surgeon, this would hamper the suprachoroidal cannulation procedure in the study eye)
10.
Previous vitrectomy, retinal detachment repair, submacular surgery, other surgical 
interventions targeting AMD, scleral buckling or glaucoma filtration surgery or any 
other extraocular or orbital procedure in the study eye that, in the opinion of the 
surgeon, would hamper the suprachoroidal cannulation procedure in the study eye
11.
History of choroidal or scleral rupture in either study or fellow eye due to uveitis 
(previous trauma in the study eye or fellow eye in the case of good vision in that eye is 
not an exclusion criterion)
12.
Uveitis or other intraocular inflammatory disease within past 3 months
13
Active infections of the anterior segment
14.
Keratoconus, penetrating keratoplasty, Descemet's stripping endothelial keratoplasty 
(DSEK), radial keratotomy (RK), Laser-assisted in situ keratomileusis (LASIK) in the 
study eye
15.
Monocular subjects
16.
Subject has known allergies, hypersensitivity, or intolerance to CNTO 2476 or its
excipients (refer to Investigator's Brochure)
17.
Medically not qualified for monitored anesthesia care intravenous sedation
18.
Previous cell therapy other than standard blood and platelet transfusions
19.
Subject has taken any disallowed therapies as noted in Section 8, (Prestudy and
Concomitant Therapy) before the planned first dose of treatment
20.1
Subject has received an investigational drug (including investigational vaccines) within
30 days before the planned first dose of treatment
21.
Active malignancy (requiring therapy) or history of malignancy requiring therapy 
within 2 years prior to Day 1 (with exception of cases of basal cell and squamous cell 
carcinoma of the skin)
22.
History of human immunodeficiency virus (HIV) disease
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
23.
Significant cognitive impairment that interferes with a subject’s ability to participate 
with the testing regimen
24.
History of organ or bone marrow transplants
25.
History of alcohol or drug abuse within past 2 years
26.
Significant hepatic dysfunction (aspartate aminotransferase [AST] or alanine 
aminotransferase [ALT] >3x upper limit of normal [ULN]), or significant renal 
dysfunction (estimated creatinine clearance 30 mL/min), or on renal dialysis
27.
Significant uncorrectable coagulopathy, thrombocytopenia (platelets <100 x 103/µL) or 
other significant bleeding risk. Note: subjects on an anticoagulant therapy should be 
considered at low risk for new thromboembolic events, and must agree to stop all 
anticoagulation therapy prior to surgery, as follows:

Warfarin 5 days

Aspirin 7 days

Oral Factor Xa inhibitors 3 days (or longer, depending on renal function)

Dabagatran 3 days

Low molecular weight heparin 1 day

Clopidogrel and ticagrelor 5 days

Prasugrel 7 days

Ticlopidine 10 days
28
Uncontrolled systemic hypertension on the day of surgery, defined as a systolic blood 
pressure 180 mm Hg. Note: if the subject’s systolic blood pressure can be controlled 
later by the subject’s medical doctor, eligibility for surgery can be re-assessed. 
29.
Subject has any condition for which, in the opinion of the investigator, participation
would not be in the best interest of the subject (eg, compromise the well-being) or that
could prevent, limit, or confound the protocol-specified assessments
30.
Subject is an employee of the investigator or study site, with direct involvement in the
proposed study or other studies under the direction of that investigator or study site, as
well as family members of the employees or the investigator
31.
Known allergy to iodinated contrast dyes
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening. 
If a subject's status changes (including laboratory results or receipt of additional medical records) 
after screening but before the first dose of treatment is given such that he or she no longer meets
all eligibility criteria, then the subject should be excluded from participation in the study. 
NCT02659098


CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017
Section 17.4, Source Documentation, describes the required documentation to support meeting 
the enrollment criteria.
4.3.
Prohibitions and Restrictions
Potential subjects must be willing and able to adhere to the following prohibitions and 
restrictions during the course of the study to be eligible for participation:
a.
A man who is sexually active with a woman of childbearing potential must use a
double-barrier method of birth control (ie, male condom, female diaphragm or cervical
cap, or condom) and all men must also not donate sperm for 3 months after receiving 
the last dose of study drug.
b.
Subjects must agree to defer blood, blood component, or tissue donation until 12 months 
post treatment
5.
TREATMENT ALLOCATION AND MASKING
Treatment Allocation
All subjects in the Safety Cohort will receive the same dose of 3.0 x 105 cells in 50 µL.
Masking
Masking is not applicable to the open-label safety phase of this study.
6.
DOSAGE AND ADMINISTRATION
6.1.
Open-label Safety Run-in Phase
Subjects in the Safety Run-in Phase will receive 3.0 x 105 cells in 50 µL dosing volume.
CNTO 2476 will be delivered using the custom-designed Delivery System and surgical 
procedure.
Each subject in the Safety Run-in Phase will receive a single subretinal administration of 
CNTO 2476. A high-level overview of the procedure for administering the single dose of 
CNTO 2476 in 1 eye is described below:

An eyelid speculum will be placed and a chandelier is inserted targeting illumination of the 
superiotemporal quadrant

A trap-door conjunctival incision will be made in the superiotemporal quadrant to expose 
the sclera

With aid of measuring template, a “suture loop” will be created between the limbus and the 
sclerotomy site

A sclerotomy incision will be created approximately 3mm in length

The cannula will be inserted through the suture loops, through the sclerotomy, and 5 mm 
into the suprachoroidal space
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CNTO 2476
Clinical Protocol CNTO2476MDG2002 Amendment 3
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Status: Approved, Date: 15 December 2017

The retina will be visualized through the pupil and the cannula is advanced to the target 
location superior to the macula

Under direct visualization of the cannula tip, the needle will be advanced and a small saline 
entry bleb is created

When successful subretinal entry has been established, the surgeon will administer 50 µL of 
CNTO 2476 cells subretinally

The needle will be withdrawn, and the cannula removed from the suprachoroidal space

The suture loops are removed and the sclera and conjunctiva will be closed
A detailed description of the surgical procedure will be available and updated as a part of the 
physician training materials.
7.
TREATMENT COMPLIANCE
The investigational product will be administered subretinally as a single dose by the retinal 
surgeon. The administration of the investigational product will take place in an operating room 
using the Delivery System. Compliance will not require any activity by the subject.
8.
PRESTUDY AND CONCOMITANT THERAPY
All pre-study therapies administered up to 30 days before first dose of treatment must be 
recorded at screening.
Peri-operative (subconjuntival vancomycin) and post-operative (PRED FORTE® and Polytrim®) 
or equivalent medication regimens are required in order to have standardization in treatments 
across sites.
Systemic concomitant therapies must be recorded throughout the study beginning with start of 
treatment to 1 year after the last dose of treatment. Systemic therapies for eye disease or any 
concomitant therapies given by ophthalmic routes must be recorded for the entire 3 years.
Concomitant therapies associated with an SAE should also be recorded for the entire 3 years.
All therapies (prescription or over-the-counter medications, including vaccines, vitamins, herbal 
supplements different from the study drug) must be recorded in the eCRF.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.
Prohibited Concomitant Medications
The following are prohibited in the 30 days prior to dosing, and discouraged thereafter:

Hydroxychloroquine (unless taking less than 6.5 mg/kg/day) 

Chloroquine (unless taking less than 3 mg/kg/day)

Thioridazine 

Chlorpromazine
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
Tamoxifen, 

Isotretinoin

Clofazimine

Cisplatin

Carmustine 

Systemic corticosteroids 20mg/day prednisone (or equivalent) for > 14 days. 
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The TIME AND EVENTS SCHEDULES is a summary of the frequency and timing of efficacy, 
immunogenicity, pharmacogenomic, PROs, and safety measurements applicable to the study.
The Time and Events Schedule lists the day associated with each visit until Day 15, and then the 
month associated with each visit through Month 12, and Month 18 through Month 36 of the 
long-term follow-up phase. From Day 7 through Month 6 a visit window of ±3 business days 
will be allowed; for the Month 12 visit, a visit window of ±7 days will be allowed. From 
Month 18 through Month 36 a visit window of ±2 weeks (14 days) will be allowed. The data on 
the visit should always be calculated from the baseline visit, and not from the prior visit.
All visit-specific, PRO assessments should be performed before any tests, procedures, or other 
consultations for that visit to prevent influencing subject perceptions.
The BCVA, low luminance BCVA (LL BCVA), and contrast sensitivity will all be performed 
using a validated testing protocol. BCVA is the best vision one can achieve with best correction
ETDRS acuity testing, and is a done using a standard ETDRS chart for visual acuity testing.
The MN Read will be used to determine reading speed (RS, [measured in characters per 
minute]), critical print size (CPS, [measured in logMAR]), as well as RA (measured in 
logMAR). 
Microperimetry will be performed using the MAIA2 system measuring the sensitivity in 
decibels. 
New technology assessments, eg, Optical Coherence Tomography Angiography (OCT-A) and 
intraoperative Optical Coherence Tomography,
may be performed at the surgeon or 
investigator’s discretion but do not substitute for any of the mandatory evaluations listed in this 
protocol.
A standard full ophthalmology examination will be performed and will include IOP, slit lamp 
examinations, and dilated fundus examinations. The order of multiple ophthalmologic 
assessments within 1 protocol time point will be the same throughout the study.
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The following imaging data will also be collected and analyzed by the Digital Angiography 
Reading Center (DARC): 

fundus photography

SD-OCT

fundus autofluorescence 

fluorescein angiography 

Indocyanin green angiography 
The NEI-VFQ-25 and the Near Vision subscale, and the SF-36 contained in the appendices, will 
be used in the study to evaluate quality of life. 
Blood may be drawn using a cannula or by other venipuncture. The exact times for each blood 
draw or assessment will be recorded. The total volume of blood to be collected from each subject 
is 107.4 mL. For each subject the amount of blood drawn is summarized in Table 4.
Table 4:
Volume of Blood to be Collected From Each Subject
Time Point for Blood Collection
Amount of Blood Collected (mL)
Screening
16.3
DNA Collection
8.5
Day 7
10.0
Day 15
10.0
Week 4
16.3
Month 2
10.0
Month 3
10.0
Month 6
10.0
Month 12
16.3
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples.
A DSMB will be established to monitor study data on an ongoing basis to ensure the continuing 
safety of the subjects enrolled in this study. Refer to Section 11.6, Data and Safety Monitoring 
Board for details. The committee will meet periodically to review interim study data. After the 
review, the DSMB will make recommendations regarding the safety and continuation of the 
study. The details will be provided in a separate DSMB charter.
9.1.1.1.
Screening Phase
Prior to the full study screening phase, optional BCVA pre-screening may be done to evaluate 
subjects for BCVA eligibility. In this case, subjects must sign an optional pre-screening ICF 
prior to testing. The site will determine results of local testing and indicate if the subject is 
eligible for full study screening. If the BCVA test indicates the subject meets the necessary 
eligibility criteria, he or she will enter the full screening phase under the full study ICF for 
determination of full study eligibility.
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All subjects will be required to give written informed consent to participate in the trial. In a 
separate consent, subjects will have the option of providing a DNA sample for genotyping. 
Subjects will also have the option of donating their eyes for histological evaluation post mortem, 
using a supplemental informed consent.
After giving written informed consent, subjects may be screened over a period of up to 45 days 
prior to treatment to assess their eligibility for the study according to the inclusion and exclusion 
criteria defined for this study. The screening process may occur over a period of days. If a 
subject fails screening for a reason determined to be temporary, they may be rescreened to 
determine eligibility by following these criteria: 

Elevated IOP, uncontrolled blood pressure, elevated liver enzymes , decreased platelets and 
decreased renal function, if correctable with treatment or time

Acute infections, after successful treatment

Time-bound restrictions (e.g., Exclusions 8, 9, 12, 20, 21 and 25) after an appropriate 
waiting period such that the exclusion no longer applies

Use of prohibited prior medications, after an appropriate waiting period.
Potential patients who fail screening for visual acuity, retinal anatomy or other ocular findings 
should not be rescreened. Any rescreening request not mentioned here should be discussed with 
the study Medical Monitor. For rescreened subjects, imaging studies do not have to be repeated 
if performed in the 60 days prior to start of new screening. For rescreened subjects, clinical 
laboratory exams (bloodwork) do not have to be repeated if performed in the 45 days prior to 
start of the new screening. 
Patient eligibility will be determined based on the results of 2 BCVA examinations performed at 
the screening visit. These examinations can occur on the same day or subsequent days. The 
better of the 2 logMAR BCVA scores will be used for eligibility and randomization. These 
examinations should be performed prior to any other ocular study procedures that would 
interfere with vision assessment such as dilation or bright light assessments. 
Visual acuity tests, contrast sensitivity, MN Read, IOP, slit lamp examinations (including lens 
mobility examination), microperimetry, fundus photography, SD-OCT, fundus autofluorescence, 
fluorescein angiography and dilated fundus examination readings will be carried out on all 
subjects. At baseline, axial length will be recorded in the CSF. Indocyanin green angiography 
will be performed for all subjects unless discussed with the Sponsor.Medical history, genomic 
material from consented subjects, demographics, physical examination, vital signs, routine 
laboratory and routine urinalysis data will also be collected during the screening visit. In 
addition, blood samples for immunogenicity, medication history, and the NEI-VFQ-25 and Near 
Vision subscale, SF-36 and FRI, will be done during the screening visit. Changes in concomitant 
medications will be recorded on Day 1. 
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9.1.1.2.
Open-label Safety Run-in Phase
The study will begin with a minimum of 7 surgeons performing approximately 3 open-label 
procedures to complete an initial Safety Cohort of 21 subjects. A minimum of 7 surgeons were 
chosen for the Safety Cohort based on the amount of users needed to identify complications with 
a surgical procedure and Delivery System. According to usability standards for medical devices, 
5 to 8 surgeons performing 1 to 5 procedures at each site for a total of 21 procedures find 
between 75% and 90% of usability defects.16
After a total of 21 subjects are enrolled in the study, a safety review of the Delivery System and 
procedure will be performed. The data will be reviewed in a meeting with the surgeons, Principal 
Investigators, and the DSMB. The data will be assessed in the context of the predefined stopping 
rules described in the DSMB Charter. Events of special interest are choroidal hemorrhage, 
endophthalmitis or infections, retinal detachments, leakage of cells into the vitreous/need for 
vitrectomy, significant loss of vision defined as loss of ≥15 letters compared to baseline in the 
first month post-surgery, and failure to deliver cells/device failure.
9.1.1.3.
End of Treatment or Early Withdrawal
Every attempt should be made to follow subjects through their final visit (Month 36). In the 
event that a subject prematurely discontinues from the study for any reason, an end-of-study visit 
should be completed (see Section 10.2 for criteria for treatment discontinuation). Assessments 
and procedures to be completed at the end-of-study visit are listed in the Time and Events 
Schedule (Table 2). 
If a subject withdraws from the study due to an AE, every reasonable attempt will be made to 
follow the subject until the AE resolves or until the investigator, in conjunction with the sponsor, 
deems the AE to be chronic or stable. All SAEs will continue to be followed as instructed in 
Section 12.3.2.
9.1.1.4.
Long-term Follow-up Phase
Subjects who complete the 12-month acute phase of the study will be followed every 6 months
for 2 years in the Long-term Follow-up Phase, as indicated in the Time and Events Schedule 
(Table 2).
9.2.
Efficacy
9.2.1.
Evaluations
Subjects who successfully complete the screening visit will present to the clinical site on Day 1 
(pre-operative visit on the treatment day), at which time CNTO 2476 will be administered. The 
Delivery System will also be assessed at this time. All study assessments are listed in the Time 
and Events Schedule (Table 1 and Table 2).
9.2.1.1.
Primary Efficacy Measure
The primary efficacy measure will be the BCVA testing performed after refraction and under 
standardized photopic lighting conditions and distance using an ETDRS logMAR chart.
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9.2.1.2.
Secondary Efficacy Measures
The BCVA will be assessed at the 6- and 12-month visits to evaluate the major secondary 
endpoints described in Section 9.2.2.
An additional assessment of growth rate of GA lesion documented at baseline to 12 months will 
be performed. Lesion size will be determined by the DARC will also be performed.
9.2.2.
Endpoints
Primary Endpoints
The endpoints of the open-label Safety Run-in Phase are all related to the objective of evaluating 
the safety profile of the procedure, Delivery System, and of the implanted hUTC cells.
Major Secondary Endpoints

Proportion of subjects losing 15 BCVA letters from baseline at 12 months following 
treatment with CNTO 2476

Change in mean number of BCVA letters from baseline at the 6- and 12-month visits
following treatment with CNTO 2476

Growth rate of GA lesion documented at baseline to 6 and 12 months following treatment 
with CNTO 2476. The area of GA is determined based primarily on fundus autofluorescence
as well as fluorescein angiography and fundus photos
9.3.
Immunogenicity
The evaluations, analytical procedures, and immunogenicity assessments done are described in 
the sections following. Additional instructions sample handling and disposition are provided in a 
separate laboratory manual. 
9.3.1.
Evaluations
Venous blood samples will be collected by the investigator site for immunogenicity assessment. 
The measurements will be taken at screening, Day 7 and 15, Week 4, Month 2, 3 6, and 12. This 
will allow dynamic monitoring of the serum antibody levels. Additional information on the blood 
volumes to be collected is provided in the Time and Events Schedule (Table 1).
Serum antibody levels pre- and post-administration of CNTO 2476 will be assessed by 
co-incubating subject serum samples and CNTO 2476. An antibody detection system will then 
be added and the bound serum antibodies are measured via flow cytometry. The titer of 
confirmed positive samples will be reported.
The serum will be separated at the investigator site laboratory and transferred to the appropriate 
storage vials supplied in the sample kit. The tubes will be stored at the prescribed temperature 
and shipped to the laboratory/storage of the Contract Research Organization (CRO), according to 
instructions. The CRO will send the samples to the laboratory assessing the serum antibodies on 
a monthly basis. The laboratory will assess the serum antibody levels and deliver the results to 
the CRO. 
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9.3.2.
Analytical Procedures
Serum samples will be screened for the presence of antibodies binding to CNTO 2476. The 
detection and characterization of antibodies to CNTO 2476 will be performed using a validated 
assay method by or under the supervision of the sponsor. Other analyses may be performed to 
verify the stability of antibodies to CNTO 2476 and/or further characterize the immunogenicity 
of CNTO 2476.
All samples collected for detection of antibodies to CNTO 2476 will also be evaluated for 
CNTO 2476 serum concentration to enable interpretation of the antibody data.
9.3.3.
Immunogenicity Assessments
Blood samples for determination of antibodies to CNTO 2476 will be collected from all subjects 
according to the Time and Events Schedule. Samples should also be collected at the final visit 
from subjects who are withdrawn from the study. Blood samples will only be collected during 
study assessments for the safety run-in phase and the randomized double-masked treatment 
phase from screening through the Month 12 postoperative visit. 
9.4.
Intraoperative Delivery System and Procedure Evaluations
The Delivery System is designed to access the suprachoroidal space and the subretinal space, and 
to deliver the cells subretinally. 
In order to evaluate the safety of the Delivery System for the intended use of delivering 
CNTO 2476 cells, device-related safety information will be collected. Relevant ophthalmic AEs 
will be evaluated. In addition, specific device performance data will be collected.
9.5.
Safety Evaluations
Details regarding the DSMB are provided in Section 11.6.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the CRF.
Any clinically significant abnormalities persisting at the end of the study/early withdrawal will 
be followed by the investigator until resolution or until a clinically stable endpoint is reached.
The study will include the valuations of safety and tolerability according to the time points 
provided in the Time and Events Schedule (Table 1 and Table 2) and as described in the 
following sections.
9.5.1.
Adverse Events
Adverse events will be reported by the investigator or the subject (or, when appropriate, by a 
caregiver, surrogate, or the subject's legally acceptable representative) for the duration of the 
study. Adverse events will be followed by the investigator as specified in Section 12, Adverse 
Event Reporting.
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9.5.2.
Clinical Laboratory Tests
Blood samples for serum chemistry and hematology and a random urine sample for urinalysis
will be collected. The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE section of the CRF. 
The laboratory reports must be filed with the source documents.
The following tests will be performed by the central laboratory (Covance Laboratories), and by 
the local laboratory (Catalent) for immunology assessments:

Hematology Panel
hemoglobin
platelet count
hematocrit
prothrombin time (PT)
red blood cell (RBC) count
partial thromboplastin time (PTT)
white blood cell (WBC) count
with differential

Serum Chemistry Panel
sodium
total bilirubin
potassium
alkaline phosphatase
chloride
lactic acid dehydrogenase (LDH)
blood urea nitrogen
uric acid
creatinine
calcium
glucose
albumin
aspartate aminotransferase (AST)
total protein
alanine aminotransferase (ALT)
gamma-glutamyltransferase (GGT)

Urinalysis (Dipstick)
specific gravity
pH
-glucose
protein
-blood
ketone
-bilirubin
urobilinogen
-nitrite
leukocyte esterase
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, and urobilinogen will be 
determined using a dipstick.
Female subjects must be post-menopausal with last menses 12 months prior, or longer, OR a 
measured follicle stimulating hormone ≥26 mIU/mL.
Additional instructions relating to the clinical laboratory tests are provided in the laboratory 
manual.
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9.5.3.
Vital Signs 
Temperature, pulse/heart rate, respiratory rate, blood pressure will be collected at the time points 
indicated in the Time and Events Schedule. Blood pressure and pulse rate measurements will be 
assessed sitting. Blood pressure and pulse rate measurements should be preceded by at least 
5 minutes of rest in a quiet setting without distractions (eg, television, cell phones).
9.5.4.
Physical Examination
The study investigator, or other authorized and appropriately qualified designee, will perform a 
targeted physical examination at the time points listed in the Time and Events Schedule.
Any clinically relevant changes occurring during the study must be recorded on the Adverse 
Event section of the eCRF. Any clinically significant abnormalities persisting at the end of the 
study or early withdrawal will be followed by the investigator until resolution or until a clinically 
stable endpoint is reached.
A targeted physical examination will be done at screening and at the 12-monthly visit only.
9.6.
Sample Collection and Handling
The actual dates and times of blood and urine sample collection must be recorded in the eCRF to 
the nearest minute, or in laboratory requisition form.
Instructions for the collection, handling, storage, and shipment of samples are found in the 
laboratory manual. Collection, handling, storage, and shipment of samples must be according to 
specifications contained in the laboratory manual.
Refer to the Time and Events Schedule for the timing and frequency of all sample collections.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the 12-month acute phase of the study if he or 
she has completed assessments at Month 12. Subjects who prematurely withdraw for any reason 
before completion of the 12-month assessments will not be considered to have completed the 
study.
A subject will be considered to have completed the Long-Term Follow-up Phase of the study if 
he or she has completed assessments at Month 36 of the study.
10.2.
Discontinuation/Withdrawal from the Study
A subject should be withdrawn from the study if the investigator believes that for safety reasons 
(eg, an AE) it is in the best interest of the subject to discontinue.
If a subject discontinues from the study before the end of the 12-month acute phase, or before the 
end of the Long-term Follow-up Phase, end-of-study assessments (Table 2) should be performed. 
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In addition, if a subject undergoes surgery but product is not administered, and the subject 
subsequently discontinues from the study, the subject will be followed for safety assessments.
A subject will be withdrawn from the study for any of the following reasons:

Lost to follow-up

Withdrawal of consent

Death
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow-up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Subjects who withdraw will not be 
replaced. If a subject withdraws from the study, end-of-study assessments (Table 2) should be 
performed.
Withdrawal from the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5,
Long-Term Retention of Samples for Additional Future Research). In such a case, samples will 
be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF and in the separate ICF for optional research 
samples.
11.
STATISTICAL METHODS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be used to analyze the efficacy and safety data is outlined 
below. In general, all data will be tabulated and displayed using descriptive methods only; no 
formal statistical testing is planned for outcome in the Safety Cohort.
Analyses will be conducted for all subjects who receive treatment in the open-label Safety
Run-in phase.
After the first 21 subjects participating in the open-label safety run-in phase have completed 
1 month of follow-up (the initial Safety Cohort), an analysis of data will be performed. These 
analyses will consist of simple descriptive statistics for key safety and efficacy measures, which 
will be described in the statistical analysis plan (SAP). 
11.1.
Subject Information
For all subjects, descriptive statistics of the baseline and demographic information by treatment 
group will be provided.
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Subject disposition will be summarized for subjects who received cell injection. The number of 
subjects who discontinued study participation early will be summarized by reason for 
discontinuation. A list of subjects who discontinued study participation early will also be 
provided. The number of subjects with left or right treated eye will be summarized. 
11.2.
Sample Size Determination
The sample size of 21 subjects is based on the number of subjects require to allow for an 
adequate clinical assessment of the safety and usability of the novel delivery system.
11.3.
Efficacy Analyses
The BCVA, LL BCVA, LLD, contrast sensitivity and growth rate of GA lesion will be 
summarized with descriptive statistics as specified in the SAP.
11.4.
Immunogenicity Analyses
The incidence of antibodies to CNTO 2476 will be summarized for all subjects who receive a 
dose of CNTO 2476 and have appropriate samples for detection of antibodies to CNTO 2476
(ie, subjects with at least 1 sample obtained after their first dose of CNTO 2476).
11.5.
Safety Analyses
Safety analyses will be performed for all subjects who receive treatment in the open-label Safety
Run-in phase.
Adverse Events
The verbatim terms used in the CRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs with onset from the 
surgery start date and onwards (ie, treatment-emergent AEs, and AEs that have worsened since 
baseline) will be included in the analysis.
The number and percentage of subjects who experienced at least 1 treatment-emergent serious 
ocular AE will be presented in summary tables by treatment group and preferred term according 
to MedDRA terminology as well as by affected eyes (events occurring in the treated eye only, in 
the fellow eye only, and in both eyes). 
Ocular TEAEs will be summarized by treatment group and preferred term according to 
MedDRA terminology, as well as by affected eyes (events occurring in the treated eye only, in 
the fellow eye only, and in both eyes). 
The number and percentage of subjects who experienced at least 1 treatment-emergent SAE will 
be presented in summary tables by treatment group and preferred term, as well as by preferred 
term within system-organ class according to MedDRA terminology. 
The number and percentage of subjects who experienced at least 1 TEAE will be presented in 
summary tables by treatment group and preferred term, as well as by preferred term within 
system-organ class according to MedDRA terminology. 
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The following lists of individual subject data will also be provided: 

list of subjects with SAEs;

list of subjects with ocular AEs;

list of subjects who died while on study (after administration of CNTO 2476 cells);

list of subjects who discontinued the study due to an AE;

list of subjects with TEAEs of severe intensity;

list of subjects with TEAEs related to eye surgery, surgical delivery system, protocol-related 
procedure or CNTO 2476 cells;

list of subjects with treatment-emergent infections.

list of all AEs for subjects who have the surgical procedure but do not receive CNTO 2476 
cells.
Surgical Evaluation
Data regarding the Delivery System and surgical procedure will be tabulated by treatment group.
A listing of all data pertaining to the Delivery System and surgical procedure, as well as any 
surgical deviations will be provided.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges will be used in 
the summary of laboratory data. Frequency tabulations of the laboratory results will be presented 
in pre- versus posttreatment cross-tabulations (with classes for below, within, and above normal 
ranges) by treatment group. Frequency tabulations of the abnormalities by treatment group will 
also be made. A listing of subjects with any laboratory results outside the reference ranges will 
be provided.
Descriptive statistics will be calculated for each laboratory analyte at baseline and for observed 
values and changes from baseline at each scheduled time point by treatment group.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, and blood pressure 
(systolic and diastolic) values and changes from baseline will be summarized at each scheduled 
time point by treatment group. The percentage of subjects with values outside standard reference 
ranges will be summarized by treatment group. A listing of subjects with any vital signs results 
outside the standard reference ranges will be provided.
11.6.
Data and Safety Monitoring Board
A DSMB will be established to monitor data on an ongoing basis to ensure the continuing safety 
of the subjects enrolled in this study. The DSMB will consist of at least 1 medical expert in the 
relevant therapeutic area, and at least 1 statistician. The committee will meet periodically to 
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review interim data. After the review, the DSMB will make recommendations regarding the 
continuation of the study.
The first formal safety review will take place when 1 month safety follow-up data are available 
for the 21 subjects in the initial Safety Cohort. In addition, the DSMB charter will specify rules 
for interrupting the study enrollment in the event of device- or procedure-related safety events 
prior to the completion of the Safety Cohort. Events of special interest are choroidal hemorrhage, 
endophthalmitis or infections, retinal detachments, leakage of cells into the vitreous/need for 
vitrectomy, significant loss of vision defined as ≥15 letters lost compared to baseline (first month
post-surgery only), and failure to deliver cells/device failure.
Since no additional subjects are to be enrolled under this amendment, there will be no further 
DSMB meetings and DSMB will be disbanded; Janssen retains the option to reform the DSMB 
should the need arise.
The DSMB’s responsibilities, authorities, and procedures, will be documented in a separate 
charter.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product (definition per the International 
Conference on Harmonisation [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects AEs starting with the signing of the ICF (refer to Section 12.3.1, All 
Adverse Events, for time of last AE recording).
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Serious Adverse Event
An SAE based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for 
Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent 1 of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between CNTO 2476, the delivery system, or the device and the event, the event 
must be reported as a serious and unexpected suspected adverse reaction even if it is a 
component of the study endpoint.
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For CNTO 2476, the expectedness of an AE will be 
determined by whether or not it is listed in the Investigator's Brochure.
Adverse Event Associated With the Use of the Drug
An AE is considered associated with the use of the drug if the attribution is possible, probable, or 
very likely by the definitions listed in Section 12.1.2.
The surgical procedure and delivery of CNTO 2476 result in a small retinal detachment per 
procedure guidelines. This in itself should not be listed as an adverse event.
12.1.2.
Attribution Definitions
Not Related
An AE that is not related to the use of CNTO 2476, or the Delivery System.
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Doubtful
An AE for which an alternative explanation is more likely, eg, concomitant drug(s), concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of CNTO 2476, or the Delivery System. An alternative 
explanation, eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in 
time is reasonable; therefore, the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of CNTO 2476, or the Delivery System. The relationship in 
time is suggestive. An alternative explanation is less likely, eg, concomitant drug(s), concomitant 
disease(s).
Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, concomitant drug(s), concomitant disease(s). The relationship in time 
is very suggestive.
12.1.3.
Severity Criteria 
An assessment of severity grade will be made using the following general categorical 
descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (eg, laboratory abnormalities).
12.2.
Special Reporting Situations
Safety events of interest for CNTO 2476 that may require expedited reporting and/or safety 
evaluation include, but are not limited to: 

Overdose 

Inadvertent or accidental exposure 

Medication error (with or without subject exposure to CNTO 2476, eg, name confusion)
Special reporting situations should be recorded in the CRF. Any special reporting situation that 
meets the criteria of a SAE should be recorded on the SAE page of the CRF. 
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12.3.
Procedures
12.3.1.
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from 
the time a signed and dated ICF is obtained until completion of the subject's last study-related 
procedure (which may include contact for follow-up of safety). Serious AEs, including those 
spontaneously reported to the investigator within 30 days after the last dose of CNTO 2476, must 
be reported using the Serious Adverse Event Form. The sponsor will evaluate any safety 
information that is spontaneously reported by an investigator beyond the time frame specified in 
the protocol.
All events that meet the definition of an SAE will be reported as SAEs, regardless of whether 
they are protocol-specific assessments. Anticipated events will be recorded and reported as 
described in Attachment 1.
All AEs, regardless of seriousness, severity, or presumed relationship to treatment, must be 
recorded using medical terminology in the source document and the eCRF. Whenever possible, 
diagnoses should be given when signs and symptoms are due to a common etiology (eg, cough, 
runny nose, sneezing, sore throat, and head congestion should be reported as "upper respiratory 
infection"). Investigators must record in the eCRF their opinion concerning the relationship of 
the AE to study therapy. All measures required for AE management must be recorded in the 
source document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all suspected unexpected serious adverse reactions (SUSARS). The investigator 
(or sponsor where required) must report SUSARS to the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless otherwise 
required and documented by the IEC/IRB.
For all studies with an outpatient phase, including Open-label studies, the subject must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the subject is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical staff only)

Site number

Subject number

Any other information that is required to do an emergency breaking of the mask.
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12.3.2.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study-site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form, which must be completed and signed by a physician from the study site, and transmitted to 
the sponsor within 24 hours. The initial and follow-up reports of an SAE should be made by 
facsimile (fax).
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject's participation in the study, must be followed until any of the 
following occurs:

The event resolves

The event stabilizes

The event returns to baseline, if a baseline value/status is available

The event can be attributed to agents other than the treatment or to factors unrelated to study 
conduct

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts)
Suspected transmission of an infectious agent by the treatment will be reported as an SAE. Any 
event requiring hospitalization (or prolongation of hospitalization) that occurs during the course 
of a subject's participation in a study must be reported as a SAE, except hospitalizations for the 
following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility)

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.
The cause of death of a subject in a study within 30 days of the last dose of CNTO 2476, whether 
or not the event is expected or associated with CNTO 2476, is considered an SAE.
12.4.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed on the Contact Information 
page(s), which will be provided as a separate document.
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13.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product/device defect related 
to manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product/device, including its labeling or package integrity. A PQC 
may have an impact on the safety and efficacy of the product/device. Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the protection of 
subjects, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. The 
sponsor has established procedures in conformity with regulatory requirements worldwide to 
ensure appropriate reporting of PQC information; all studies conducted by the sponsor or its 
affiliates will be conducted in accordance with those procedures.
The provisions for a PQC apply to the CNTO 2476 product, as well as the Delivery System.
13.1.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after 
being made aware of the event.
If the defect is combined with a SAE, the study-site personnel must report the PQC to the 
sponsor according to the SAE reporting timelines (refer to Section 12.3.2, Serious Adverse 
Events). A sample of the suspected product should be maintained for further investigation if 
requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
TREATMENT INFORMATION
14.1.
Physical Description of CNTO 2476
CNTO 2476 is an allogeneic somatic cell therapy medicinal product derived from the isolation 
and ex vivo expansion of hUTC. It is a cryopreserved cell suspension that is thawed immediately 
(within 2 hours) prior to administration to patients and ready for administration after thaw.
14.2.
Packaging
CNTO 2476 supplied for this study is manufactured and provided under the responsibility of the 
sponsor. CNTO 2476 cryopreserved drug product (CDP) is a cell suspension formulated in 
chemically defined freezing medium containing CryoStor™-SCO 4B (custom formulation) and 
Balanced Salt Solution® (BSS) Sterile Irrigating Solution. CNTO 2476 is filled in Crystal 
Zenith® resin vials and stored at < −120ºC. Each single-use vial contains 330 μL of cell 
suspension of which 50 μL will be administered. The overfill is required to transfer and fill the 
Delivery System. The cells will be administered in the subretinal space of the eye using the
Delivery System.
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Each vial is enclosed in a paperboard carton with appropriate labeling on the carton.
14.3.
Labeling
Treatment labels will contain information to meet the applicable regulatory requirements.
14.4.
Preparation, Handling and Storage
Each site will be provided with an Investigational Product Manual with detailed instructions for 
proper preparation, handling and storage of CNTO 2476.
CNTO 2476 must be stored at controlled temperatures ranging from −321°F to −184°F (−196°C to 
−120°C). CNTO 2476 is shipped to the clinical site in a liquid nitrogen vapor-phase shipper that is 
also used for short-term storage up to 7 calendar days after shipment. The distribution is on a just-
in-time basis for each treatment in the trial. The shipment for a subject will be triggered when 
enrolled or randomized through the IWRS.
At the time of surgery, CNTO 2476 will be thawed in a controlled manner per the instructions in 
the Investigational Product Manual.
14.5.
Investigational Product and Device Accountability
The investigator is responsible for ensuring that all CNTO 2476, Delivery System devices
received at the site are inventoried and accounted for throughout the study, per the requirements 
in the Investigational Product Manual. All CNTO 2476 will be stored and disposed of according 
to the sponsor's instructions, per the Investigational Product Manual. Study-site personnel must 
not combine contents of the CNTO 2476 containers.
15.
STUDY-SPECIFIC MATERIALS
The following will be provided to the investigator/clinical site as reference materials:

Investigator Brochure

Ophthalmic Examination Manuals

Investigational Product Manual

Study Manual

Laboratory Manual

PRO questionnaires (NEI-VFQ-25, SF-36, and FRI)

IWRS Manual

eDC Manual

Sample ICF
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16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
Age-related macular degeneration is a debilitating and common cause of blindness in persons over 
60 years of age. For GA, the severe dry form of AMD, there is no approved therapy. Preliminary 
clinical data suggests that CNTO 2476 may improve visual acuity in patients with GA.
The primary risk is related to the novel delivery procedure and subretinal access kit; there may also 
be risk associated with the cell therapy. For this reason, the study is designed with an open-label 
Safety Run-in Phase and Safety Cohort to ensure safety of the surgical procedure prior to the 
randomized portion of the study; an independent DSMB will provide oversight through the first 
12 months of the study. Extensive training for proper use of the subretinal access kit will be 
provided to all surgeons, and all procedures will be monitored by representatives of the sponsor.
In addition to adherence to Good Clinical Practices (GCPs), the study will also follow Good Tissue 
Practices (GTPs) to maximize and manage the safety of injected human cells. Subjects will be 
asked to be followed for up to 36 months to assess the long-term safety outcomes of the cell 
therapy.
Potential subjects will be fully informed of the risks and requirements of the study and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they 
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and 
potential AEs of the study, and provide their consent voluntarily will be enrolled. Consent will be 
provided in a format that is accessible to subjects with severe visual impairment.
The total blood volume to be collected is approximately 107.4 mL, and is considered to be within 
the normal range allowed for this subject population over the time period (3 years) proposed for 
this study, and is within the range of Red Cross blood donations.
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on GCP, GTP, and applicable regulatory and country-specific 
requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human subjects. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
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16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments

Sponsor-approved ICF (and any other written materials to be provided to the subjects)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable

Investigator's curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB)

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects

Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the ICF, applicable recruiting materials, and 
subject compensation programs, and the sponsor has received a copy of this approval. This 
approval letter must be dated and must clearly identify the IEC/IRB and the documents being 
approved.
Approval for the collection of optional samples for research and for the corresponding ICF must 
be obtained from the IEC/IRB. Approval for the protocol can be obtained independent of this 
optional research component. 
During the study the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct)

Revision(s) to ICF and any other written materials to be provided to subjects

If applicable, new or revised subject recruiting materials approved by the sponsor

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable

New edition(s) of the Investigator's Brochure and amendments/addenda

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually)

Reports of AEs that are serious, unlisted/unexpected, and associated with the treatment
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
New information that may adversely affect the safety of the subjects or the conduct of the 
study

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects

Report of deaths of subjects under the investigator's care

Notification if a new investigator is responsible for the study at the site

Development Safety Update Report and Line Listings, where applicable

Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study. The 
reapproval should be documented in writing (excluding the ones that are purely administrative, 
with no consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion.
16.2.3.
Informed Consent
Each subject must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any 
study-related activity. The ICF(s) that is/are used must be approved by both the sponsor and by 
the reviewing IEC/IRB and be in a language that the subject can read and understand. The 
informed consent should be in accordance with principles that originated in the Declaration of 
Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and sponsor 
policy.
Before enrollment in the study, the investigator or an authorized member of the study-site 
personnel must explain to potential subjects the aims, methods, reasonably anticipated benefits, 
and potential hazards of the study, and any discomfort participation in the study may entail. 
Subjects will be informed that their participation is voluntary and that they may withdraw 
consent to participate at any time. They will be informed that choosing not to participate will not 
affect the care the subject will receive. Finally, they will be told that the investigator will 
maintain a subject identification register for the purposes of long-term follow-up if needed and 
that their records may be accessed by health authorities and authorized sponsor personnel
without violating the confidentiality of the subject, to the extent permitted by the applicable 
law(s) or regulations. By signing the ICF the subject is authorizing such access, including 
permission to obtain information about his or her survival status, and agrees to allow his or her 
study physician to recontact the subject for the purpose of obtaining consent for additional safety 
evaluations, if needed, and subsequent disease-related treatments, or to obtain information about 
his or her survival status.
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The subject will be given sufficient time to read the ICF and the opportunity to ask questions. 
After this explanation and before entry into the study, consent should be appropriately recorded 
by means of the subject's personally dated signature. After having obtained the consent, a copy of 
the ICF must be given to the subject.
Subjects will be asked for consent to provide optional samples for research where local 
regulations permit. After informed consent for the study is appropriately obtained, the subject 
will be asked to sign and personally date a separate ICF indicating agreement to participate in the 
optional research component. Refusal to participate in the optional research will not result in 
ineligibility for the study. A copy of this signed ICF will be given to the subject.
If the subject is unable to read or write, an impartial witness should be present for the entire 
informed consent process (which includes reading and explaining all written information) and 
should personally date and sign the ICF after the oral consent of the subject is obtained.
All study sites will be asked by the sponsor to obtain informed consent using a validated 
electronic system instead of a paper-based process. If both parties (sponsor and the study site) 
agree, and if participation is allowed by local regulations and IEC/IRB requirements, the means 
to facilitate such a process will be provided to the sites by sponsor. The actual mechanism of 
consenting will be facilitated by the use of an eTablet device (eg, iPad®), but overall the consent 
process will remain the same, as described in this section. At these study sites, subjects will still 
be required to review the entire informed consent as a written document on the eTablet and then 
to apply their handwritten signature electronically by the use of a stylus directly onto the eTablet. 
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original 
medical records (source data/documents) for study-related monitoring, audit, IEC/IRB review, 
and regulatory inspection. This consent also addresses the transfer of the data to other entities 
and to other countries.
The subject has the right to request through the investigator access to his or her personal data and 
the right to request rectification of any data that are not correct or complete. Reasonable steps 
will be taken to respond to such a request, taking into consideration the nature of the request, the 
conditions of the study, and the applicable laws and regulations.
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Status: Approved, Date: 15 December 2017
Exploratory DNA and immunogenicity research is not conducted under standards appropriate for 
the return of data to subjects. In addition, the sponsor cannot make decisions as to the 
significance of any findings resulting from exploratory research. Therefore, exploratory research 
data will not be returned to subjects or investigators, unless required by law or local regulations. 
Privacy and confidentiality of data generated in the future on stored samples will be protected by 
the same standards applicable to all other clinical data.
16.2.5.
Long-Term Retention of Samples for Additional Future Research 
Samples collected in this study may be stored for up to 15 years (or according to local 
regulations) for additional research. Samples will only be used to understand CNTO 2476, to 
understand visual acuity impairment associated with GA secondary to AMD, to understand 
differential responders, and to develop tests/assays related to CNTO 2476 and visual acuity 
impairment associated with GA secondary to AMD. The research may begin at any time during 
the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be 
stored for research.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment 
by the sponsor. All protocol amendments must be issued by the sponsor, and signed and dated by 
the investigator. Protocol amendments must not be implemented without prior IEC/IRB 
approval, or when the relevant competent authority has raised any grounds for non-acceptance, 
except when necessary to eliminate immediate hazards to the subjects, in which case the 
amendment must be promptly submitted to the IEC/IRB and relevant competent authority. 
Documentation of amendment approval by the investigator and IEC/IRB must be provided to the 
sponsor. When the change(s) involves only logistic or administrative aspects of the study, the 
IRB (and IEC where required) only needs to be notified.
During the course of the study, in situations where a departure from the protocol is unavoidable, 
the investigator or other physician in attendance will contact the appropriate sponsor 
representative (see Contact Information page[s] provided separately). Except in emergency 
situations, this contact should be made before implementing any departure from the protocol. In 
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and 
agree on an appropriate course of action. The data recorded in the CRF and source documents 
will reflect any departure from the protocol, and the source documents will describe this 
departure and the circumstances requiring it.
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17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of CNTO 2476 and 
Delivery System to the study site:

Protocol and amendment(s), if any, signed and dated by the principal investigator

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study-site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable

Documentation of investigator qualifications (eg, curriculum vitae)

Completed investigator financial disclosure form from the principal investigator, where 
required

Signed and dated clinical trial agreement, which includes the financial agreement

Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators

Documentation of subinvestigator qualifications (eg, curriculum vitae)

Name and address of any local laboratory conducting tests for the study, and a dated copy of 
current laboratory normal ranges for these tests, if applicable

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(eg, accreditation/license), if applicable
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17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study-site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data 
collected in the CRF: subject identification, eligibility, and study identification; study discussion 
and date of signed informed consent; dates of visits; results of safety and efficacy parameters as 
required by the protocol; record of all AEs and follow-up of AEs; concomitant medication; 
CNTO 2476 and devise receipt/dispensing/return records; treatment administration information; 
and date of study completion and reason for early discontinuation of study drug or withdrawal 
from the study, if applicable. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study will be reviewed with the investigator 
before the study and will be described in the monitoring guidelines (or other equivalent 
document).
The following data will be recorded directly into the CRF and will be considered source data:

Demographics

History of smoking

Blood pressure and pulse/heart rate

Height and weight

Details of physical examination

Patient Reported Outcomes
The minimum source documentation requirements for Section 4.1, Inclusion Criteria and 
Section 4.2, Exclusion Criteria that specify a need for documented medical history are as 
follows:
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
Referral letter from treating physician or

Complete history of medical notes at the site

Discharge summaries
Inclusion and exclusion criteria not requiring documented medical history must be verified at a 
minimum by subject interview or other protocol required assessment (eg, physical examination, 
laboratory assessment) and documented in the source documents.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in an electronic format. 
Electronic Data Capture (eDC) will be used for this study. The study data will be transcribed by 
study-site personnel from the source documents onto an electronic eCRF, and transmitted in a 
secure manner to the sponsor within the timeframe agreed upon between the sponsor and the 
study site. The electronic file will be considered to be the eCRF.
Worksheets and intraoperative videos may be used for the capture of some data to facilitate 
completion of the eCRF (ie, data collection during cell delivery procedure). Any such worksheets 
and videos will become part of the subject's source documentation. All data relating to the study 
must be recorded in CRFs prepared by the sponsor. Data must be entered into CRFs in English.
Study site personnel must complete the CRF as soon as possible after a subject visit, and the 
forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (eg, PRO questionnaires) will be completed by the same individual 
who made the initial baseline determinations whenever possible. The investigator must verify
that all data entries in the CRFs are accurate and correct.
All CRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. If necessary, queries will be generated in the eDC tool.
If corrections to a CRF are needed after the initial entry into the CRF, this can be done in 
3 different ways:

Study site personnel can make corrections in the eDC tool at their own initiative or as a 
response to an auto query (generated by the eDC tool).

Study site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct 
transmission of clinical laboratory data from a central laboratory and all outside vendors into the 
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study database into the sponsor's data base. Written instructions will be provided for collection, 
handling, storage, and shipment of samples.
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRFs for accuracy and completeness during 
on-site monitoring visits and after transmission to the sponsor; any discrepancies will be resolved 
with the investigator or designee, as appropriate. After upload of the data into the study database 
they will be verified for accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRFs 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 
retained for a longer period if required by the applicable regulatory requirements or by an 
agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address of the 
new custodian. Under no circumstance shall the investigator relocate or dispose of any study 
documents before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such 
reports.
17.8.
Monitoring
The sponsor/designee will perform on-site monitoring visits as frequently as necessary. The 
monitor will record dates of the visits in a study site visit log that will be kept at the study site.
The first post-initiation visit will be made as soon as possible after enrollment has begun. At 
these visits, the monitor will compare the data entered into the eCRFs with the hospital or clinic 
records (source documents). The nature and location of all source documents will be identified to 
ensure that all sources of original data required to complete the eCRF are known to the sponsor 
and study-site personnel and are accessible for verification by the sponsor study-site contact. If 
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electronic records are maintained at the study site, the method of verification must be discussed 
with the study-site personnel.
Direct access to source documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents will be discussed with the study-site personnel. 
The sponsor expects that, during monitoring visits, the relevant study-site personnel will be 
available, the source documentation will be accessible, and a suitable environment will be 
provided for review of study-related documents. The monitor will meet with the investigator on a 
regular basis during the study to provide feedback on the study conduct.
The sponsor will conduct on-site monitoring and support on Day 1 of the study, and throughout 
the surgical procedure. Representatives from the sponsor company, Janssen and/or its designees 
may be present at the clinical facility, in the operating room during surgery or observing 
remotely. This is to ensure oversight of aspects of the surgical procedure and protocol.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed with the last study assessment for the last subject 
participating in the study. The final data from the study site will be sent to the sponsor (or 
designee) after completion of the final subject assessment at that study site, in the time frame 
specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. Study sites will be closed upon study completion. A
study site is considered closed when all required documents and study supplies have been 
collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further treatment development
17.10. On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
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with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection and comparison with the CRFs. Subject 
privacy must, however, be respected. The investigator and study-site personnel are responsible 
for being present and available for consultation during routinely scheduled study-site audit visits 
conducted by the sponsor or its designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding CNTO 2476 or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including pharmacogenomic or exploratory research data, 
generated as a result of this study, are considered confidential and remain the sole property of the 
sponsor. The investigator agrees to maintain this information in confidence and use this 
information only to accomplish this study, and will not use it for other purposes without the 
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of CNTO 2476, and thus may be 
disclosed as required to other clinical investigators or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the sponsor with all data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain CRF data from all study sites that participated in the study, and direct transmission 
of clinical laboratory data from a central laboratory into the sponsor's database. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator. Results of pharmacogenomic or 
exploratory analyses performed after the Clinical Study Report has been issued will be reported 
in a separate report and will not require a revision of the Clinical Study Report. Study subject 
identifiers will not be used in publication of results. Any work created in connection with 
performance of the study and contained in the data that can benefit from copyright protection 
(except any publication by the investigator as provided for below) shall be the property of the 
sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
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arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 12 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the Uniform Requirements for Manuscripts Submitted to 
Biomedical Journals, which state that the named authors must have made a significant 
contribution to the design of the study or analysis and interpretation of the data, provided critical 
review of the paper, and given final approval of the final version.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or disclose the existence of and the results of clinical studies as 
required by law.
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REFERENCES
1.
Allikmets R, Singh N, Sun H, et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is 
mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997;15:236-246. 
2.
Cuenca N, Pinilla I, Sauve Y, Lund R. Early changes in synaptic connectivity following progressive 
photoreceptor degeneration in RCS rats. Eur J Neurosci. 2005;22:1057-1072. 
3.
de Jong PT. Age-related macular degeneration. N Engl J Med. 2006;355:1474-1485. 
4.
Fujihara M, Nagai N, Sussan TE, Biswal S, Handa JT. Chronic cigarette smoke causes oxidative damage and 
apoptosis to retinal pigmented epithelial cells in mice. PLoS ONE. 2008;3:e3119. 
5.
Gal A, Li Y, Thompson DA, et al. Mutations in MERTK, the human orthologue of the RCS rat retinal 
dystrophy gene, cause retinitis pigmentosa. Nat Genet. 2000;26:270-271. 
6.
Glotin AL, Debacq-Chainiaux F, Brossas JY, Faussat AM, Treton J, Zubielewicz A, et al. Prematurely 
senescent ARPE-19 cells display features of age-related macular degeneration. Free Radic Biol Med. 
2008;44:1348-1361. 
7.
Investigator’s Brochure: CNTO 2476, Edition 9, 2013
8.
Johnson PT, Brown MN, Pulliam BC, Anderson DH, Johnson LV. Synaptic pathology, altered gene 
expression, and degeneration in photoreceptors impacted by drusen. Invest Ophthalmol Vis Sci. 
2005;46:4788-4795. 
9.
Liang FQ, Godley BF. Oxidative stress-induced mitochondrial DNA damage in human retinal pigment 
epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration. Exp Eye Res. 
2003;76:397–403. 
10.
Lindblad AS, Clemons TE. Responsiveness of the National Eye Institute Visual Function Questionnaire to 
progression to advanced age-related macular degeneration, vision loss, and lens opacity: AREDS Report no. 
14. Arch Ophthalmol. 2005;123:1207-1214. 
11.
Liu J, Itagaki Y, Ben-Shabat S, Nakanishi K, Sparrow JR. The biosynthesis of A2E, a fluorophore of aging 
retina, involves the formation of the precursor, A2-PE, in the photoreceptor outer segment membrane. J Biol 
Chem. 2000:275;29354–29360. 
12.
Nowak JZ. Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacol Rep. 
2006;58:353-363. 
13.
Strauss O. The retinal pigment epithelium in visual function. Physiol Rev. 2005;85:845-881. 
14.
Strauss O, Stumpff F, Mergler S, Wienrich M, Wiederholt M. The Royal College of Surgeons rat: an animal 
model for inherited retinal degeneration with a still unknown genetic defect. Acta Anat (Basel).
1998;162:101-111. 
15.
Sullivan RK, Woldemussie E, Pow DV. Dendritic and synaptic plasticity of neurons in the human age-related 
macular degeneration retina. Invest Ophthalmol Vis Sci. 2007 Jun;48:2782-2791. 
16.
The Eye Diseases Prevalence Research Group. Prevalence of Age-Related Macular Degeneration in the United 
States. Arch Ophthalmol. 2004;122:564-572. 
17.
Virzi RA. Refining the test phase of usability evaluation; how many subjects is enough? Human Factors. 
1992;34:457-468. 
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Attachment 1: Anticipated Events
Anticipated Event
An anticipated event is an adverse event (serious or non-serious) that commonly occurs as a consequence 
of the underlying disease or condition under investigation (disease related) or background regimen.
For the purposes of this study the following events will be considered anticipated events: 

Fatal and non-fatal myocardial infarction

Angina pectoris

Fatal and non-fatal stroke

Transient ischemic attack

Chronic obstructive pulmonary disease (COPD), COPD exacerbation and chronic bronchitis
Reporting of Anticipated Events
These events will be captured on the CRF and in the database, and will be reported to the sponsor as 
described in Section 12.3.1, All adverse events. Any event that meets serious adverse event criteria will 
be reported to the sponsor within the appropriate timeline as described in Section 12.3.2, Serious 
Adverse Events. These anticipated events are exempt from expedited reporting as individual single cases 
to Health Authorities. However, if based on an aggregate review, it is determined that an anticipated event 
is possibly related to study drug, the sponsor will report these events in an expedited manner.
Anticipated Event Review Committee (ARC)
An Anticipated Event Review Committee (ARC) will be established to perform reviews of pre-specified 
anticipated events at an aggregate level. The ARC is a safety committee within the sponsor’s organization 
that is independent of the sponsor’s study team. The ARC will meet to aid in the recommendation to the 
sponsor’s study team as to whether there is a reasonable possibility that an anticipated event is related to 
the study drug.
Statistical Analysis
Details of statistical analysis of anticipated events, including the frequency of review and threshold to 
trigger an aggregate analysis of anticipated events will be provided in a separate Anticipated Events 
Safety Monitoring Plan (ASMP).
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INVESTIGATOR AGREEMENT
NCT02659098

SAP_001.pdf: 
1
Approved, Date: 22 January 2019
Janssen Research & Development *
Statistical Analysis Plan
A Phase 2b, Multicenter, Double-masked, Randomized Study Evaluating the Safety and 
Clinical Response of Subretinal Administration of CNTO 2476 in Subjects with Visual 
Acuity Impairment Associated with Geographic Atrophy Secondary to Age Related 
Macular Degeneration
Protocol CNTO2476MDG2002; Phase 2b
Palucorcel  (CNTO 2476)
Status:
Approved
Date:
22 January 2019
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-ERI-118270351
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
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Palucorcel  (CNTO 2476)
Statistical Analysis Plan CNTO2476MDG2002
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Approved, Date: 22 January 2019
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 3
ABBREVIATIONS ........................................................................................................................................ 3
1.
INTRODUCTION.................................................................................................................................. 4
1.1.
Trial Objectives ................................................................................................................................ 4
1.2.
Trial Design ...................................................................................................................................... 4
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 5
1.4.
Sample Size Justification ................................................................................................................. 5
1.5.
Randomization and Masking............................................................................................................ 5
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 5
2.1.
Study Day......................................................................................................................................... 6
2.2.
Baseline ........................................................................................................................................... 6
2.3.
Visit Windows................................................................................................................................... 6
2.4.
Pooling Algorithm for Analysis Centers............................................................................................ 6
2.5.
Analysis Sets.................................................................................................................................... 6
2.6.
Definition of Subgroups.................................................................................................................... 7
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW......................................... 7
4.
SUBJECT INFORMATION.................................................................................................................. 7
4.1.
Demographics and Baseline Characteristics ................................................................................... 7
4.2.
Medical History................................................................................................................................. 7
4.3.
Disposition Information..................................................................................................................... 8
4.4.
Treatment Compliance..................................................................................................................... 8
4.5.
Extent of Exposure........................................................................................................................... 8
4.6.
Protocol Deviations .......................................................................................................................... 8
4.7.
Prior and Concomitant Medications ................................................................................................. 8
5.
SAFETY............................................................................................................................................... 9
5.1.
Ocular AEs ....................................................................................................................................... 9
5.2.
All AEs.............................................................................................................................................. 9
5.3.
Events of Special Interest ................................................................................................................ 9
5.4.
Surgery and Delivery System ........................................................................................................ 10
5.5.
Clinical Laboratory Tests................................................................................................................ 11
5.6.
Vital Signs ...................................................................................................................................... 11
6.
EFFICACY ......................................................................................................................................... 12
6.1.
BCVA.............................................................................................................................................. 12
6.2.
Imaging Results ............................................................................................................................. 12
6.3.
Low Luminance BCVA ................................................................................................................... 13
6.4.
Contrast Sensitivity ........................................................................................................................ 13
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 13
8.
IMMUNOGENICITY ........................................................................................................................... 14
9.
HEALTH ECONOMICS AND HEALTH OUTCOMES....................................................................... 14
REFERENCES............................................................................................................................................ 15
ATTACHMENTS......................................................................................................................................... 16
1.
DATA HANDLING RULES FOR MISSING OR PARTIAL DATES .................................................. 16
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AMENDMENT HISTORY
ABBREVIATIONS
AE
adverse event
AMD
age-related macular degeneration
BCVA
best corrected visual acuity
BMI
body mass index
CGIC
Clinician Global Impression of Change
CI
confidence interval
CMH
Cochran Mantel Haenszel
CRO
Contract Research Organization
CSR
Clinical Study Report
CST
central subfield thickness
DA
disc area
DARC
Digital Angiography Reading Center
DSMB
Data Safety Monitoring Board
eCRF
electronic case report form
eDC
electronic data capture
ETDRS
Early Treatment Diabetic Retinopathy Study
FAF
fundus autofluorescence
FDA
Food and Drug Administration
FRI
Functional Reading Index questionnaire
GA
geographic atrophy
ICH
International Conference on Harmonization
IP
investigational product
ITT
Intent-to-Treat
IWRS
interactive web response system
LLBCVA
low luminance BCVA
LLD
low luminance difference
LLT
lowest level term
logMAR
log of the minimum angle of resolution
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified Intent-to-Treat
NEI-VFQ-25
National Eye Institute Visual Function Questionnaire
OCT
optical coherence tomography
PGIC-Q
Patient Clinician Global Impression of Change – Quality of Life
PGIC-S
Patient Clinician Global Impression of Change – Symptoms
PI
principal investigator
RS
reading speed
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SD-OCT
Spectral-Domain Optical Coherence Tomography
SF-36
Short Form (36) Health Survey
SOC
System Organ Class
SSG
statistical support group
TE
treatment-emergent
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Approved, Date: 22 January 2019
1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, general analysis 
definitions and statistical methods for analyses planned for the final clinical study report. 
1.1.
Trial Objectives
Primary Objectives
The primary objective of the Open-label Safety Run-in Phase is to evaluate the safety and 
performance profile of the suprachoroidal surgical approach and the Delivery System. 
Major Secondary Objectives
The major secondary objectives of this study are the following: 

to assess the safety and performance profile of the Delivery System, the safety and 
tolerability of the suprachoroidal surgical approach, and the safety and tolerability of CNTO 
2476 cells in the open-label Safety Run-in Phase

to assess the effects of CNTO 2476 on anatomic correlates of treatment, including change in 
the area of geographic atrophy (GA)

to assess the effects of CNTO 2476 on additional and alternative efficacy outcomes 
including duration of clinical response.
1.2.
Trial Design
This is a multicenter Phase 2b study. A target of approximately 21 subjects will be enrolled in 
this study. Protocol amendment 3 represents a significant reduction in scope and duration of the 
study based on the sponsor’s decision to discontinue the Palucorcel development program.
The study includes only an initial open-label safety phase. 
The target population will be subjects at least 55 years of age and no older than 90 years with a 
confirmed diagnosis of bilateral GA of the macula secondary to age-related macular 
degeneration (AMD), with associated vision loss, confirmed within 45 days prior to initial 
randomization/enrollment by the central reading center using fundus and/or autofluorescence
photography. In subjects with neovascular AMD in 1 eye, the eye with GA must be the worse 
eye. In subjects with bilateral GA and the vision between both eyes is not clinically equal, the 
eye with the worse vision will be treated in order to minimize risk to the subject’s vision. In 
cases where the best corrected visual acuity (BCVA) of the 2 eyes is clinically equal, the eye 
with more extensive GA as demonstrated on the imaging studies will become the study eye. 
The Safety Run-in Phase consists of approximately 21 subjects (the first 3 subjects at each of 
approximately 8 sites) who will first be enrolled in an open-label assessment of the safety profile
of the procedure and the Delivery System. The first 3 subjects at the first 8 sites (approximately 
21 subjects in total) will be the initial Safety Cohort. A minimum of seven different surgeons are 
required to ensure most of the possible failure modes will be identified. Enrollment will be 
actively managed to ensure that experience and learning from earlier procedures are promptly 
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Approved, Date: 22 January 2019
transferred to the subsequent procedures, and to ensure that an appropriate number of subjects 
are enrolled at the time of the planned safety assessments.  
The safety profile of the procedure and the Delivery System will be assessed after the first 
21 subjects (the initial Safety Cohort) have been treated with a single dose of 3.0 x 105 cells in 50 
µL dosing volume and followed for a minimum period of 1 month. An external Data and Safety 
Monitoring Board (DSMB) will be commissioned for this study. The 2nd Safety Cohort and the 
randomized double-masked portion of this study were eliminated from the study as of Protocol
Amendment 3.
The study will consist of a 12-month acute phase, followed by a 2-year maximum duration 
follow-up period (3 years total) for all subjects.
The DSMB will monitor study data on an ongoing basis to ensure the continuing safety of the 
subjects enrolled in this study. The committee will meet periodically to review interim study 
data. After the review, the DSMB will make recommendations regarding the safety and 
continuation of the study. 
1.3.
Statistical Hypotheses for Trial Objectives
The primary hypothesis of the open label safety phase of this study is that the novel subretinal 
Delivery System is sufficiently safe and usable to deliver cells to the subretinal space. An 
additional hypothesis is that Palucorcel is safe and well tolerated when delivered as a single dose 
to the subretinal space.
1.4.
Sample Size Justification
The sample size of 21 subjects is based on the number of subjects require to allow for an 
adequate clinical assessment of the safety and usability of the novel Delivery System.
1.5.
Randomization and Masking
Not applicable, because the study only enrolled the initial open-label safety cohort. 
2.
GENERAL ANALYSIS DEFINITIONS
Analyses will be conducted using SAS Version 9.2 or higher1. Continuous variables, including 
numerical variables assessed on a discrete scale, will be analyzed using descriptive statistics, 
including number of subjects, mean, median, standard deviation, maximum, and minimum. 
Minimum and maximum will be reported using the same decimal precision as the corresponding 
raw data, mean and median will be reported using one more decimal digit than the raw data. 
Standard deviation will be reported using two more decimal digits than the raw data. For 
categorical variables, analyses will include counts of subjects and percentages. The treated eye is 
the eye designated for treatment. The fellow eye is the other eye. Where applicable, results will 
be summarized by “Treated Eye” or “Fellow Eye” or “Both Eyes”, not left or right eye.
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2.1.
Study Day
Study Day will be computed relative to the Surgery Date, where the Surgery Date is Day 1. 
Study Day will be defined as follows:
-
(Key Date – Surgery Date + 1), if Key Date is equal or greater than the Surgery Date;
-
(Key Date – Surgery Date), if Key Date is prior to Surgery Date;
where Key Date can be a date of assessment, onset of an adverse event, or start of concomitant 
medication. 
2.2.
Baseline
For all assessments except for BCVA measurements (i.e., logMAR and total letters correct, both 
standard and low luminance), baseline will be defined as the most recent value prior to the 
Surgery Date (and time, if applicable).  Thus the baseline could be derived based on Screening or 
Day 1 pre-op assessments or unscheduled pre-op assessments where applicable. 
Baseline BCVA is assessed at an optional pre-screening visit (not recorded on the electronic case 
report form [eCRF] thus not used for analysis) and at the regular Screening visit (twice at that 
visit).  For BCVA logMAR and total letters correct (both standard and low luminance), the better 
score at these 2 assessments will be used for baseline. For BCVA logMAR, a lower score is 
better.  For total letters correct, a higher value is better.
Re-screening is allowed per protocol and the subject is not necessarily required to repeat every 
test during the 2nd screening. When a subject is re-screened, he/she receives a new subject ID. If 
a baseline value is not present for the current subject ID for this type of subject, it will be 
necessary to use the screening/baseline value captured in the 1st screening visit for that subject 
(captured using their previous subject ID) as the baseline value.
2.3.
Visit Windows
All “by-visit” analyses will be presented by scheduled study visit as recorded on the eCRF; no 
visit windows will be used. Unscheduled assessments will be presented in by-subject data 
listings.
2.4.
Pooling Algorithm for Analysis Centers
Not applicable.  Data from all investigative sites (centers) will be combined together for analysis 
irrespective of the site in which the subject undergoes evaluations.
2.5.
Analysis Sets
The initial Safety Cohort is defined as the first 21 subjects enrolled in the Open-label Safety 
Run-in Phase of the study who received surgery.  Results will be presented as treatment group 
“CNTO 2476 3.0x105 cells”.
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2.6.
Definition of Subgroups
Not applicable.
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
A DSMB will be established to monitor data on an ongoing basis to ensure the continuing safety 
of the subjects enrolled in this study. The DSMB will consist of at least 1 medical expert in the 
relevant therapeutic area, and at least 1 statistician. The committee will meet periodically to 
review interim data. After the review, the DSMB will make recommendations regarding the 
continuation of the study.
The first formal safety data review will take place when 1-month safety follow-up data are 
available for the 21 subjects in the initial Safety Cohort. In addition, the DSMB charter will 
specify rules for interrupting the study enrollment in the event of device- or procedure-related 
safety events prior to the completion of the initial Safety Cohort. Events of special interest are 
choroidal hemorrhage, endophthalmitis or infections, retinal detachments, leakage of cells into 
the vitreous/need for vitrectomy, significant loss of vision defined as ≥15 letters lost compared to 
baseline (at the Week 4 post-surgery follow-up visit only), and failure to deliver cells/device 
failure. 
Since no additional subjects are to be enrolled as of Protocol Amendment 3, there will be no 
further DSMB meetings and DSMB will be disbanded. Janssen retains the option to reform the 
DSMB should the need arise.
The DSMB’s responsibilities, authorities, and procedures, will be documented in a separate 
charter.
The statistical analyses planned for the DSMB are provided in a separate DSMB SAP. 
4.
SUBJECT INFORMATION
4.1.
Demographics and Baseline Characteristics
The following characteristics will be summarized: age (both as a continuous variable and with 
frequency counts for the following age groups: <65, ≥65 to <75, ≥75 years), sex, race, ethnicity, 
baseline weight, baseline height, baseline body mass index (BMI), tobacco substance usage; and 
the following baseline characteristics for both the treated and fellow eye: axial length, BCVA 
logMAR score, BCVA total letters correct, optical coherence tomography (OCT) central subfield 
thickness (CST) in microns (μ), total area of GA by fundus autofluorescence (FAF) in mm2, and 
square root of total area of GA by FAF in mm. 
Demographics and baseline characteristics for individual subjects will be presented in a data 
listing.
4.2.
Medical History
General Medical History and Ocular Medical History will be summarized. The number and 
percentage of subjects with abnormalities recorded in the general medical history will be 
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tabulated by system organ class (SOC) and preferred term (PT).  The number and percentage of 
subjects with ophthalmic disorders recorded in ocular medical history (which includes both past 
and ongoing) will be tabulated by SOC, PT and eye (treated, fellow, or both).
General Medical History and Ocular Medical History for individual subjects will be presented in 
data listings.
4.3.
Disposition Information
The number of subjects will be tabulated for the following disposition categories: received open-
label surgery, completed 6 months of follow-up, discontinued prior to month 6, completed 12 
months of follow-up, discontinued prior to month 12, completed total study follow-up, and 
discontinued after month 12 prior to end of study. Reasons for discontinuation will also be 
tabulated for subjects who discontinue prior to month 6, prior to month 12 or prior to end of 
study.
Subject disposition information for individual subjects will be presented in a data listing.
4.4.
Treatment Compliance
Not applicable for this study as the investigational product will be administered subretinally as a 
single dose by the retinal surgeon. The administration of the investigational product will take 
place in an operating room using the Delivery System. Compliance will not require any activity 
by the subject.
4.5.
Extent of Exposure
The number of subjects who received cells (investigational product [IP] was delivered to the 
subretinal space) will be tabulated as part of the Summary of Surgery and Delivery System.  
4.6.
Protocol Deviations
All Major Protocol Deviations will be documented in the study database. 
The number of subjects with major protocol deviations during the study will be summarized by 
category. Subjects with more than one deviation will be counted in all applicable categories.
Major protocol deviations for individual subjects will be presented in a data listing.
4.7.
Prior and Concomitant Medications
Prior and concomitant medications will be coded using the WHO Drug dictionary. Medication 
stopped prior to the Surgery Date will be considered as prior. Medications that are not considered 
prior, i.e., taken on or after the Surgery Date, will be considered concomitant medications. 
Missing or incomplete medications’ start and end dates will be handled as described in 
Attachment 1 in order to determine whether the medications are concomitant or not. 
Prior and concomitant ocular medications will be tabulated by medication class and standardized 
medication name. Prior and concomitant non-ocular medications will be tabulated separately. A 
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subject taking the same prior/concomitant medication multiple times will only be counted once 
for that prior/concomitant medication.
Prior and concomitant ocular and non-ocular medications for individual subjects will be 
presented in a data listing.
5.
SAFETY
The verbatim terms used in the eCRF by investigators to identify adverse events (AEs) will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). All reported AEs with 
onset from the surgery start date and onwards (i.e., treatment-emergent (TE) AEs, and AEs that 
have worsened since baseline) will be included in the analysis. Note that after Month 12, only 
serious AEs and ocular AEs are collected as per protocol. Missing or incomplete AE onset dates 
will be handled as described in Attachment 1.
5.1.
Ocular AEs
Ocular TE AEs include those with system organ class (SOC) = “Eye Disorders” or those with 
eye specified on the eCRF. The number and percentage of subjects who experienced at least 1 
ocular TE AE will be presented in summary tables by preferred term according to MedDRA 
terminology as well as by affected eyes (events occurring in the treated eye only, in the fellow 
eye only, and in both eyes).  
Serious ocular TE AEs will be summarized similarly.
Ocular TE AEs will be summarized by severity, and by relationship indicated on the eCRF 
(study treatment, device, and surgical procedure).
Ocular TE AEs will also be summarized by timing: for those with onset on or before the Week 4 
visit date, and those with onset after the Week 4 visit date.
Individual subject ocular AEs will be presented in a data listing.
5.2.
All AEs
The number and percentage of subjects who experienced at least 1 TE AE will be presented in 
summary tables by SOC and preferred term according to MedDRA terminology.
Serious TE AEs will be summarized and presented in a data listing. 
Individual subject non-ocular AEs will be presented in a data listing.
5.3.
Events of Special Interest
The events of special interest and how they are defined as per data captured in the clinical 
database are listed below. 

Retinal Detachment: A TE AE in the treated eye with preferred term “Retinal 
detachment” or a lowest level term (LLT) of “Rhegmatogenous retinal detachment”, 
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“Central serous retinal detachment”, “Haemorrhagic detachment of retinal pigment 
epithelium”, “Detachment of macular retinal pigment epithelium”, “Haemorrhagic 
detachment of retinal pigment epithelium” or “Vitreoretinal detachment”.

Significant choroidal hemorrhage: A TE AE in the treated eye with preferred term 
“Choroidal haemorrhage” or “Retinal haemorrhage” or LLT of  “Choroidal bleeding”, 
“Choroidal haemorrhage and rupture”, “Expulsive choroidal haemorrhage”, 
“Haemorrhagic choroidal detachment”, “Retinal bleeding”, “Bleeding intraretinal”, 
“Retinal dot and blot haemorrhages”, “Retinal blot haemorrhages”, “Retinal haemorrhage 
spotted”, “Subretinal haemorrhage”, “Preretinal haemorrhage”, or “Retinal nerve fiber 
layer hemorrhage”. For these terms, the severity must be greater than mild (must be 
indicated as moderate or severe).

Leakage of cells or need for vitrectomy: A “Yes” response to the Surgery and Delivery 
Device Details eCRF item “Was any IP visible in the vitreous after delivery?” on either 
surgery attempt (either the 1st or the 2nd attempt) or the text “vitrectomy” present in the 
Procedures eCRF item “Therapeutic or Diagnostic Procedures” with a start date/time on 
or after the date of surgery.  

Failure to deliver cells: A “No” response to the Surgery and Delivery Device Details 
eCRF item “Was the IP delivered to the target delivery location?” or a Surgical Deviation 
of “Dose of IP not fully administered”. The response must be on the last surgery attempt 
for the subject (i.e., if there was a 2nd surgery attempt, the response must be on the 2nd
attempt for that subject).

Endophthalmitis: A TE AE in the treated eye with preferred term “Endophthalmitis” or 
LLT of “Acute endophthalmitis”, “Chronic endophthalmitis”, “Sterile endophthalmitis”, 
“Aseptic endophthalmitis”. “Infectious endophthalmitis”, “Purulent endophthalmitis” or 
“Mycotic endophthalmitis”.    

Significant loss of vision: defined as a decrease of ≥ 15 BCVA letters from baseline in 
the treated eye at the Week 4 visit.  Unscheduled BCVA assessments after surgery prior 
to the Week 4 visit and assessments after Week 4 will not be considered here.  
The Events of Special Interest will be summarized for the Safety Cohort. For each event, the 
count and percentage of subjects who had the event and the Exact Binomial 95% CI will be 
presented. Individual subject events will be presented in a data listing.
5.4.
Surgery and Delivery System
The Surgery and Delivery System details captured on the eCRFs will be summarized. Individual 
subject data will be presented in a data listing.
Data from the 1st and 2nd (if applicable) surgical attempt will be summarized separately.
The count and percentage of subjects with surgical deviations will be presented, and individual 
subjects will be presented in a data listing.
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5.5.
Clinical Laboratory Tests
Clinical laboratory data will be summarized by type of lab test. Descriptive statistics will be 
presented for each laboratory test at baseline and at each scheduled follow-up time point, and for 
the change from baseline.
Frequency tabulations of subjects with TE abnormal clinical laboratory results will be presented 
for each test for each scheduled follow-up time point. TE abnormal low results are defined as 
those below the laboratory normal range where baseline was not below the normal range low 
value. TE abnormal high results are those defined as those above the laboratory normal range 
where baseline was not above the normal range high value. An overall tabulation will also be 
presented for subjects with at least 1 occurrence of a TE abnormal result at any follow-up time 
point for that test. A listing of subjects’ laboratory results (all results at scheduled and 
unscheduled time points) will be provided, with flags for TE abnormal results.
5.6.
Vital Signs
Descriptive statistics of temperature, pulse/heart rate, respiratory rate, and blood pressure 
(systolic and diastolic) values and changes from baseline will be summarized at each scheduled 
time point. 
Frequency tabulations of subjects with TE abnormal vital signs results will be presented for each 
test for each follow-up time point. TE abnormal low results are defined as those below the 
reference range value where baseline was not below the reference range low value. TE abnormal 
high results are defined as those above the reference range where baseline was not above the 
reference range high value. An overall tabulation will also be presented for subjects with at least 
1 occurrence of a TE abnormal result at any follow-up time point for that test. A listing of 
subjects’ vital signs results (all results at scheduled and unscheduled follow-up time points) will 
be provided, with flags for values outside the reference ranges.
Table 5: Vital Signs Reference Ranges
Test
Reference 
Range 
Low
Reference 
Range 
High
Temperature (C)
36
38
Pulse (beats/min)
50
120
Systolic Blood Pressure (mm HG)
90
180
Diastolic Blood Pressure (mm HG)
50
105
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6.
EFFICACY
6.1.
BCVA
The primary efficacy measure will be the BCVA testing performed after refraction and under 
standardized photopic lighting conditions and distance using an ETDRS logMAR chart.
If the BCVA assessment was done, but total letters correct is missing because neither the 4m nor 
the 1m assessments could be done, (i.e., only highest degree of vision was done), the BCVA total 
letters correct will be assigned a value of 0 and BCVA logMAR score will be assigned a value of 
1.7 (using the formula logMAR = 1.7 – [0.02 x total letters correct]). 
Descriptive statistics will be presented for BCVA (letters and logMAR) at baseline and at each 
scheduled follow-up time point, and for the change from baseline, for the treated and fellow eye.
The count and percentage of BCVA responders at each follow-up time point (responder=yes for 
subjects who have BCVA change from baseline >=15 letters) will be summarized for the treated 
and fellow eye.
BCVA data for individual subjects will be presented in a data listing.
6.2.
Imaging Results
Certain parameters obtained from OCT assessments will be evaluated by 2 or 3 image readers 
interpreting the same image. For such parameters, two readers provide their assessments initially. 
If their assessments do not agree to a certain degree, a third reader provides an additional 
evaluation. For the purposes of statistical summaries, in the case of numerical measurements, a 
median value across the readers will be used. In the case of categorical parameters, a category 
provided by majority (two readers) will be used.
OCT measurements may be obtained post-surgery on study day 1 and/or on follow-up study day 
2 to assist in surgery training purposes. These data will not be included in statistical summaries 
or analyses but will be included in any subject data listings provided.
Descriptive statistics will be presented for OCT CST, total area of GA by FAF in mm2, and 
square root of total area of GA by FAF in mm, at baseline and at each scheduled follow-up time 
point and for the change from baseline, for the treated and fellow eye.
The yearly rate of change in GA area at an assessment is calculated as the change from baseline 
in the square root of total area of GA by FAF in mm, divided by the number of days of follow-up 
for that assessment, multiplied by 365. The number of days of follow-up for a given assessment 
time point is calculated as that visit date – surgery date + 1. This measurement will be 
summarized using descriptive statistics at the 3- , 6- and 12-month follow-up time points for the 
treated eye, and at the 3- and 12-month follow-up time points for the fellow eye.  Note for the 
fellow eye, scans are only read by the central reader for a subset of time points. 
Imaging data for individual subjects will be presented in a data listing.
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The microperimetry and specialized OCT image analysis data will be examined by expert 
specialty laboratory reviewers. Analysis of microperimetry data is beyond the scope of this 
document and no statistical tables are planned for this effort.
6.3.
Low Luminance BCVA
Low Luminance BCVA (LLBCVA) indicates the best possible vision that an eye can achieve 
with the use of trial frames/lenses following refraction and visual assessment under low 
luminance conditions. 
If the LLBCVA assessment was done, but total letters correct is missing because neither the 4m 
nor the 1m assessments could be done, (i.e., only highest degree of vision was done), the total 
letters correct will be assigned a value of 0 and logMAR will be assigned a value of 1.7 (using 
the formula logMAR = 1.7 – [0.02 x total letters correct]).   
Low Luminance Difference (LLD) is defined as the difference between standard photopic BCVA 
total letters correct and LLBCVA total letters correct. 
The results for LLBCVA (letters and logMAR) and LLD (letters) at baseline and at each follow-
up time point, and for the change from baseline, will be summarized with descriptive statistics 
for the treated eye and fellow eye.
LLBCVA data for individual subjects will be presented in a data listing.
6.4.
Contrast Sensitivity
The Pelli-Robson test measures contrast sensitivity using a single large letter size with contrast 
varying across groups of letters. The chart uses letters (6 per line), arranged in groups whose 
contrast varies from high to low. Subjects read the letters, starting with the highest contrast level 
(log contrast level 0.00), until they are unable to read two or three letters in a single group. Each 
group has three letters of the same contrast level. The number of letters read correctly at each log 
contrast level is recorded on the eCRF. The subject is assigned a threshold score based on the log 
contrast of the last group in which two or three letters were correctly read. A threshold score of 
2.0 indicates normal contrast sensitivity of 100 percent. Scores of less than 2.0 signify poorer 
contrast sensitivity. A score of less than 1.5 is consistent with visual impairment and a score of 
less than 1.0 represents visual disability. 
Descriptive statistics will be presented for contrast sensitivity threshold scores at baseline and
each scheduled follow-up time point and for the change from baseline for the treated eye and 
fellow eye.
Contrast sensitivity data for individual subjects will be presented in a data listing.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
Not applicable.
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8.
IMMUNOGENICITY
Immunogenicity data including the sample ADA (anti-drug antibodies) status and mean result 
FACS (fluorescence activated cell sorting) screen for individual subjects will be presented in a 
data listing.
9.
HEALTH ECONOMICS AND HEALTH OUTCOMES
Not applicable. Since PROs and questionnaire results (NEI-VFQ-25, SF-36, and Near Vision 
Subscale, FRI, PGIC-S, PGIC-Q, CGIC) are not included as study objectives as of Protocol 
Amendment 3, these data will not be summarized in tables or listings for the CSR.
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REFERENCES
1.
SAS Institute Inc. Version 9.2, Cary, NC.
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ATTACHMENTS
1.
DATA HANDLING RULES FOR MISSING OR PARTIAL DATES
Onset/Start Date
If only the day part of the event onset/start date is missing and occurs in the same month and 
year as the Surgery Date, then the Surgery Date will be used as the onset/start date of the event.
Otherwise, if only the day part of the event onset date is missing, the first day of the month will 
be used to complete the onset/start date of the event.
If only the day and the month parts of the event onset/start date are missing and the event occurs 
in the same year as the Surgery Date, then the Surgery Date will be used as the onset/start date of 
the event. Otherwise, if only the day and the month parts of the event onset/start date are 
missing, January 1st will be used to complete the onset/start date of the event.
If the event onset/start date is equal to the Surgery Date, but the clock time is missing, then the 
event will be considered treatment emergent; i.e., as if onset/start time was during or after 
surgery.
If the time of onset of an event is missing, no imputation will be made.
Stop Date
If only the day part of the event stop date is missing, the last day of the month will be used to 
complete the stop date of the event.
If only the day and the month parts of the event stop date are missing, December 31st will be 
used.
If the stop date is completely missing and the ongoing status is also missing, the event will be 
considered as ongoing.
Any medication which is ongoing will be considered concomitant.
The imputed onset and stop dates will be verified to ensure that the onset date is prior or equal to 
the stop date.
The imputed dates will be used to determine the treatment-emergent status of the AE or the 
concomitant/prior status of medications, and to calculate study day and/or duration as needed.
medications, and to calculate study day and/or duration as needed.
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