Phase I/II Randomized, Prospective, Double-masked, Sham-controlled Study of Intravitreal Autologous Bone Marrow CD34+ Stem Cell Therapy for Central Retinal Vein Occlusion
Phase: PHASE1
Conditions: Central Retinal Vein Occlusion
Sponsor: The Emmes Company, LLC

PROTOCOL 
Treatment of Central Retinal Vein 
Occlusion Using STem Cells Study 
(TRUST) 
(Phase I/II Randomized, Prospective, Double-masked, Sham-
controlled Study of Intravitreal Autologous Bone Marrow 
CD34+ Stem Cell Therapy for Central Retinal Vein Occlusion) 
IND#: 17023 
Study Chair/Principal Investigator: 
Susanna S. Park, MD, PhD 
Study Funder:  
 
 
 
National Eye Institute (NEI) 
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Enrollment Center:  
 
 
Department of Ophthalmology & Vision Science 
 
 
 
 
 
 
University of California Davis Eye Center 
 
 
 
 
 
 
Sacramento, CA  95817 
Data Coordinating Center (DCC):  
Emmes 
 
 
 
 
 
 
401 N. Washington St, Suite 700 
 
 
 
 
 
 
Rockville, MD  20850 
Study Leadership 
Study Chair/Principal Investigator: 
 
Susanna S. Park, MD, PhD 
DCC Principal Investigator:  
 
Jennifer McCormack, MS 
NEI Program Officer:  
 
 
Maryann Redford, DDS, MPH 
Co-investigators/Contributors 
Jan A. Nolta, PhD 
Director of Stem Cell Program, Division of Hematology & Oncology 
University of California Davis Medical Center 
Mehrdad Abedi, MD 
Division of Hematology & Oncology 
University of California Davis Cancer Center 
Rasmus Hoeg, MD 
Division of Hematology & Oncology 
University of California Davis Cancer Center 
Gerhard Bauer, BS 
Laboratory Director of Good Manufacturing Lab 
University of California Davis Medical Center 
Ala Moshiri, MD, PhD 
Department of Ophthalmology & Vision Science 
University of California Davis Eye Center 
Glenn Yiu, MD, PhD 
Department of Ophthalmology & Vision Science 
University of California Davis Eye Center 
Kareem Moussa, MD 
Department of Ophthalmology & Vision Science 
University of California Davis Eye Center 
 

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TABLE OF CONTENTS 
1.0 
LIST OF ABBREVIATIONS ............................................................................................ 1 
2.0 
STUDY SCHEMA ............................................................................................................ 3 
3.0 
STUDY SYNOPSIS ......................................................................................................... 4 
4.0 
BACKGROUND & SIGNIFICANCE ................................................................................ 6 
5.0 
OBJECTIVES.................................................................................................................10 
5.1 
Primary Objective........................................................................................................10 
5.2 
Secondary Objective ...................................................................................................10 
5.3 
Exploratory Objectives ................................................................................................10 
6.0 
STUDY DESIGN ............................................................................................................11 
6.1 
Description of Study ....................................................................................................11 
6.1.1 
Study Organization and Administration ................................................................11 
6.1.2 
Study Masking Considerations .............................................................................13 
6.1.3 
Study Participant Demographics and Recruitment ...............................................14 
6.1.4 
Study Retention Strategies and Timeline .............................................................15 
6.1.5 
Study Procedures and Visit Schedule ..................................................................17 
6.1.6 
Study and Data Monitoring ...................................................................................25 
6.2 
Rationale for Study Design .........................................................................................26 
6.3 
Outcome Measures .....................................................................................................27 
6.3.1 
Primary Safety and Feasibility Outcome Measures ..............................................27 
6.3.2 
Secondary Outcome Measures ............................................................................27 
6.3.3 
Exploratory Outcome Measures ...........................................................................29 
6.4 
Safety Plan .................................................................................................................29 
6.5 
Compliance with Laws and Regulations ......................................................................32 
7.0 
MATERIALS AND METHODS .......................................................................................33 
7.1 
Participants .................................................................................................................33 
7.1.1 
Participant Selection ............................................................................................33 
7.1.2 
Inclusion/Exclusion Criteria ..................................................................................33 
7.2 
Method of Treatment Assignment ...............................................................................35 
7.3 
Study Treatment .........................................................................................................35 
7.4 
Concomitant and Excluded Therapies.........................................................................36 
7.5 
Study Assessments and Monitoring of Study Progress ...............................................36 
7.6 
Participant Discontinuation/Replacement ....................................................................36 

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7.7 
Study Discontinuation .................................................................................................37 
7.8 
Statistical Methods ......................................................................................................37 
7.8.1 
General Design ....................................................................................................37 
7.8.2 
Analysis of Primary and Secondary Outcomes ....................................................38 
7.8.3 
Sample Size Considerations ................................................................................39 
7.9 
Data Quality Assurance ..............................................................................................40 
8.0 
ASSESSMENT OF SAFETY ..........................................................................................41 
8.1 
Definitions ...................................................................................................................41 
8.2 
Pregnancy ..................................................................................................................42 
8.3 
Vision Threatening Adverse Events ............................................................................42 
8.4 
Causality .....................................................................................................................42 
8.5 
Naming and Grading of Adverse Events .....................................................................43 
8.6 
Adverse Event Reporting ............................................................................................43 
8.7 
Regulatory Reporting ..................................................................................................43 
9.0 
REFERENCES ...............................................................................................................44 
APPENDIX A: ETHNIC DISTRIBUTION OF PATIENTS SEEN AT THE UNIVERSITY OF 
CALIFORNIA DAVIS EYE CENTER EYE CLINIC BETWEEN 11/1/12 TO 10/31/13 BASED ON 
PATIENTS’ RESPONSE ..........................................................................................................46 
APPENDIX B: DETERMINING CHILDBEARING POTENTIAL ................................................47 
 
LISTING OF TABLES 
TABLE 1: Enrollment Center Personnel − Masking for Randomized Treatment Assignment .....14 
TABLE 2: Study Visit Schedule .................................................................................................19 
TABLE 3: Secondary Efficacy Outcome Measures ...................................................................28 
LISTING OF FIGURES 
FIGURE 1: Long-term incorporation of human CD34+ stem cells in retinal vasculature after 
intravitreal injection. ................................................................................................................... 7 
FIGURE 2: Fundus changes following intravitreal injection of autologous CD34+ stem cells in an 
eye with central retinal vascular occlusion.. ................................................................................ 7 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AF 
Autofluorescence 
AMD 
Age-related Macular Degeneration 
AREDS 
Age-Related Eye Disease Study 
BCVA 
Best Corrected Visual Acuity 
CBC 
Complete Blood Count 
CF 
Counting Fingers 
CNVM 
Choroidal Neovascular Membrane 
CRVO 
Central Retinal Vein Occlusion 
DCC 
Data Coordinating Center 
DSMC 
Data and Safety Monitoring Committee 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EC 
Enrollment Center 
ERG 
Electroretinography 
ERM 
Epiretinal Membrane 
FA 
Fluorescein Angiography 
FDA 
Food and Drug Administration 
FP 
Fundus Photography 
FSH 
Follicle-stimulating Hormone 
GCP 
Good Clinical Practices 
GMP 
Good Manufacturing Practice 
IND 
Investigational New Drug 
IOP 
Intraocular Pressure 
NEI 
National Eye Institute 
MM 
Medical Monitor 
MOP 
Manual of Procedures 
OCT 
Optical Coherence Tomography 
OCTA 
Optical Coherence Tomography Angiography 
PI 
Principal Investigator 
ROS 
Review of Systems 
RPE 
Retinal Pigment Epithelium 
RVO 
Retinal Vein Occlusion 

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Abbreviation 
Definition 
SAE 
Serious Adverse Event 
TRUST 
Treatment of Central Retinal Vein Occlusion Using Stem Cells Study 
UC 
University of California 
VEGF 
Vascular Endothelial Growth Factor 
VEGFR-2 
VEGF receptor-2 
VFQ 
Visual Functioning Questionnaire 
 

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2.0 
STUDY SCHEMA 
 
 
 
 

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3.0 
STUDY SYNOPSIS 
The goal of this phase I/II prospective, randomized, sham-controlled, double-masked clinical trial 
is to determine whether intravitreal autologous CD34+ stem cell therapy is safe, feasible and 
potentially beneficial in eyes with vision loss from central retinal vein occlusion (CRVO). Retinal 
Vein Occlusion (RVO) is a leading retinal vascular cause of vision loss in the elderly. CD34+ stem 
cells in human bone marrow are mobilized into the circulation in response to tissue ischemia for 
tissue revascularization and repair. Since local delivery of CD34+ stem cells benefits ischemic 
tissue, intravitreal delivery of CD34+ stem cells may benefit vision and retinal ischemia in eyes 
with RVO. A pilot clinical trial has shown no major safety or feasibility concerns using intravitreal 
autologous CD34+ bone marrow stem cells. In this proposed expanded phase I/II study, 
approximately 20 participants (20 eyes) with persistent vision loss from CRVO will be enrolled 
and followed for 1 year. Only eyes with CRVO will be enrolled to maintain uniformity in the study 
population. Total study duration will be approximately 60 months. This single-center study will be 
conducted at the University of California Davis (Enrollment Center). The Data Coordinating Center 
will be Emmes. The Study Chair/Principal Investigator will be Dr. Susanna Park. The study will be 
conducted under an IND cleared from the FDA. A Data and Safety Monitoring Committee (DSMC) 
will oversee the study. Participants will be randomized 1:1 to immediate cell therapy/deferred 
sham therapy or immediate sham therapy/deferred cell therapy, where deferred therapy refers to 
the therapy administered at month 6 and immediate therapy refers to therapy administered at 
baseline (either sham or cellular). At month 6, the (immediate) cell treated eye will receive sham 
treatment and the (immediate) sham treated eye will receive cellular therapy. The cell therapy 
involves a bone marrow aspiration, isolation of CD34+ cells from the aspirate under Good 
Manufacturing Practice (GMP) conditions, and intravitreal injection of the isolated CD34+ cells. 
The sham therapy involves a sham bone marrow aspiration with penetration of the skin but with 
no penetration of the bone and a sham injection without penetrating the eye. The participant, 
examining ophthalmologist, visual acuity examiner, photographers and OCT, perimetry, and ERG 
technicians will remain masked to study treatment assignment for study duration. A 
comprehensive eye examination with ETDRS best-corrected visual acuity, optical coherence 
tomography (OCT) and OCT angiography (OCTA), autofluorescence, fundus photography, 
fluorescein angiography, microperimetry, and electroretinography will be performed at baseline 
and serially. A subset of participants with good fixation on microperimetry and clear media on 
exam and commercial-grade OCTA and who give consent will have ultra-high resolution cellular 
retinal imaging using research-grade OCT and OCTA and adaptive optics-OCT at baseline. 
These participants with high quality images will have repeat imaging at 1 month after receipt of 
cellular treatment, with at least 2 of the participants randomized to the immediate sham 
therapy/deferred cellular therapy arm also having imaging 1 month after sham therapy. Post-
release flow cytometry characterization will be performed to determine the composition of the 
CD34+ enriched final product in terms of hematopoietic versus angiogenic stem cells based on 
cell surface markers (i.e., CD133(+)/CD45(+)/CD34(+) vs CD31(+)/VEGFR-2(+)/CD45(-) 
/CD34(+)) provided there are an adequate number of cells, as determined by the GMP lab. The 
primary outcome measures for the safety and feasibility of the stem cell therapy will be the 
incidence and severity of ocular and systemic adverse events reported during Study Period 1 (i.e., 
the day of the first treatment (Treatment 1) up to but not including the day of the second treatment 
(Treatment 2)) and the mean and range of number of CD34+ cells isolated and the number 
injected into the eye. The secondary safety outcome measures are the incidence and severity of 
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outcome measures will be the changes in visual function, retinal perfusion and morphology 
following cell therapy. The long-term objective is to determine whether intravitreal autologous 
CD34+ cell therapy can minimize, or reverse vision loss associated with retinal ischemia without 
compromising safety. 
 
 

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4.0 
BACKGROUND & SIGNIFICANCE 
Bone marrow is one of the richest sources of adult stem cells.1-3 These adult stem cells have been 
extensively studied and appear to play an important role in normal tissue repair and maintenance 
in the body.4 Among these cells, CD34+ cells have been used clinically extensively for bone 
marrow transplantation and more recently explored in clinical trials as potential treatment for 
various ischemic conditions.3-10 
Human CD34+ stem cells are often referred to as “hematopoietic stem cells” because they can 
be stimulated to differentiate into blood cells of various lineages. However, the multi-potency of 
the CD34+ cells extends beyond hematologic cell lines and the full regenerative capacity of these 
cells has yet to be explored.1,5,8,11,12 In fact, the exact function of CD34 is not clear although it has 
been implicated to play a role in cell-cell interaction. Since endothelial progenitor cells, for 
instance, also express CD34 on their surface, a CD34+ population from bone marrow will include 
the revascularization population.8,11,12 Since Asahara et al. described in 1997 the potential role of 
circulating CD34+ cells as endothelial precursor cells for tissue regeneration and angiogenesis 
following ischemia, clinical trials have explored the use of local intravenous infusion of autologous 
CD34+ cells from bone marrow as potential therapy for ischemia conditions such as 
cardiomyopathy and shown therapeutic benefit without safety issues.4-9 
Hematopoietic stem cells, including human CD34+ cells, have the capacity to home into injured 
or damaged tissue, including ischemic tissue.13-15 This property makes these cells different from 
embryonic and induced pluripotent stem cells. In animal models of retinal ischemia or retinal 
injury, CD34+ cells have been shown to home into the damaged retinal tissue when administered 
intravitreally.16-18 Transretinal migration of these cells following intravitreal injection has been 
demonstrated in an animal model of retinal laser injury.18 Long-term studies were conducted in 
NOD-SCID mice with acute retinal ischemia-reperfusion injury to determine the long-term effect 
of intravitreal injection of human CD34+ cells. This acute retinal ischemia model can be 
considered an animal model of retinal vein occlusion (RVO). Intravitreal injection of human CD34+ 
cells from bone marrow was well-tolerated long-term and the human cells were detected 
incorporated into the mouse retinal vasculature as long as 6 months following intravitreal injection 
with apparent normalization of the retinal vasculature and retinal morphology (Figure 1).17 No 
long-term ocular or systemic safety issues were noted. 
The regenerative effect of CD34+/hematopoietic stem cells from bone marrow extend beyond 
vascular repair. Intravitreal injection of autologous lineage-negative murine hematopoietic stem 
cells from bone marrow has been shown to slow down hereditary retinal degeneration in mice.15 
Since these cells were identified in the retinal vasculature and not the outer retina, a paracrine 
trophic regenerative effect on the photoreceptor was speculated. Our group has shown that 
intravitreal injection of human CD34+ cells from bone marrow in murine eyes with hereditary 
retinal degeneration and systemic immunosuppression results in rapid homing and integration of 
the human cells to the retinal surface layer.19 Alterations in expression of over 300 genes in the 
murine retina were noted on microarray analysis. Pathways affected included those controlling 
apoptosis, photoreceptor maintenance and transduction. Again, the findings support a paracrine 
effect of intravitreal CD34+ cells on degenerating outer retina. 

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Based on these encouraging preclinical observations, two separate small clinical trials were 
conducted in Germany and Brazil exploring the use of intravitreal autologous bone marrow 
mononuclear cells as potential therapy for various ischemic or degenerative retinal conditions.20,21 
The mononuclear cell fraction of the bone marrow aspirate consists of a crude cellular mixture 
which contains mostly lymphocytes and monocytes and a low concentration of CD34+ cells 
(< 0.2%).22 In both studies, intravitreal injection of these mononuclear cells was well tolerated and 
without adverse effects but minimal improvement in visual function was observed in treated eyes. 
 
 
 
 
FIGURE 1: Long-term incorporation of 
human CD34+ stem cells in retinal 
vasculature after intravitreal injection. 
Immunohistochemical staining of the 
retinal vasculature of NOD-SCID mice 6 
months after intravitreal administration of 
human CD34+ cells isolated from bone 
marrow in an eye with acute ischemia-
reperfusion injury. The human cells 
(green) are identified incorporated into 
the mouse retinal vasculature which 
appears to have normalized.17 
FIGURE 2: Fundus changes following intravitreal injection of autologous 
CD34+ stem cells in an eye with central retinal vascular occlusion. Fundus 
photography of an eye with persistent vision loss from a combined central 
retinal vein and artery occlusion 9 months earlier (left). Improvement in vision 
and fundus exam noted 3 months after intravitreal injection of autologous bone 
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By selecting out the CD34+ cells from bone marrow mononuclear cell fraction of the bone marrow 
aspirate, a higher concentration of these effector cells can be administered locally, potentially 
enhancing the therapeutic effect.4-9 The study investigators have initiated a phase 1 study 
exploring the safety and feasibility of intravitreal injection of autologous CD34+ cells from bone 
marrow as potential treatment for ischemic or degenerative retinal conditions. This is based on 
an IND cleared by the Food and Drug Administration (FDA) and cross-referenced for the current 
IND (i.e., IND #13307). A total of 9 participants have enrolled in this study. The results of the first 
six participants who enrolled and completed the study have been published.23 No ocular or 
systemic safety issues were noted in any enrolled participants during the six-month follow-up of 
the study and during the extended two-year follow-up as part of standard of care.23 No feasibility 
issues were noted. The bone marrow aspiration was well tolerated under local anesthesia and a 
desired number of CD34+ cells could be obtained for intravitreal injection from a single bone 
marrow aspirate in each participant. Among the first six study eyes, the eye with retinal ischemia 
from a combined central retinal vein and artery occlusion appeared to have the most dramatic 
improvement in vision and fundus findings following intravitreal cell therapy (Figure 2).23 Some 
improvement in the retinal microvascular abnormalities on fluorescein angiography and fundus 
photography could be observed within three months following the study treatment. 
The rationale for using intravitreal autologous CD34+ cells from bone marrow for retinal 
regeneration following ischemic injury from RVO are the following: (1) there is a large unmet need 
given incidence of RVO. Retina vein occlusion is a leading vascular cause of vision loss in the 
elderly, second only to diabetic retinopathy. The incidence of RVO is 1 to 2% in 10 to 15 years 
among the population older than 40 years of age.24-26 Approximately 16 million persons are 
afflicted with the condition worldwide.26 The incidence of RVO increases with age and affects all 
ethnic and racial groups. The vision loss associated with RVO partially may be attributed to 
macular edema which can be treated with intravitreal drug therapy or laser photocoagulation.27-29 
However, even with resolution of macular edema, vision loss persists from macular ischemia and 
associated retinal degeneration. In fact, RVO is one of the leading causes of unilateral blindness 
in the elderly population.24 In this study, only patients with CRVO will be enrolled for uniformity. 
(2) CD34+ cells include endothelial progenitor cells (EPCs) that play an important role in tissue 
and vascular repair from ischemia.4 As such, clinical trials have been conducted showing efficacy 
of local administration of CD34+ cells isolated from bone marrow in ischemic conditions such as 
cardiomyopathy.4-9 (3) Preclinical studies show that human CD34+ cells from bone marrow have 
ability to home and integrate into the damaged retinal vasculature long term following intravitreal 
administration without abnormal cellular proliferation or other adverse effects.16,17 Since CD34+ 
cells can have both paracrine trophic effects and direct engraftment into the damaged retinal 
vasculature following intravitreal injection, these CD34+ cells can have regenerative effects on 
the retina and retinal vasculature via multiple mechanisms and at multiple levels.17,22 (4) A pilot 
phase 1 clinical study conducted by investigators showed no major safety or feasibility issues 
associated with this cell therapy.23 (5) Among the retinal conditions treated with this cell therapy 
in the pilot clinical trial, the participant with CRVO had the most dramatic functional and anatomic 
improvement following this cell therapy.23 (6) Since RVO is typically acute and non-progressive, 
it is an ideal retinal ischemic model to study the regenerative potential of cell therapy in an early 
clinical trial.30 Regenerative effects of cell therapy may be observed more readily in a non-
progressive condition like RVO when compared to the chronic progressive condition such as 
diabetic retinopathy. The retinal vascular changes associated with RVO are clinically evident on 

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examination and on fluorescein angiography, unlike retinal vascular disorders such as retinal 
artery occlusion. 
In this expanded phase I/II study, approximately 20 participants with persistent vision loss from 
CRVO with or without concurrent retinal artery occlusion will be enrolled and followed for one year 
to obtain safety and feasibility information regarding this stem cell therapy. The study has been 
designed as a randomized, prospective, double-masked sham-controlled study to obtain potential 
efficacy signals and trends. The study outcome will determine whether intravitreal autologous 
CD34+ cell therapy warrants further investigation as potential regenerative therapy for retinal 
disease. 
 

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5.0 
OBJECTIVES 
5.1 Primary Objective 
The primary objective of the study is to assess the safety and feasibility of the stem cell therapy, 
which will be determined by the following outcome measures: 
• 
Primary safety outcome: Incidence and severity of ocular and systemic adverse events 
reported during Study Period 1 (i.e., the day of the first treatment (Treatment 1) up to but 
not including the day of the second treatment (Treatment 2)) 
• 
Feasibility outcome: The mean and range of number of CD34+ cells isolated from the 
bone marrow aspirate and the number injected into the eye 
• 
Secondary safety outcome: Incidence and severity of ocular and systemic adverse events 
reported throughout study duration 
5.2 Secondary Objective 
The secondary objective is to determine the effect of stem cell therapy on retinal function and 
morphology. Secondary efficacy outcomes include changes in best corrected visual acuity 
(BCVA), microperimetry, OCT/OCTA, electroretinography (ERG), fundus photography, 
fluorescein angiogram, autofluorescence, and quality of life. 
5.3 Exploratory Objectives 
Exploratory aims include descriptive analysis of changes in the retina and retinal vasculature at a 
cellular level using adaptive optics-OCT imaging, descriptive and quantitative analysis of changes 
in retinal vascular density and retinal morphology using ultrahigh resolution swept-source OCT 
and OCTA. An additional exploratory aim includes quantitative analysis of the hematopoietic and 
endothelial stem cell subcomponents and subcomponent of cells with VEGFR-2 in the harvested 
CD34+ cell population. A study survey will collect participants’ experiences with various aspects 
of the study, including their impressions on timing of receipt of stem cell injection vs sham 
injection. 
 

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6.0 
STUDY DESIGN 
6.1 Description of Study 
This is a phase I/II randomized, prospective, double-masked, sham-controlled study to determine 
the feasibility, safety and potential efficacy of intravitreal injection of autologous adult CD34+ stem 
cells from bone marrow (herein referred to as cellular therapy) in participants with vision loss from 
CRVO. 
All potential participants diagnosed with CRVO will be screened by the PI or designee for study 
eligibility based on available clinical information. Those whose medical record suggests they may 
be eligible for the study will be asked to attend one or more screening visits at the UC Davis Eye 
Center. Informed consent will be obtained prior to conduct of any study procedures. Participants 
will undergo pre-treatment screening assessment and baseline testing to evaluate the extent of 
the condition and to confirm eligibility for the study. Once the participant is confirmed to be eligible, 
he/she will be randomized 1:1 to immediate cell therapy/deferred sham therapy or immediate 
sham therapy/deferred cell therapy. 
Participants who are randomized to immediate cell therapy/deferred sham therapy will undergo a 
bone marrow aspiration followed by intravitreal injection of isolated CD34+ cells after baseline 
testing. Follow-up assessments will occur at 1 day, 1 week, 1 month, 3 months and 6 months post 
stem cell injection. Within 1 month of the 6-month follow-up study visit, participants will receive a 
sham bone marrow aspiration and sham injection. At least 1 day will separate the 6-month follow-
up study visit and the sham therapy. Participants will continue to be followed at 1 day, 1 week, 1 
month, 3 months and 6 months for a total follow-up of 12 months after the stem cell injection (and 
6 months following the sham injection). For participants who did not complete the study 
satisfaction survey at the 12-month visit, an exit visit may occur following the 12-month visit to 
allow the survey to be completed. 
Participants who are randomized to immediate sham therapy/deferred cell therapy will undergo a 
sham bone marrow aspiration followed by sham injection after baseline testing. Follow-up 
assessments will occur at 1 day, 1 week, 1 month, 3 months and 6 months post sham injection. 
Within 1 month of the 6-month follow-up study visit, participants will undergo a bone marrow 
aspiration followed by intravitreal injection of isolated CD34+ cells. At least 1 day will separate the 
6-month follow-up study visit and the cellular therapy. Follow-up assessments will occur at 1 day, 
1 week, 1 month, 3 months and 6 months thereafter for a total follow-up of 12 months after the 
sham injection (and 6 months following the stem cell injection). For participants who did not 
complete the study satisfaction survey at the 12-month visit, an exit visit may occur following the 
12-month visit to allow the survey to be completed. The Study Schema is provided in Section 2.0. 
6.1.1 Study Organization and Administration 
This is a single-center clinical trial. The study organization consists of the following: 
Study Funder: Under a cooperative agreement mechanism, The National Eye Institute (NEI) 
provides funding for the study. The NEI Program Officer has been in communication with the 
Study Chair/PI from study conception and had invaluable input in study design. In consultation 
with the investigative group, the NEI Program Officer appointed members of the Data and Safety 
Monitoring Committee (DSMC) to oversee the study. 

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Study Chair/Principal Investigator (PI): The Study Chair is also the PI for this single-center study. 
Dr. Susanna Park will function in this role. She conceived of this study and will take the 
administrative leadership for the study to ensure that the study progresses successfully and in a 
timely manner. She designed the study, wrote the Study Protocol and Manual of Procedures in 
conjunction with the Data Coordinating Center (DCC). She has submitted the regulatory 
documents to the FDA and obtained a new IND clearance for the proposed study (i.e., IND # 
17023). She also submitted documents to the local IRB and has obtained study approval. She 
will work with the DCC to submit annual reports and any amendments recommended by the 
DSMC to the regulatory agencies. She will take a leadership role in study recruitment at the 
Enrollment Center (EC) and supervise the Clinical Trials Team at the Enrollment Center to ensure 
that the study is progressing according to the study protocol and in a timely manner. She will be 
responsible for ensuring that all adverse events (AEs) are entered into the study database and 
working in conjunction with the DCC to ensure those AEs meeting reporting requirements are 
indeed reported to the appropriate regulatory bodies in a timely manner. She will represent the 
study at the biannual meeting of the DSMC and take leadership in data analysis and manuscript 
preparation at study closeout. 
Data Coordinating Center (DCC): The Data Coordinating Center (DCC, Emmes) will provide 
clinical trials management support throughout the course of the study, including in the following 
areas: data management; randomization; site activation; protocol monitoring including conduct of 
site initiation, interim and closeout visits; safety oversight; statistical leadership; data analysis and 
DSMC support. The DCC has been working with the Study Chair/PI on the study design and 
preparation of the Study Protocol and Manual of Procedures (MOP). The DCC will conduct a site 
visit before study initiation to verify that the study personnel at the Enrollment Center are 
adequately trained, to evaluate the facility and to ensure all required essential regulatory 
documents are approved. The DCC will work with the Study Chair/PI to finalize the data collection 
forms for the study before study initiation. The DCC will use a web-based electronic data capture 
(EDC) system for data collection and data management and will train the Study Coordinators at 
the Enrollment Center on the use of the EDC system. During the study, the DCC will be in regular 
communication with the Study Chair/PI to give updates on study progress. The DCC will 
continuously monitor safety information provided by the site throughout the course of the study. 
The DCC will organize and coordinate the biannual DSMC meetings and provide interim updates 
on study progress at these meetings. The DCC will conduct interim monitoring site visits 
throughout the course of the study, as well as conduct a study closeout visit. Final data analysis 
will also be the responsibility of the DCC, in collaboration with the Study Chair/PI. 
Data and Safety Monitoring Committee (DSMC): Members of the DSMC are appointed by the NEI 
Program Officer in consultation with the investigative group. Members are selected for their 
relevant medical experience and expertise, knowledge of clinical trial methodology, and absence 
of conflicts of interest. The DSMC will meet prior to study initiation to review and approve the 
study protocol and informed consent. After study initiation, the DSMC will meet approximately 
every six months to review study progress until study closeout. These meetings will be organized 
by the DCC and attended by the NEI Program Officer, Study Chair/PI, DCC PI, Project Manager, 
and statistician, and members of the DSMC. 
Enrollment Center (EC): For this single-center study, the Enrollment Center will be the University 
of California Davis Eye Center. The Study Chair, Dr. Susanna Park, will also be the PI of the 
Enrollment Center. She will be responsible for ensuring that all study personnel, including the 

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Study Coordinators, are knowledgeable about the study protocol and will work with the DCC to 
ensure all are properly trained in study procedures. She will also take the leadership role in 
submitting the regulatory documents to the local IRB and Stem Cell Oversight Committee, and 
the FDA. The UC Davis Eye Center Clinical Trials Team, under the supervision of the PI, will 
perform the baseline and follow-up study evaluations. 
6.1.2 Study Masking Considerations 
Given the nature of the study treatment and the study design in which participants are receiving 
both a stem cell injection and a sham injection, it is recognized that masking may be difficult to 
ensure. Nonetheless, efforts will be made to preserve masking as described below. 
To maintain the masking for the study duration of each participant’s follow-up period, there will be 
separate ophthalmologists designated for administration of study therapy and study visit follow-
up examination after study therapy (TABLE 1). The PI will remain masked as the examining 
ophthalmologist for the study duration. The treating ophthalmologist will be an experienced retinal 
specialist and faculty member of the UC Davis Eye Center. He/she will remain unmasked to 
therapy assignment and perform the eye examinations during the first week of each participant’s 
follow-up after sham or cellular therapy. An experienced retinal specialist from the Enrollment 
Center will be available as a backup unmasked treating ophthalmologist, and a separate 
experienced retinal specialist from the Enrollment Center will be available as a backup masked 
examining ophthalmologist. However, all efforts will be made to have the study therapy 
administered by the main treating ophthalmologist and all masked study examinations performed 
by the masked examining ophthalmologist (PI) to minimize confounding variables. 
Study Coordinators from the UC Davis Eye Center Clinical Trials Team will be assigned to the 
study to manage the day-to-day activities regarding the study under the supervision of the PI, with 
the unmasked Study Coordinator being provided only general guidance from the masked PI. 
Study Coordinators will conduct study visits according to their masked or unmasked delegated 
assignment. 
The masked and unmasked Study Coordinators will be responsible for scheduling all study visits 
taking utmost care to preserve the masking. Prior to randomizing the participant, the masked 
Coordinator will schedule the Treatment 1 and Treatment 2 study visits working under the 
pretense that both procedures involve stem cell therapy. Once the participant is randomized, the 
unmasked Study Coordinator will provide both the study hematologist and the GMP laboratory 
with information regarding which Treatment study visit will require bone marrow/cellular therapy 
and which will require sham aspiration/sham injection. The unmasked Study Coordinator will also 
schedule the post Treatment Day 1 and Week 1 study visits for both Study Periods. 
The photographers and technicians obtaining OCT, perimetry and electroretinography (ERG) will 
be masked to the participants’ treatment assignment to avoid bias in outcome assessment. The 
advanced retinal imaging team (described in Section 6.1.5), however, will be unmasked for the 
duration of the study. 
At the time of informed consent and enrollment into the study and at the beginning of every study 
visit thereafter, participants will be reminded not to discuss details of the study procedures or their 
impressions of which injection they received with any member of the study team to preserve 
masking of the study team (i.e., investigators, technicians.) 

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TABLE 1: Enrollment Center Personnel − Masking for 
Randomized Treatment Assignment 
Study Roles 
Masked Status 
Principal Investigator 
Masked 
Examining Ophthalmologist 
Masked 
Masked Study Coordinator 
Masked 
Hematologist 
Unmasked 
Visual Acuity Examiner 
Masked 
Treating Ophthalmologist 
Unmasked 
Unmasked Study Coordinator 
Unmasked 
Photographers 
Masked 
OCT Technicians 
Masked 
Perimetry Technicians 
Masked 
ERG Technicians 
Masked 
Study Participants 
Masked 
Advanced Retinal Imaging Team 
Unmasked 
GMP Laboratory Team 
Unmasked 
The bone marrow aspiration and CD34+ cell isolation will be conducted by study co-investigators 
at the Enrollment Center. Certified hematologists who are faculty members of the UC Davis 
Cancer Center will perform the bone marrow aspiration or sham aspiration. Members of the 
Institute of Regenerative Cures leadership will oversee the CD34+ cell isolation from bone marrow 
aspirate in the Good Manufacturing Practice (GMP) laboratory. These co-investigators and 
contributors have a long-term working relationship with the PI and have participated in similar 
roles in the Phase 1 clinical trial for this cellular therapy. They are committed to this study. 
6.1.3 Study Participant Demographics and Recruitment 
Approximately twenty participants with history of persistent vision loss from CRVO in the study 
eye with or without concurrent retinal artery occlusion will be consented and enrolled if they meet 
study eligibility criteria. The vision loss must be persistent and over 6 months in duration as 
mandated by the FDA. The participants who meet the eligibility criteria will mostly be recruited 
from the clinic population of the Retina Clinic at the University of California Davis Eye Center and 
via referral from community ophthalmologists. There are at least four retinal specialists within the 
UC Davis Eye Center who can refer patients for the study. They are all investigators in the study. 
In addition, there are approximately fifteen community retinal specialists within the Sacramento, 
CA area who have expressed interest in referring patients for this study. They include retinal 
specialists in an HMO and a high-volume retina-only private practice. CRVO is a relatively 
common condition; thus, no major problem is anticipated in terms of availability of patients with 
CRVO. Although many of the patients seen in the Retina Clinic are patients undergoing treatment 
for macular edema or retinal neovascularization, these conditions often stabilize after treatment, 
but vision loss often persists. In eyes with severe macular ischemia, treatment of macular edema 
may be deferred if no visual benefit is anticipated with standard of care treatment. 

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Before study enrollment begins, the study will be registered on www.clinicaltrials.gov. Based on 
past experience of the PI, registering an actively enrolling clinical trial on this website results in 
direct self-referral of patients who might be interested in enrolling in the study. A recruitment letter 
will also be written and emailed to retinal specialists, general ophthalmologists, and optometrists 
in northern California. Patients and their providers from outside the Sacramento, CA region may 
contact the Enrollment Center directly via phone call or email to be considered for enrollment. 
These patients’ medical records will be screened for eligibility by the study coordinator and PI. 
For patients living outside the Sacramento, CA area, enrollment preference will be given to 
patients residing within a five-hour driving distance of the Enrollment Center in Sacramento, CA 
in order to maximize study retention. 
Gender and ethnicity are not exclusion criteria for the study since CRVO afflicts individuals of both 
genders and all ethnicities and races.25 Thus, the anticipated ethnic distribution of the enrolled 
participants will likely reflect the ethnic/racial distribution of the clinic population at UC Davis Eye 
Center (APPENDIX A). The gender distribution will likely be equal among enrolled participants. 
No pregnant women will be enrolled since this is an experimental therapy with an unknown safety 
profile. Patients must be at least 18 years of age to enroll since they must be of age to sign the 
informed consent. The anticipated age distribution for this study enrollment will likely reflect the 
increasing prevalence of this condition from 1% to 5% as patients age from 40 years to 80 years 
of age.24-26 Since there is more severe irreversible vision loss associated with RVO among 
patients > 60 years of age, the anticipated age distribution will be as follows: 
> 60 years of age:  
75% 
40 to 60 years of age: 
20% 
18 to 40 years of age: 
  5% 
6.1.4 Study Retention Strategies and Timeline 
To maximize study retention during the 12-month follow-up period of the study, enrollment priority 
will be given to potential participants who are highly motivated to participate in the study. In 
addition, details of the study scheduled follow-up visits and tests will be reviewed with each 
potential participant before obtaining informed consent. Priority enrollment consideration will be 
given to potential participants living locally or within 5 hours driving distance of the Enrollment 
Center located in Sacramento, CA. In addition, enrollment priority will be given to potential 
participants who are of good general health and with good social and family support, as 
determined by the study staff based on interactions with the potential participant. 
Once the patient is enrolled, both Study Coordinators and the PI will continually educate the 
participant on the nature of the study and the importance of continued follow-up and participation 
to minimize drop outs and missed visits. In addition, the Study Coordinators will contact the 
participants within a week of scheduled follow-up visits as a reminder of the appointment. This 
will be done by telephone or email. If a participant misses a study visit, he/she will be contacted 
promptly by the Study Coordinators to reschedule the visit within the time window allowed for that 
visit. Every effort will be made to maintain contact with the study participants even if the participant 
misses a scheduled study visit. The Study Coordinator involved in these appointment reminders 
and rescheduling will be either the masked or unmasked Study Coordinator depending on 
whether the study visit will be conducted by a masked or unmasked investigator. 

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All efforts will be made to make each study visit as efficient and pleasant as possible for the study 
participants. The masked and unmasked investigators and Study Coordinators will make every 
effort to address any issues or concerns regarding the study that may be raised by the participants 
and to develop a personal rapport with each of the study participants. 
The anticipated timeline for the study is as follows: 
Study Start-up: 
12 months 
Recruitment/Enrollment: 
42 months 
Follow-up: 
12 months 
Study Closeout: 
  6 months 
Total duration of study: 
72 months 
Study Start-up (approximately 12 months): 
Study start-up is anticipated to take approximately 12 months. This time period will be used to 
finalize the protocol, study documents, case report forms, and electronic data capture system; to 
form and hold the initial meeting of the DSMC and ensure all study personnel are trained in study 
procedures. The IND for the study was cleared by the FDA on July 7, 2016. The local IRB has 
previously approved the study protocol and informed consent form. Any changes to the study 
protocol and informed consent form recommended by the DSMC will be submitted to the FDA 
and local regulatory agencies (IRB and Stem Cell Oversight Committee) for final approval before 
study enrollment begins. The UC Davis Eye Center (Enrollment Center) clinical trial team has 
been involved in many multi-center clinical trials funded by NEI and has an excellent track record. 
In addition, the Enrollment Center is involved in the on-going phase I study of this cellular therapy 
and no hurdles or difficulties have been encountered implementing the study cellular therapy. 
Thus, the team is experienced in all aspects of this proposed study except the randomized 
treatment assignment, sham-control design, and masking procedures. 
The DCC (Emmes) has contributed to the study design and the Manual of Procedures prior to 
study start-up. There has been continuous communication between the DCC and the Study 
Chair/PI and this communication will continue through study start-up and through the duration of 
the study. 
Study Recruitment (approximately 42 months): 
Recruitment is anticipated to take the 42 months. Note the FDA had initially mandated that 
enrollment be staggered by at least two weeks in the event that there is a safety issue observed 
associated with the study therapy. Although this mandate has been lifted recently in the cross-
referenced IND based on available safety data of the pilot study, a conservative rate of enrollment 
is advised and planned. For the early part of enrollment for this phase I/II study (i.e., first 6 months 
of the enrollment period starting from the date the study was open to enrollment), enrollment will 
be staggered by at least 2 weeks. 
An additional factor affecting rate of enrollment is the limited number of days the treatment can 
be administered. Available treatment days will be limited since the participant, the hematologist, 
the GMP facility, and the study treating ophthalmologist must all be available concurrently for 
study treatment to be administered. Furthermore, enrollment is anticipated to be slower than 
expected due to travel restrictions imposed by the COVID-19 pandemic that began during the 
study enrollment. 

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During the recruitment period, a biannual update on study enrollment and study retention rate will 
be presented to the DSMC by the DCC. Any study-related safety issues will also be presented. 
In addition, the Study Chair/PI will communicate at least monthly with the DCC regarding the 
recruitment schedule and study progress. 
Study Follow-up (approximately 12 months): 
Following the end of the study recruitment period, an additional 12 months will be required to 
allow all participants to complete the study. During this period, all efforts will be made by the 
masked investigators and Study Coordinator at the Enrollment Center to avoid early study 
dropout. Because participants remain masked to therapy assignment during the follow-up, it is 
anticipated that there will be minimal dropout during the first six months until all participants 
receive the second study therapy. At that point, all participants will have received the cellular 
therapy, and more likely that participants may consider dropping out of the study. The Enrollment 
Center team will make every effort to encourage the study participants to keep all follow-up study 
visits to ensure participants are adequately followed for safety following this experimental therapy 
and so that the study can gain information regarding the effects of the cellular therapy, whether 
they be potentially beneficial or adverse. 
Study Closeout (approximately 6 months): 
Once the last participant enrolled has terminated from the study, study closeout will begin. Study 
closeout is estimated to take approximately 6 months. During the study closeout period, the DCC 
protocol monitor will conduct a site closeout visit and once all data issues have been resolved, 
the database will be locked. Final data analysis will be conducted by the DCC and in conjunction 
with the PI and the DSMC. The final study manuscripts will be written and prepared for publication 
by the PI and study collaborators by the end of study closeout and submitted to peer-reviewed 
journals after review and approval by the DSMC and the DCC. 
6.1.5 Study Procedures and Visit Schedule 
TABLE 2 summarizes the study visit schedule and procedures for the participants enrolled in the 
two arms of the study. Each potential participant will be screened by the PI or designee for study 
eligibility prior to enrollment based on available clinical information. A written informed consent 
will be obtained after a detailed explanation of the tests, potential risks and benefits of the study 
therapy, the study randomization, and scheduled follow-up visits. 
Each participant will undergo pre-therapy screening assessments and baseline testing to confirm 
the diagnosis and evaluate the extent of the condition. The screening tests include a 
comprehensive eye examination including ETDRS BCVA (best corrected visual acuity), 
fluorescein angiography, fundus photography, microperimetry, and optical coherence tomography 
(OCT)/OCT angiography. The screening tests will be performed within one month of first study 
therapy although results of any of these study procedures performed up to 45 days prior to first 
study therapy may be used to confirm diagnosis and determine eligibility for the study at the 
investigator’s discretion if no change in visual function or eye examination is noted during the 
period. In addition, the medical and ophthalmic history and concomitant list of medications, if any, 
will be reviewed to ensure that the patient qualifies for the study based on the inclusion and 
exclusion criteria of the study. A blood sample to perform a CBC test will be obtained, and vital 
signs will be taken. If the patient is a woman of child-bearing potential, a urine pregnancy test will 

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be performed within 2 weeks prior to study treatment. Details regarding whether a participant is 
of childbearing potential is outlined in APPENDIX B. 
Data on any participant who signs the informed consent but fails to meet all eligibility criteria based 
on the screening evaluation will be collected along with the reason(s) for not qualifying for the 
study. 
 

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TABLE 2: Study Visit Schedule 
 
Screening 
Period 
Study Period 1 
Study Period 2 
Study 
Exit^^ 
Visit 
Screening/ 
Baseline 1 
Study 
Treatment 
1 
Day 
1 
Week 
1 
Month 
1  
Month 
3 
Month 6/ 
Baseline 2 * 
Study 
Treatment 
2 * 
Day 
1 
Week 
1  
Month 
1 
Month 
3 
Month 
6 
 
Target Month 
+ 
- 
- 
- 
1 
3 
6 
- 
- 
- 
7 
9 
12 
^^ 
Target Day 
- 
0 
1 
7 
28 
91 
181 
182 
183 
190 
210 
273 
364 
^^ 
Window 
+ 
- 
- 
±2 d 
±7 d 
±14 d 
±30 d 
±30 d 
- 
±2 d 
±7 d 
±14 d 
±30 d 
^^ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
History/ROS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ophthalmic 
History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X# 
X 
X 
 
 
X 
X# 
X 
X 
 
 
 
 
CBC 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Urine Pregnancy 
Test** 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
ETDRS VA 
X 
X^ 
X^ 
X^ 
X 
X 
X 
X^ 
X^ 
X^ 
X 
X 
X 
 
Micro-Perimetry 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
Eye Exam & IOP 
X 
X@ 
X 
X 
X 
X 
X 
X@ 
X 
X 
X 
X 
X 
 
Fundus 
Photography 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 

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TABLE 2: Study Visit Schedule 
 
Screening 
Period 
Study Period 1 
Study Period 2 
Study 
Exit^^ 
Visit 
Screening/ 
Baseline 1 
Study 
Treatment 
1 
Day 
1 
Week 
1 
Month 
1  
Month 
3 
Month 6/ 
Baseline 2 * 
Study 
Treatment 
2 * 
Day 
1 
Week 
1  
Month 
1 
Month 
3 
Month 
6 
 
Target Month 
+ 
- 
- 
- 
1 
3 
6 
- 
- 
- 
7 
9 
12 
^^ 
Target Day 
- 
0 
1 
7 
28 
91 
181 
182 
183 
190 
210 
273 
364 
^^ 
Window 
+ 
- 
- 
±2 d 
±7 d 
±14 d 
±30 d 
±30 d 
- 
±2 d 
±7 d 
±14 d 
±30 d 
^^ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FA 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
OCT/OCTA 
X 
  
 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
Inclusion/ 
Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AF 
X 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
ERG*** 
X 
 
 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
NEI VFQ 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Advanced retinal 
imaging @@ 
X  
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Hematology 
Consult 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Cellular or Sham 
Therapy## 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Enrollment Pause 
Guideline Review 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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TABLE 2: Study Visit Schedule 
 
Screening 
Period 
Study Period 1 
Study Period 2 
Study 
Exit^^ 
Visit 
Screening/ 
Baseline 1 
Study 
Treatment 
1 
Day 
1 
Week 
1 
Month 
1  
Month 
3 
Month 6/ 
Baseline 2 * 
Study 
Treatment 
2 * 
Day 
1 
Week 
1  
Month 
1 
Month 
3 
Month 
6 
 
Target Month 
+ 
- 
- 
- 
1 
3 
6 
- 
- 
- 
7 
9 
12 
^^ 
Target Day 
- 
0 
1 
7 
28 
91 
181 
182 
183 
190 
210 
273 
364 
^^ 
Window 
+ 
- 
- 
±2 d 
±7 d 
±14 d 
±30 d 
±30 d 
- 
±2 d 
±7 d 
±14 d 
±30 d 
^^ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post Procedure 
Satisfaction 
Survey 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
Study Satisfaction 
Survey 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: AF—fundus autofluorescence; CBC—complete blood count; FA—fluorescein angiography; IOP—intraocular pressure; OCT/OCTA—optical coherence tomography and 
angiography; VA—visual acuity; ROS—review of systems. 
Shaded cells represent visits which are conducted by unmasked staff. 
+Screening assessments may be done in one or more visits within 1 month of study treatment at Day 0 although results from within 45 days prior to study treatment at Day 0 may be considered 
at the discretion of the investigator. 
*The Baseline 2 visit and the Study Treatment 2 visit must be separated by at least one day but no more than 30 days. 
#Vital signs at Study Treatment 1 and Study Treatment 2 will be performed just before and after bone marrow or sham aspiration. 
**For females of child-bearing potential (see APPENDIX B for definition), urine pregnancy testing should be done within 2 weeks prior to sham or cellular therapy. 
^Using refraction previously obtained at Baseline visit. 
@Study Treatment 1 and Study Treatment 2 eye examinations will be done before and after sham or cellular therapy. 
***Includes full field and multifocal ERG. 
@@ Includes research-grade ultra-high-resolution OCT and OCTA and adaptive optics-OCT in select patients who sign a separate consent. Advanced retinal imaging will be done on a separate 
day than the standard OCT/OCTA due to the time required for imaging. Imaging will be performed at baseline and participants with high quality images will have repeat imaging at 1 month after 
stem cell treatment, with at least 2 of the participants randomized to the deferred cellular therapy arm also having imaging after sham therapy. The images will be acquired and processed by 
unmasked investigators. Images will be masked prior to their review by a masked investigator and groups of images will be reviewed together to preserve masking. 
## For Immediate Cell Therapy/Deferred Sham Therapy group, study treatment at Day 0 consists of bone marrow aspiration followed by intravitreal injection of CD34+ cells, and study treatment 
at 6 months consists of sham bone marrow aspiration followed by sham injection. For Immediate Sham Therapy/Deferred Cell Therapy group, treatment at Day 0 consists of sham bone marrow 
aspiration followed by sham injection, and study treatment at 6 months consists of bone marrow aspiration followed by intravitreal injection of CD34+ cells. 
^^ The incorporation of the Exit Visit results from changes made to protocol v8.0 where follow-up was shortened to one year. For those participants who completed the Month 12 visit prior to the 
approval of protocol v8, they will complete the Exit Visit within 30 days of the approval of protocol v8.0. The Exit Visit is comprised of review and close-out of AEs and concomitant medication 
records, and completion of the study satisfaction survey. 
 

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Once the participant qualifies for the study, the participant will be randomized 1:1 to either of the 
following study treatments: immediate cell therapy/deferred sham therapy or immediate sham 
therapy/deferred cellular therapy, where cell therapy consists of bone marrow aspiration and 
intravitreal injection of isolated CD34+ cells and sham therapy consists of sham bone marrow 
aspiration and sham injection. Immediate therapy refers to procedure administered at baseline 
while deferred therapy refers to procedure administered at month 6 of the study. The following 
assessments will be completed prior to study treatment that occurs on Day 0 and may be 
performed before or after randomization depending on the clinic or participant scheduling needs: 
autofluorescence, full field and multifocal electroretinography (ERG) and quality of life 
questionnaire. Additional imaging using a research-grade ultra-high-resolution OCT/OCTA and 
adaptive optics-OCT instruments will also be performed on a select subgroup of participants who 
qualify and consent. 
Prior to randomization, the participant will meet with the study hematologist to review the 
aspiration procedure. The hematologist will review the participant’s medical history, concomitant 
medications and blood work (including CBC) to ensure that the participant is a good candidate for 
a bone marrow aspiration. Any abnormal lab work and review of systems will be reviewed by the 
hematologist to determine whether it would impact the outcome of the bone marrow aspiration 
procedure and continued enrollment in the study. 
Using the DCC’s electronic data capture (EDC) system, Advantage eClinical®, the unmasked 
Study Coordinator will randomize the participant, and will disseminate this information in a 
confidential manner to the hematologist and GMP laboratory as described in section 6.1.2. 
On the morning of the study procedure, the participant will meet with the hematologist and the 
unmasked study coordinator to ensure there are no new contraindications to proceeding with 
study treatment that day. 
The aspiration procedure will generally be performed in the minor procedure room at University 
of California Davis Eye Center or at the University of California Davis Alpha Stem Cell Clinic after 
premedication with oral medications to minimize anxiety and pain. Local anesthesia will be given 
at the site of the planned aspiration. Just before the aspiration procedure, there will be a surgical 
timeout to confirm the participant’s identity, participant’s (study) ID, and procedure to be 
performed. 
The bone marrow aspiration consists of an Illinois needle inserted into the iliac crest region. 
Approximately 10 to 50 ml of bone marrow aspirate will be obtained from the iliac crest per 
participant after no more than four separate bone punctures. After the bone marrow is obtained, 
the site of the insertion will be cleaned and bandaged, and the participant will be instructed 
regarding care of the puncture site. The marrow will be placed in heparinized tubes and 
transported promptly to the GMP laboratory of the Institute for Regenerative Cures. 
For the sham aspiration, an Illinois needle will be attached to a syringe and will be used to 
penetrate the skin in the iliac crest region to simulate the skin changes following bone marrow 
aspiration. The bone, however, will not be penetrated. After the needle is withdrawn, the site of 
the insertion will be cleaned and bandaged, and the participant will be instructed regarding care 
of the puncture site. 
For the cellular therapy portion, GMP-grade CD34+ BMSCs will be isolated using a Ficoll column 
to isolate the mononuclear cell fraction and the Miltenyi CliniMACS system will be used to isolate 

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the CD34+ cells from the mononuclear cell fraction. There will be no genetic research testing 
performed. The isolated CD34+ cells will be washed, subjected to stat sterility assays (including 
endotoxin assay and gram stain), and stat viability testing with trypan blue staining and 
resuspended in 0.15 cc volume of BSS Plus. The final stem cell product (0.1 cc containing at least 
800,000 viable nucleated CD34+ cells (where the cell count is based on the Miltenyi CliniMACS 
cell sorting process as noted above) will be sent to the Eye Center in a 1 ml tuberculin syringe for 
intravitreal injection. The remaining 0.05 cc of the final stem cell product will be used for post-
release analysis to characterize the final stem cell product. This will include flow cytometry for 
CD34 and CD3 content and 7-AAD viability testing. Additional analysis for potency and 
characterization of the final product will be performed. These additional analyses will include flow 
cytometric panel analysis for hematopoietic stem cells that are CD133(+)/CD45(+)/CD34(+) 
versus angiogenic cells (i.e., endothelial progenitor cells) that are CD31(+)/VEGFR-2(+)/CD45(-
)/CD34(+). In addition, the post release flow cytometry panel will include analysis of CD34+ cells 
with VEGF receptor-2 (VEGFR-2), namely VEGFR-2+/CD34+, as well as, % CD133(+); % 
CD31(+); % CD45(+); % VEGFR-2 (+). 
On the morning of the study procedure, ETDRS VA is performed prior to the aspiration procedure 
and study injection. In addition, the unmasked treating ophthalmologist will perform a complete 
eye exam including fundus examination and a slit lamp examination of the study eye to ensure 
there are no new changes from baseline. This is done prior to study injection. The isolated CD34+ 
cells will be injected intravitreally by the unmasked treating ophthalmologist (retinal specialist) 
under local anesthesia. The intravitreal injection will be performed within two hours and on the 
same day following release of the final stem cell product from the GMP laboratory. 
Just before intravitreal injection or sham injection, there will be a surgical timeout to confirm the 
participant’s identity, participant’s (study) ID, procedure to be performed and the eye in which the 
injection will be performed. Once the study eye is confirmed, the eye will be gently massaged for 
5 minutes to soften the eye. The study eye will be anesthetized with topical proparacaine eye 
drops. Additional anesthesia at the discretion of the treating ophthalmologist will consist of either 
a cotton-tipped applicator soaked with 4% lidocaine or lidocaine gel applied 2 to 5 minutes over 
the injection site or administration of 2% lidocaine subconjunctival injection over the injection site 
using a sterile 30g needle. Povidone-iodine (5%) will be instilled in the fornix and the injection site 
and the participant will be asked to blink once to evenly coat the surface of the eye with povidone-
iodine. A sterile lid speculum will be placed to keep the eyelid open during the procedure. A cotton-
tipped applicator soaked in 5% povidone-iodine will be applied to the conjunctiva directly over the 
intended injection site. The povidine-iodine is allowed to dry for 30 to 60 seconds. Or, IF THE 
PATIENT IS ALLERGIC TO IODINE, one drop of topical antibiotic (zymar) will be applied every 
5 minutes for 3 doses prior to injection. Then, a sterile eyelid speculum will be placed to keep the 
eyelids open during the procedure. 
For the intravitreal injection, the isolated cells (suspended in sterile saline volume of 0.1 cc) will 
be injected into vitreous through the pars planar (i.e., 4mm behind the limbus) using a 30-gauge 
needle. For the sham injection, an empty uncapped tuberculin syringe will be placed with gentle 
pressure at the injection site to simulate intravitreal injection (i.e., nothing will be injected into the 
eye) after applying conjunctival lidocaine with a cotton-tipped applicator. 
After stem cell injection or sham injection, the lid speculum will be removed, and the participant’s 
vision will be measured to make sure it is at least counting fingers (CF). Indirect ophthalmoscopy 

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will be performed to ensure that the central retinal artery is perfused and to ensure that there are 
no complications associated with the injection. Intraocular pressure (IOP) will be measured after 
injection. If the vision is hand motions or light perception and IOP is > 40 mm Hg, glaucoma 
medications will be started to lower IOP. If the vision is no light perception and IOP is > 40 mm 
Hg, a paracentesis will be performed after reapplying 2 to 3 drops of 5% povidine-iodine solution 
and opening the eyelid with a sterile  lid speculum. A 30g needle attached to a 1 mL syringe will 
be used to remove a maximum of 1 mL of aqueous from the anterior chamber. The lid speculum 
will be removed and visual acuity of at least counting fingers will be confirmed. Indirect 
ophthalmoscopy will be performed to confirm perfusion of the central retinal artery. 
Following stem cell injection or sham injection, a complete eye examination will be performed to 
ensure there is no new change after the injection. This will include a slit lamp examination which 
will check for hyphema or cells visible in the anterior vitreous. Then, the eye will be washed with 
balanced saline solution, followed by application of antibiotic eye drop and erythromycin or similar 
antibiotic eye ointment. Then, the eye examination chair will be reclined to allow the participant to 
be in the supine position for 30 minutes. Thereafter, the participant will be discharged and 
instructed to use topical antibiotic drops four times a day in the injected eye for one week. The 
number of viable nucleated CD34+ cells to be injected per eye will be recorded and will range 
from 800,000 to 10 million, depending on the yield of the bone marrow aspiration and the isolation 
procedure and where the cell count is based on the Miltenyi CliniMACS cell sorting process. The 
percent viability of the cells as noted pre-release using trypan blue staining by the GMP laboratory 
will also be recorded. Any irregularity in size or shape of the cells in the final product as noted by 
the GMP laboratory staff will also be recorded. 
The participants will have a complete eye examination 1 day and 1 week (±2 days) after their first 
study treatment (either cell or sham) by the unmasked treating ophthalmologist. Thereafter, a 
follow-up examination 1 month (±7 days), 3 months (±14 days) and 6 months (±30 days) will be 
conducted by the masked examining ophthalmologist. At month 6, the participant will receive the 
second study treatment (either cellular or sham therapy which is the opposite of what they 
originally received) by the unmasked treating ophthalmologist. Prior to the receipt of the second 
study treatment, the participant will meet with the study hematologist to review the aspiration 
procedure. Similar to the first consult, the hematologist will review the participant’s medical 
history, concomitant medications, and blood work (including CBC) to ensure that the participant 
is still a good candidate for bone marrow aspiration. Any abnormal lab work and review of systems 
will be reviewed by the hematologist to determine whether it would impact the outcome of the 
bone marrow aspiration procedure and continued treatment in the study. In addition, females of 
child-bearing potential must have a negative pregnancy test within 2 weeks of the second study 
treatment. Similar to what occurs for the first treatment, the study team will meet with the 
participant on the morning of the study procedure to ensure there are no new contraindications to 
proceeding with study treatment that day. 
Following the study injection, the unmasked treating ophthalmologist will conduct a follow-up 
exam 1 day and 1 week after this second study treatment. The masked examining 
ophthalmologist will conduct an exam 1 month, 3 months (±14 days) and 6 months (±30 days) 
after the second study treatment (i.e., at approximately 7, 9 and 12 months after the first study 
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The bone marrow aspiration wound site will be inspected visually for infection at the 1 day and 1 
week (±2 days) post-procedure examinations by the unmasked treating ophthalmologist. 
Fundus photography, fluorescein angiography, and autofluorescence will be performed at 
screening/baseline and at 3 months (±14 days) and 6 months (±30 days) after each treatment, 
and as needed at the discretion of the investigator to assess any significant change upon clinical 
examination. Commercial-grade OCT/OCT angiography, microperimetry and ERG will be 
performed at screening/baseline and at 1 month (±7 days), 3 months (±14 days) and 6 months 
(±30 days) after each treatment, or as needed at the discretion of the investigator to assess any 
significant change in retinal function and perfusion. The NEI VFQ questionnaire will be completed 
at screening/baseline and at 6 months following each study treatment. A study feedback 
questionnaire will be administered at 1 week after each study treatment and at study exit. 
Select participants, who at screening have stable fixation on microperimetry and clear media 
(study eye) defined as Optovue OCTA signal strength of 6 or greater using the 3mm macular 
scan, will be invited to participate in an optional sub-study. The sub-study involves ultra-high-
resolution OCT/OCTA and adaptive optics-OCT imaging. Imaging will be performed at baseline 
and participants with high quality images will have repeat imaging at 1 month after receipt of stem 
cell therapy. Approximately 2 of the participants randomized to immediate sham therapy/deferred 
cellular therapy will also have imaging done 1 month after receipt of sham therapy. Thus, the 
Advanced Retinal Imaging team will be unmasked investigators for the study duration. Since this 
is a time-consuming procedure, it may be scheduled on a separate date from other procedures 
requiring fixation, such as perimetry or ERG. The processed images will be evaluated for 
qualitative abnormalities by a masked investigator in bulk at a later date. The quantitative 
assessment of the images, e.g., retinal thickness and vascular density, will be assessed by the 
unmasked Advanced Retinal Imaging team after completion of image processing. 
The schedule of assessments is presented in TABLE 2. 
6.1.6 Study and Data Monitoring 
During the course of the study, the PI and the DCC will work in conjunction with the DSMC to 
ensure that the trial is conducted properly and in accordance with the study protocol. Before study 
initiation, the DCC will organize the initial meeting of the DSMC to allow the committee members 
to review, offer advice, and approve the study protocol, informed consent form, and other 
supporting study documents. During this meeting, the overall plan for safety monitoring and 
procedures and guidelines for reporting adverse events will be reviewed and approved by the 
DSMC. In addition, the overall plan for statistical analysis and monitoring the study for early 
stopping and/or pausing enrollment will be discussed. Thereafter, the DSMC will meet on an 
approximate biannual basis. The DCC will produce data tables and conduct analyses as 
appropriate for review by the DSMC. 
Protocol monitoring will be a continuous process performed both at the DCC and at the Enrollment 
Center. The DCC staff will be in regular communication with both Study Coordinators and the PI, 
via email or teleconference, at least monthly to discuss general study issues and to assure the 
site is up to date with data completion. At least monthly, data quality reviews will be conducted to 
assess level of missing data, review requests for missing values and missing forms exceptions, 
and run data checks for missing and inconsistent data. Any departure from procedures or 
requirements outlined in the protocol will be classified as protocol deviations. 

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Prior to study initiation, a site initiation visit will be conducted by a DCC protocol monitor to ensure 
the site possesses adequate facilities and staffing to conduct the study, that site personnel have 
sufficient knowledge to ensure the study is conducted in accordance with GCP, applicable 
regulations, and the approved protocol, and that they are adequately trained in study policies and 
procedures. Interim monitoring visits will be conducted to monitor for informed consent 
documentation, protocol adherence, reporting of protocol deviations, study outcomes, participant 
safety, maintenance of appropriate source documentation and regulatory reviews. Protocol 
monitoring visits conducted by a DCC monitor will occur approximately every 6 months after 
enrollment begins. A site close-out visit will be conducted at the conclusion of the study. Complete 
and accurate regulatory documentation, complete data entry, and no pending action items are 
required before the site is closed out. 
6.2 Rationale for Study Design 
Human CD34+ cells in bone marrow are mobilized into the circulation in response to tissue 
ischemia and play an important role in tissue revascularization.4,22 By injecting the isolated CD34+ 
cells from bone marrow directly into the vitreous cavity, the regenerative potential of these cells 
may be maximized to treat retinal ischemia. Animal studies have shown that intravitreally injected 
human CD34+ cells home into sites of retinal injury and ischemia and may play a role in 
revascularization. This has been demonstrated in animal models of diabetic retinopathy, acute 
retinal ischemia-reperfusion injury and retinal laser injury,13-19 Thus, we hypothesize that these 
CD34+ cells may help cells in the retina recover from ischemia and regain visual function. RVO 
is the condition to be studied since it is the second most common retinal vascular cause of vision 
loss. With RVO the retinal ischemic event is usually acute, rather than chronic and progressive 
as noted in diabetic retinopathy, potentially allowing therapeutic effect of cellular therapy to be 
appreciated more readily. Since this is primarily an early phase safety and feasibility study, we 
will only enroll individuals with severe persistent vision loss from CRVO despite standard of care 
treatment with laser, surgery or intravitreal anti-vascular endothelial growth factor (VEGF) or 
corticosteroid therapy, if eligible (refer to Section 7.1.2 Inclusion/Exclusion Criteria). CRVO was 
selected to maintain uniformity in the study eye. It is of note that at least six participants with vision 
loss from various ischemic and degenerative retinal conditions have already been treated with 
this cellular therapy as part of a phase I study, and no safety or feasibility issues were noted 
during the 6 to 24 month follow-up.23 Among the study eyes, the eye with vision loss from a 
combined CRVO and retinal artery occlusion appeared to have the greatest improvement by 
visual acuity, ERG, fluorescein angiography and microperimetry following this cellular therapy. 
The improvement was noted as early as one month following cell injection and sustained during 
the six-month follow-up period of the study. This proposed expanded phase I/II study is planned 
to further explore the effect of intravitreal autologous CD34+ cells in eyes with persistent vision 
loss from CRVO. By conducting a larger study of CRVO with longer follow-up, more feasibility 
and safety information can be obtained regarding this therapy. By comparing retinal functional 
and anatomic changes following study treatment to sham treatment, some efficacy information 
can also be obtained. Autologous CD34+ cells will be used to avoid cell rejection issues. These 
CD34+ cells will be harvested from bone marrow, one of the richest sources for these cells.1-3 
Although CD34+ cells mobilized into the circulation have been used for bone marrow 
transplantation, these mobilized cells may not completely share the characteristics of CD34+ cells 
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The study is a randomized prospective study in which participants and all study personnel 
participating in eye examinations and outcome assessment will remain masked for the study 
duration of 12 months. Only the advanced retinal imaging team, treating ophthalmologist, the 
hematologist conducting bone marrow aspiration, and the study coordinator conducting these 
treatment and immediate post-treatment examination visits will be unmasked. All participants will 
remain masked for the study duration. The study design allows all participants to receive cellular 
therapy by month 6. The rationale for this study design is based on the expectation that 
participants receiving intravitreal cell injection would likely note a beneficial effect of cellular 
therapy, if any, by month 3 based on the observations of the preliminary phase I study.22 
The proposed clinical trial is supported by preclinical observations. Human CD34+ cells from bone 
marrow have been shown to be multi-potent and observed to home into ischemic retinal blood 
vessels and damaged retinal cells very quickly following intravitreal injection in animal models.15-
19 These human cells could be detected in mouse retinal vasculature as long as 6 months 
following intravitreal injection in a murine model of acute retinal ischemia-reperfusion with 
apparent normalization of the retinal vasculature.17 No long-term safety issues were noted locally 
or systemically in the murine study. Of note, the number of CD34+ cells injected into the murine 
eyes in these preclinical safety studies is equivalent to about 10 million CD34+ cells injected in 
human eyes if adjusted for differences in eye size and volume. Thus, the upper limit of number of 
viable nucleated CD34+ cells to be injected intravitreal for this phase I/II study will be 10 million, 
where the cell count is based on the Miltenyi CliniMACS cell sorting process. 
6.3 Outcome Measures 
6.3.1 Primary Safety and Feasibility Outcome Measures 
The primary outcome measures for the safety and feasibility of the stem cell therapy are the 
following: 
• 
Incidence and severity of ocular and systemic adverse events reported during Study 
Period 1 (i.e., the day of the first treatment (Treatment 1) up to but not including the day 
of the second treatment (Treatment 2) 
• 
The mean and range of number of CD34+ cells isolated from the bone marrow aspirate 
and the number injected into the eye 
6.3.2 Secondary Outcome Measures 
The secondary safety outcome measures are the incidence and severity of ocular and systemic 
adverse events reported throughout study duration. 
The secondary efficacy outcome measures for the study will be used to describe the effect of 
therapy on retinal function and morphology as outlined in TABLE 3. 
 
 

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TABLE 3: Secondary Efficacy Outcome Measures 
Modality 
Outcome Measure 
Visual Acuity 
ETDRS Visual Acuity Letter Score 
Microperimetry 
% Reduced Sensitivity 
Average Threshold 
OCT 
Macular Thickness by ETDRS zone 
Macular Volume 
Average Macular Thickness 
Presence of CME 
Presence of Subretinal Fluid 
Integrity of Photoreceptor Layer (IS/OS Junction) 
Integrity of Photoreceptor Layer (ELM) 
Presence and number of hyper-reflective foci in vitreous, intraretinal 
and subretinal 
Length of longest DRIL in line scans 
Presence of ERM 
Presence of VMT/VMA 
OCTA 
Foveal avascular zone size 
Automated Superficial and Deep Vascular Density (VD) by ETDRS 
zone 
VD Analysis of Superficial plexus and deep plexus 
RNFL Thickness 
Whole image capillary density % 
Inside disc capillary density % 
Retinal peripapillary capillary density % 
Multifocal ERG 
Number of abnormal amplitude hexagons 
Mean amplitude S.D. 
Number of abnormal latency hexagons 
Mean Latency S.D. 
Full-field ERG 
% normal amplitude for a-wave and b-wave under scotopic conditions 
% normal latency for a-wave and b-wave under scotopic conditions 
% normal amplitude for a-wave and b-wave under photopic conditions 
% normal latency for a-wave and b-wave under photopic conditions 
% of normal Flicker amplitude and latency 
% normal amplitude for Dark adapted 3.0 ERG + OP a-wave and b-
wave under scotopic conditions 
% normal latency of Dark adapted 3.0 ERG + OP a-wave and b-wave 
under scotopic conditions 
Autofluorescence (AF) 
Area of decreased autofluorescence 
Area of increased autofluorescence 

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TABLE 3: Secondary Efficacy Outcome Measures 
Modality 
Outcome Measure 
Fundus Photography 
Degree of retinal hemorrhages by ETDRS/Networc zones 
Degree of pigment changes by ETDRS/Networc zones 
Degree of retinal fibrosis by ETDRS/Networc zones 
Degree of NV by ETDRS/Networc zones 
Degree of pre-retinal hemorrhage by ETDRS/Networc zones 
Fluorescein Angiogram (FA) 
Foveal avascular zone integrity 
Area of non-perfusion within ETDRS Grid 
Area of non-perfusion within Networc Grid 
Grade of capillary non-perfusion 
Number of microaneurysms 
Grade of telangiesctatic vascular changes 
Quality of Life 
Mean total score 
Mean subscale scores 
 
6.3.3 Exploratory Outcome Measures 
Exploratory outcome measures include: 
• 
Changes in the retina and retinal vasculature at a cellular level as visualized using 
Adaptive optics-OCT instrument in the study eye at 1 month following each treatment. 
• 
Changes in the retinal vascular density and retinal morphology using ultrahigh resolution 
swept-source OCT and OCTA in the study eye at 1 month following each treatment. 
• 
Characterization of the hematopoietic and endothelial stem cell subcomponents and 
subcomponent of cells with VEGFR-2 in the harvested CD34+ cell population. 
• 
Number of participants who were able to correctly identify the timing of receipt of sham 
and cellular therapies. 
6.4 Safety Plan 
To ensure safety of participants and integrity of data in this trial, the following data and safety 
monitoring plan will be followed during the study: 
1. The site investigators will continuously monitor participant safety and be responsible for 
reporting adverse events and serious adverse events (SAEs) from the Enrollment Center 
to the DCC Medical Monitor (MM) through Advantage eClinical, the electronic data capture 
system developed and maintained by the DCC. In order to maintain masking, the 
unmasked treating ophthalmologist will review any AE or SAE noted within 14 days 
following study treatments and determine severity and possible relationship to study 
treatment or procedure. He/she will report these adverse events to the Medical Monitor as 
noted above. Any AE or SAE noted later than 14 days after study treatments will be 
reviewed by the masked investigator (usually PI) who will review the events for severity 
and possible relationship to study therapy or procedure. The AE or SAE will be reported 
to the MM as noted above. To maintain masking as much as possible, for SAEs 

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determined by the MM to be related to study treatment and unexpected, the MM will share 
the SAE narrative with the PI. The reporting to the IRB of record will be done in a masked 
fashion as “Cellular Therapy/Sham Therapy”. The investigator who originally reported the 
adverse event will be responsible for determining relationship to therapy and severity and 
following events through resolution. 
2. The site Principal Investigator is required to review all unanticipated problems involving 
risk to participants or others, serious adverse events, and all participant deaths associated 
with the protocol and provide an unbiased written report of the event. 
3. The DCC Medical Monitor will continuously monitor safety information provided by the site 
throughout the trial. All SAEs will be reviewed at the time they are reported. The DCC 
Medical Monitor will communicate the reporting of the SAE via email to the PI, the NEI 
Project Officer and the DSMC after review and confirmation of SAE has been completed. 
The Medical Monitor will also indicate whether he/she concurs with the details of the report 
provided by the site investigator. Reviews will be conducted in Advantage eClinical and 
will be a part of the safety database. All adverse events will be reviewed on a weekly basis 
to observe trends or unusual events. If any concerning safety patterns are noted, this 
information will be conveyed to the PI for further discussion. During these discussions, 
masking will be preserved as much as possible unless safety considerations dictate 
otherwise. 
4. Data and Safety Monitoring Committee (DSMC): An independent DSMC will review 
participant data biannually, or on a schedule otherwise requested by the DSMC, to monitor 
for the occurrence of any unexpected risks or futility of treatment during the course of the 
study. The DSMC will convene and operate based on a pre-established charter created 
prior to the initiation of the trial. The DSMC will be permitted to seek additional independent 
expertise, as needed. The DSMC will provide safety oversight of the trial, monitor the 
progress of the study, and recommend continuation or modification of the trial, as 
appropriate. A summary of the review, including the recommendation to continue or modify 
the study, will be distributed to the site for submission to the local regulatory agencies. 
This study will be conducted under an IND that has been cleared by the FDA because the study 
explores the safety of an experimental treatment for treating retinal disease. Thus, the study will 
comply with the adverse events definitions and reporting requirements for clinical trials 
established by the FDA and as outlined in Section 8.0 of the study protocol. 
There were no observed adverse effects of intravitreal injection of human CD34+ cells from bone 
marrow in animal models.17 In addition, there were no systemic or ocular adverse events noted 
among the participants that have already been treated with intravitreal autologous CD34+ bone 
marrow stem cells under the cross-referenced IND for this study treatment.23 Nonetheless, in 
order to minimize the risk of intraocular infection (i.e., endophthalmitis) or any other adverse 
effects that may be associated with intravitreal injection or cell therapy, the following precautions 
will be taken: 
• 
The fluid obtained from washing the cells after CD34+ cell isolation will be cultured for 14 
days. 
• 
Gram stain and endotoxin measurement of the fluid obtained from washing the isolated 
cells will be performed stat and before the cells are released for intravitreal injection. 

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• 
The study eye will be cleansed with 5% betadine and sterile lid speculum will be used to 
open the eyelid before intravitreal injection is performed. Antibiotic drops will be used after 
the injection for one week. 
• 
The injected participants will be examined one day, one week and one month after 
injection to look for evidence of endophthalmitis or other side effects of the injection. The 
1 day and 1-week evaluation will be done by the unmasked treating ophthalmologist. The 
1-month evaluation will be conducted by the masked ophthalmologist (usually PI). 
Intravitreal injection of drug is routinely done in the eye clinic under topical anesthesia with 
minimal risk of side effects from the injection. Endophthalmitis incidence has been 
reported to be < 1% per injection and usually diagnosed during the first week after 
injection.29 Retinal tear and detachment, bleeding, cataract, and transient glaucoma are 
also potential side-effects of the injection but occur much less frequently. If these new 
conditions occur within 1 month of study procedure, they may be related to study 
treatment. Otherwise, it will be assumed unlikely to be related to study treatment. If any of 
these conditions occur, the participant will be promptly treated based on what is 
considered standard of care. 
• 
Enrollment will be staggered by at least two weeks during the first 6 months of the 
enrollment period starting from the date the study is open to enrollment in case any 
adverse event associated with the study treatment is observed. Thereafter, enrollment 
may be slightly accelerated to maintain study timeline. 
In addition, the following pause guidelines have been established. If any of the following events 
occur, enrollment will be paused, and the data reviewed by the DSMC. 
1. Development of any new intraocular tumor in the injected eye during the study period in 
any participant. 
2. Endophthalmitis or Severe Inflammation resulting in > 3 lines of vision loss attributable to 
the study therapy in any participant, i.e., final culture of cell isolate shows organism despite 
negative immediate release tests, or this AE is noted in two or more participants despite 
negative final culture and immediate release tests. 
3. Loss of vision of > 3 lines not attributed to normal progression of the eye condition, noted 
in two or more participants during the study period. The DSMC will be notified at the time 
that one participant has loss of vision of > 3 lines, but a pause would not be triggered until 
a second participant experiences the event. 
4. New retinal vascular event in the study eye during the study period noted in two or more 
participants not attributable to normal progression of the underlying eye condition during 
the study period. 
5. Development of ocular neovascularization in the study eye not attributable to normal 
progression of the underlying eye condition during the study period in two or more 
participants. 
6. Development of new sustained elevation in intraocular pressure above 30 mmHg not 
controlled with medical therapy and/or paracentesis and directly attributed to the studied 
therapy in any participant. 

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7. Any adverse event leading to enucleation or loss of the eye directly related to study 
therapy. 
These guidelines may be further refined by the DSMC before initiation of the study. In the event 
any of these pause guidelines are triggered during the course of the study, both the IRB and FDA 
will be notified within 7 days and the study enrollment will be paused until further notice from the 
FDA and/or IRB. The study participant will be followed and treated according to standard of care 
until condition stabilizes or resolves. 
6.5 Compliance with Laws and Regulations 
This study will be conducted in accordance with current U.S. Food and Drug Administration (FDA) 
Good Clinical Practices (GCP), and the Institutional Review Board and Stem Cell Oversight 
Committee of the University of California Davis Medical Center. 
 

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7.0 
MATERIALS AND METHODS 
7.1 Participants 
7.1.1 Participant Selection 
All participants will be enrolled at the Retina Clinic at the University of California Davis Eye Center. 
The participants may include patients already being treated in the clinic and patients referred to 
the Enrollment Center for consideration for study enrollment. All patients with persistent vision 
loss from CRVO will be considered for enrollment if they meet the eligibility criteria. 
7.1.2 Inclusion/Exclusion Criteria 
7.1.2.1 Study Eye Inclusion/Exclusion Criteria 
Inclusion criteria for the study eye are: 
1. Clinical diagnosis of central retinal vein occlusion (CRVO) confirmed by review of medical
records and screening assessment.
2. BCVA obtained during the screening period is in the range of 20/40+ to 20/400- (ETDRS
letter score in the range of 18 to 73, inclusive).
3. Duration of vision loss from CRVO > 6 months to ≤ 42 months.
Exclusion criteria for the study eye are: 
1. Previous eye treatment with intravitreal or periocular steroids, laser or intraocular surgery
within 6 months prior to enrollment (i.e., date ICF signed) or treatment is expected to be
given during the study period.
2. For eyes requiring treatment to prevent recurrent macular edema, on-going intravitreal
anti-VEGF treatment is expected to be given at an interval < every 8 weeks during the
study period or anti-VEGF therapy was started less than 24 weeks prior to informed
consent.
3. History or concurrent ocular herpes infection.
4. Active non-herpetic eye infection diagnosed within 8 weeks from enrollment (i.e., date ICF
signed).
5. Glaucoma requiring treatment with more than 2 medications, laser or intraocular surgery.
6. Active uveitis or history of recurrent uveitis or uveitis involving the posterior segment.
7. Presence of cataract that is impairing vision.
8. Presence of lens or lens implant subluxation.
9. History of ocular trauma that is currently impairing vision.
10. Any concurrent optic nerve or retinal disease that is visually significant or likely to progress
to visual significance during the 1-year study follow-up. The excluded eyes include eyes
with AREDS category 2 to 3 age-related macular degeneration (AMD) with foveal
involvement of drusen or RPE changes, and any AREDS category 4 AMD eyes. For eyes
with ERM, the excluded eyes include eyes with OCT evidence of foveal deformation. For
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CNVM are excluded. For glaucoma eyes, eyes requiring glaucoma laser trabeculectomy 
or glaucoma surgery to maintain IOP are excluded. 
11. Active retinal or iris neovascularization. 
12. Macular edema requiring on-going therapy or where such treatment is expected during 
the study period, with the exception of anti-VEGF treatment given at an interval of 8 weeks 
or greater. 
13. Significant media opacity precluding view of the fundus for examination, photography or 
optical coherence tomography (OCT) including cataract and vitreous haze. 
14. High myopia (> 9 diopters) 
15. Amblyopia 
16. Other cause contributing to vision loss at screening. 
17. History of any of the following procedures: corneal transplant, glaucoma surgery, or 
intraocular silicone oil. 
7.1.2.2 Participant-Level Inclusion/Exclusion Criteria 
Participants must meet the following inclusion criteria: 
1. Age > 18 years of age. 
2. Female participants of child-bearing potential (see APPENDIX B for definition) must not 
be pregnant or breastfeeding and have a negative urine pregnancy test within 14 days 
prior to sham injection and/or CD34+ cell injection. 
3. Females of childbearing potential must have had a hysterectomy, be completely abstinent 
from intercourse or must agree to practice effective contraception for the duration of the 
study. Acceptable methods of contraception include hormonal contraception, intrauterine 
device, barrier methods (diaphragm, condom) with spermicide, or surgical sterilization 
(tubal ligation). 
4. Able and willing to sign informed consent. 
5. Able to keep follow-up appointments for at least 12 months as determined by the 
investigator. 
Participants with any of the following criteria will be excluded from the study: 
1. Concurrent treatment with an investigational drug or device. 
2. Concurrent use of systemic immunosuppressive therapy or history of use within 3 months 
prior to enrollment (i.e., date ICF signed). 
3. Concurrent use of anticoagulation therapy except for aspirin without an acceptable safe 
stopping plan for study treatments. 
4. Known history of coagulopathy or other hematologic abnormality that may put participant 
at risk for bleeding or infection or raise concerns about quality or quantity of CD34+ cells 
isolated. 
5. History of allergy to fluorescein dye. 

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6. Participant who has had a prior or concomitant malignancy with the exception of the 
following: 1) adequately treated basal or squamous cell carcinoma of the skin, or 2) any 
other malignancy from which the patient has remained disease free for more than five 
years. 
7. Current active systemic infection as evidenced by fever greater than 100.4 or any 
evidence of systemic infection as determined by the study physician. 
8. Any diagnosis of active infection or vaccination within 8 weeks prior to receipt of study 
treatment. 
9. Diabetes mellitus with known systemic complications by self-report or physician-
determined by medical history or examination. 
10. History of prior radiotherapy to head/neck area. 
11. Poorly controlled hypertension with systolic > 180 or diastolic > 95. 
12. Serious medical or psychiatric condition that, in the opinion of the Investigator, would make 
study participation hazardous to the participant or compromise study findings or would 
prevent the participant from completing the study. 
13. Any physical characteristic that precludes ability to perform study diagnostic testing. 
7.1.2.3 Selection of Study Eye 
If both eyes meet all of the study eye eligibility criteria outlined in section 7.1.2.1, the study eye 
will be the one with the worse visual acuity as noted at the screening visit. If visual acuity is the 
same, then the eye with stable fixation on microperimetry will be selected as the study eye. If both 
eyes have stable fixation, then the eye with lower macular sensitivity will be the study eye. 
7.2 Method of Treatment Assignment 
This is a randomized, prospective, double-masked, sham-controlled study. Eligible participants 
will be randomized in a 1:1 ratio, using a computerized block randomization scheme, to immediate 
cellular therapy/deferred sham therapy or immediate sham therapy/deferred cellular therapy, 
where cellular therapy consists of bone marrow aspiration and intravitreal injection of isolated 
CD34+ cells and sham therapy consists of sham aspiration and sham injection. 
Randomization will occur after informed consent has been obtained and once a participant is 
confirmed to be eligible. Great care will be taken to choose participants who are highly motivated 
to participate so as to prevent drop-out post-randomization. 
7.3 Study Treatment 
Bone marrow aspiration, CD34+ stem cell isolation and intravitreal administration will be 
performed using sterile techniques. All three procedures will be done on the same day to 
maximize viability of the isolated cells. Similarly, the corresponding sham bone marrow aspiration 
and sham injection will be administered within the same day. The number of viable nucleated 
CD34+ cells to be injected in the eye will vary from 800,000 to 10 million cells per eye, depending 
on the volume of the marrow aspirated and the efficiency of the stem cell isolation procedure, 
where the cell count is based on the Miltenyi CliniMACS cell sorting process. On average, we 
anticipate injecting about one million CD34+ stem cells per eye in a volume of 0.1 ml.23 
 
 

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7.4 Concomitant and Excluded Therapies 
All participants will be treated with topical antibiotics in the study eye for one week after the 
intravitreal injection (including eyes with sham injection) to minimize the risk of infection. During 
the course of the study, no other intraocular injection (with the exception of maintenance anti-
VEGF therapy as described below), retinal laser or surgeries will be administered in the study eye 
unless the participant develops a new ocular condition that requires therapy as part of standard 
of care. An adverse event form will be completed in Advantage eClinical to report the occurrence 
of any new ocular condition requiring intervention. The report will include specification of the 
intervention taken for the new condition. (See section 8.6.) In addition, a concomitant medications 
form will be completed to provide information about all medications/interventions the participant 
takes/receives. If the study eye develops macular edema which would need to be treated with 
intravitreal anti-VEGF therapy as standard of care, intravitreal anti-VEGF therapy will be 
administered but will not be administered 4 weeks before or after either study procedures. New 
macular edema with Central Macular thickness of > 300 microns with concurrent decrease in 
BCVA of 2 or more lines will be used as criteria for initiating intravitreal anti-VEGF therapy as part 
of standard of care. Among patients who have been maintained on intravitreal anti-VEGF therapy 
as standard of care prior to study enrollment at an interval of 8 weeks or greater, intravitreal anti-
VEGF therapy will be continued as part of standard of care but not administered 4 weeks before 
or after study procedures. All elective eye surgeries or procedures will be deferred until the end 
of the study if possible. Participants may receive vaccinations (e.g., seasonal flu, COVID-19); 
except within 8 weeks prior to receipt of any study treatment (Treatment 1 and 2). 
7.5 Study Assessments and Monitoring of Study Progress 
All participants will be examined 1 day, 1 week (±2 days), 1 month (±7 days), 3 months (±14 
days), and 6 months (±30 days) following each of the two therapies (sham or cellular). These 
examinations will evaluate for any ocular adverse effect associated with the therapy and to gauge 
for any possible benefit. The details of the diagnostic tests to be performed are as outlined in 
TABLE 2 for the 2 study groups. Participants will follow the same follow-up schedule regardless 
of which study group they are assigned. 
During the first week after cellular therapy, the bone marrow aspiration site will be visually 
inspected for evidence of infection or bleeding. To maintain masking, a similar post-procedure 
examination will be performed for the participants receiving sham therapy. 
The study progress will be monitored by the Study Chair/PI and the DCC. After every six months 
or on a schedule approved by the DSMC, a summary of study enrollment, study retention, adverse 
events, and study outcomes as appropriate will be presented and reviewed by the DSMC. An 
annual report of the study progress will be submitted to the local regulatory agencies and the 
FDA. 
7.6 Participant Discontinuation/Replacement 
Participants have a right to withdraw from the study at any time and for any reason. The 
Enrollment Center may request to withdraw a participant because of protocol deviation, 
administrative reasons, safety concerns, inadequate number of viable nucleated CD34+ cells 
harvested for intravitreal injection (where the cell count is based on the Miltenyi CliniMACS cell 
sorting process) or any other valid and ethical reasons. A study termination form will be completed 
citing the reason for the termination. In the event that a participant is terminated from the study 

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after randomization and prior to receipt of treatment (cellular or sham) at the Treatment 1 visit 
regardless of the reason, an additional participant will be accrued as a replacement. In the event 
that a participant receives the first treatment but opts not to receive the second treatment, an 
additional participant will be accrued as a replacement, but the original participant will be 
encouraged to return for all study visits to ensure the participant’s safety is not compromised. The 
replacement participant will receive both treatments and will be followed for 12 months, the same 
as any other participant enrolled in the study. If a participant is terminated or withdraws from the 
study following the receipt of the second treatment, the participant will again be encouraged to 
return for all study visits for safety monitoring but will not be replaced. A maximum of one 
participant may be replaced, regardless of timing of withdrawal. If a participant terminates the 
study due to having less than 800,000 viable nucleated CD34+ cells (where the cell count is based 
on the Miltenyi CliniMACS cell sorting process) in the final product for intravitreal injection, the 
participant will have the option to receive the harvested cells as part of the on-going open-label 
pilot study provided that the harvested cells pass the release criteria for quality and sterility. 
7.7 Study Discontinuation 
This study may be terminated by the Study Chair/PI, Enrollment Center, FDA, the local regulatory 
agencies or NEI at any time. The DSMC may also recommend termination. Reasons for 
terminating the study may include the following: 
1. The incidence and severity of adverse events in this or other studies indicates a potential 
health hazard to participants 
2. Participant enrollment is unsatisfactory 
3. Data recording is inaccurate or incomplete 
7.8 Statistical Methods 
7.8.1 General Design 
This is a phase I/II randomized, prospective, double-masked, sham-controlled study to determine 
the feasibility, safety and potential efficacy of intravitreal injection of autologous adult CD34+ cells 
from bone marrow in participants with vision loss from CRVO. Participants will be randomized 1:1 
to immediate cellular therapy/deferred sham therapy or immediate sham therapy/deferred cellular 
therapy. After their first treatment (cellular or sham), participants will be followed for 6 months, at 
which time participants who initially received sham treatment will receive cellular treatment and 
vice versa. 
7.8.1.1 Outcomes 
The primary outcome measures for the safety and feasibility of the stem cell therapy are incidence 
and severity of ocular and systemic adverse events reported during Study Period 1 (i.e., the day 
of the first treatment (Treatment 1) up to but not including the day of the second treatment 
(Treatment 2)), and the mean and range of number of CD34+ cells isolated from the bone marrow 
aspirate and the number injected into the eye. All adverse events reported throughout the study 
duration will also be examined as the secondary safety outcome measure. 
The secondary efficacy outcome measures will be used to describe the effect of therapy on retinal 
function and morphology in the study eye. They include visual acuity letter score based on the 
ETDRS chart, macular sensitivity from microperimetry, OCT parameters including macular 
thickness and macular volume, OCT angiography parameters including foveal avascular zone 

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size and vascular density, parameters from multifocal ERGs including macular signal amplitude 
and latency and number of abnormal amplitude and latency hexagons, parameters from full-field 
ERG including measurements of the “a” and “b” wave amplitudes and latency under scotopic and 
photopic conditions and flicker amplitude, area of decreased and increased autofluorescence, 
foveal avascular zone integrity and percent of the retina with capillary non-perfusion on 
fluorescein angiography, degree of retinal hemorrhages, pigment changes, retinal fibrosis, NV 
and pre-retinal hemorrhage on fundus photography, and total score and subscale scores on 
vision-related quality of life as measured on the NEI VFQ-25. Each will be examined at baseline, 
and serially following each treatment. See Section 6.3.2 for a complete list of planned outcome 
measures. 
Exploratory outcomes include descriptive analysis of changes in the retina and retinal vasculature 
at a cellular level as visualized using Adaptive optics-OCT instrument following cellular therapy 
and sham therapy, changes in the retinal vascular density and retinal morphology using ultrahigh 
resolution swept-source OCT and OCTA following cellular therapy and sham therapy, and 
characterization of the hematopoietic and endothelial stem cell subcomponents and 
subcomponent of cells with VEGFR-2 in the CD34+ cell population. We will also characterize 
participants' experience with various aspects of the study, including their impressions on timing 
of receipt of cellular therapy vs sham therapy, through the use of participant surveys. The latter 
is to determine if masking was maintained among participants during the study. We will report on 
the number of participants who were able to correctly identify the timing of receipt of the sham 
and cellular therapies. 
7.8.2 Analysis of Primary and Secondary Outcomes 
7.8.2.1 Safety and Feasibility 
Any ocular or systemic adverse events (AEs) from all participants will be utilized to summarize 
safety data for this phase I/II study. All reported AEs will be analyzed and subdivided into pre-
treatment and post-treatment AEs, where post-treatment is defined as those occurring on or after 
the day of the first treatment (cellular or sham). AEs will be summarized by presenting the number 
of events, and also by counts and frequencies for the number of participants with AEs, and the 
severity and relatedness of each AE to study treatment (i.e., CD34+ cells) or study procedure 
(i.e., intravitreal injection). Events related to bone marrow or sham aspiration will also be 
presented. Detailed listings of post-treatment AEs and pre-treatment AEs will be provided. All AEs 
will be coded using MedDRA® dictionary version 21.0 or higher. A similar approach will be taken 
to the presentation of Serious Adverse Events (SAEs). 
Time trends in the occurrence of adverse events are also of interest. The primary safety outcome 
will be assessed at month 6 (at the end of Study Period 1). Adverse events that occur during the 
Study Period 1 will be broken down by whether the AE occurred following the sham or cellular 
treatment to assess differences in the adverse event experience between the two treatment arms. 
In addition, in order to assess whether there are any trends in when adverse events are reported 
from time of cellular therapy, we will also present adverse events based on how much time has 
elapsed from receipt of cellular therapy. Depending on how many events are reported, we may 
create categories for reporting purposes (e.g., events reported between Day 0 and 1-month post-
therapy, events reported between 1 and 6 months, events reported between 6 and 12 months, 
etc.). In this analysis, data will be collapsed over both treatment arms. 

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To assess feasibility, the number and percent of study participants undergoing successful bone 
marrow aspiration will be summarized. The mean and range of volume of bone marrow aspirate, 
number of CD34+ cells isolated and number of CD34+ cells injected intravitreally will be 
described. 
7.8.2.2 Efficacy 
All secondary outcome analyses will follow a similar form and strategy as outlined in the SAP. 
Data from the study eye will be presented. Tables and graphs of each outcome and change from 
baseline in each outcome will accompany the results of the analyses as appropriate and will be 
used to visualize the trends over time. See Section 6.3.2 for a list of outcomes of interest. A 
(modified) intent-to-treat approach will be followed in which all participants who were randomized 
and received the first injection (cellular or sham) will be included in the analysis and analyzed in 
the arm to which they were randomized. 
The primary analysis will be a comparison at 6 months between those who receive immediate 
cellular therapy vs those who receive immediate sham therapy. A t-test will be used for continuous 
outcomes and Fisher’s exact test or an appropriate non-parametric test may be used for 
categorical outcomes. Comparisons at other time points prior to 6 months may also be performed. 
An additional analysis will look at treatment effect duration for those who receive immediate 
cellular therapy and assess whether the treatment effect remains the same at 6 and 12 months 
or increases/decreases as time passes. 
As noted in Section 6.3.2, there are many outcomes of interest within each modality. P-values 
calculated from the statistical tests noted above will only be used as an indication of strength of 
association and should not be used for hypothesis testing. 
7.8.2.3 Exploratory Endpoints 
The following exploratory analyses will be performed: 
• 
Analysis of changes in retina and retinal vasculature at a cellular level as visualized using 
Adaptive optics-OCT instrument in the study eye at 1 month following each treatment. 
• 
Analysis of changes from baseline in retinal vascular density and retinal morphology 
ultrahigh resolution swept-source OCT and OCTA at 1 month following each treatment. 
• 
Analysis correlating percent hematopoietic and endothelial stem cell subcomponents and 
percent of cells with VEGFR-2 in the CD34+ cell population with primary and secondary 
outcome measures. 
• 
Descriptive analysis of number of participants who were able to correctly identify the timing 
of receipt of sham and cellular therapies. 
7.8.3 Sample Size Considerations 
There is no formal sample size calculation for this small phase I/II study. A sample size of 20 
participants was chosen to ensure that it is financially feasible to conduct the study and logistically 
possible to complete the study enrollment within the study period. The primary objective is to 
assess the safety and feasibility of the stem cell therapy; however, it is desired to obtain some 
gauge of potential efficacy of this cell therapy. Thus, participants will be randomized 1:1 to 
immediate cellular therapy/deferred sham or immediate sham/deferred cellular therapy. After their 
first treatment (cellular or sham), participants will be followed for 6 months, at which time 

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participants who initially received sham treatment will be given stem cell treatment and vice versa. 
The small sample size is not ideal, but for practical purposes, it would be difficult to increase the 
sample size significantly without increasing the enrollment period for the study. 
Although the study as designed may not be large enough to determine efficacy, some efficacy 
signals might be observed with the current study design. Such a signal may warrant further 
investigation of this treatment for CRVO. When a phase II/III randomized controlled trial is 
planned, appropriate statistical analysis and sample size calculation will be determined. 
It is recognized that the study has limited power to show efficacy; however, we hope to obtain 
some trends in change in visual function or retinal morphology or perfusion that may suggest 
efficacy to justify a larger randomized prospective clinical trial. Power calculations are presented 
in the separate Statistical Analysis Plan (SAP) for the proposed method of analyzing the 
secondary outcomes. 
7.9 Data Quality Assurance 
The Data Coordinating Center (DCC) will develop and apply data management procedures during 
the course of this study to ensure accuracy and reliability of data. In addition, the DCC will conduct 
a site visit prior to study initiation, at study close-out, and approximately biannually during the 
course of the study as outlined in the Manual of Procedures. In addition, the DCC will be in regular 
communication, at least monthly, with the Study Chair/PI and/or Study Coordinator(s) regarding 
any study related issues. These communications and site visits are to ensure that the Enrollment 
Center is adhering to the study protocol, the study personnel are adequately trained, the facility 
meets the standards for the study, participant enrollment is progressing as scheduled, and the 
data collected is of good quality. The collected data will be summarized by the DCC and presented 
to the DSMC every 6 months or on a schedule approved by the DSMC for review during the 
course of the study. An annual report of the study progress and interim findings will be submitted 
to the local regulatory agency and FDA. 
 

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ASSESSMENT OF SAFETY 
The safety of intravitreal injection of autologous CD34+ cells isolated from bone marrow will be 
assessed through regular eye examinations during the 12 months participants are enrolled in the 
study. Adverse events (e.g., signs, symptoms, disease, syndrome, illness) including new or 
worsening ocular conditions that occur from the time the participant signs informed consent until 
the final study visit will be recorded, regardless of suspected cause in accordance with the study 
protocol and Manual of Procedures. An adverse event (AE) and/or serious adverse event (SAE) 
form will be completed and the information will be entered into Advantage eClinical. 
8.1 Definitions 
An adverse event (AE) is any untoward medical occurrence, whether or not considered treatment- 
or procedure-related, which occurs during the conduct of the study. Medical conditions or 
diseases present before a participant has study treatment on Day 0 are only considered adverse 
events if they worsen after the participant has signed ICF (temporal association). 
A suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the study treatment caused the adverse event. A reasonable possibility implies that there is 
evidence that the study treatment caused the event. 
An adverse reaction is any adverse event caused by the study treatment. 
A Serious Adverse Event (SAE) is defined as any adverse event that suggests a significant 
hazard, contraindication, side effect, or precaution. This includes, but may not be limited to any 
of the following events: 
1. Death 
2. Life-threatening (Life-threatening means that the study participant was, in the opinion of 
the investigator, at immediate risk of death from the reaction as it occurred.) 
3. Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
4. Inpatient hospitalization or prolongation of existing hospitalization 
5. Congenital abnormality or birth defect 
6. Important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical intervention to 
prevent one of the outcomes listed in the above definition of serious event 
7. Vision-threatening (Refer to Section 8.3, Vision threatening Adverse Events) 
Hospitalization or surgery for diagnostic or elective procedures for a preexisting condition is not 
considered an SAE. A pre-existing condition can be an SAE if the frequency, intensity or character 
of the condition worsens after signing of informed consent. If any questions arise regarding what 
may qualify as an adverse event or SAE, the Medical Monitor at the DCC will be consulted. 
Unexpected Event or Reaction: An event or reaction is considered “unexpected” when its nature 
(specificity) or severity is not consistent with applicable product information, such as safety 
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8.2 Pregnancy 
Pregnancy in and of itself, is not regarded as an AE. A confirmed pregnancy in a participant (by 
urine or blood test) should be reported to the DCC via the Advantage eClinical system as soon as 
the Investigator has been made aware of the pregnancy. The decision to terminate the participant 
from the study will be made by the PI or designee and the participant following consultation with 
the DSMC. The PI or designee will use his/her expert judgment, based on an assessment of the 
potential benefit/risk to the participant, to determine if it is in the participant’s best interest to 
continue participation in the study. 
The pregnancy should be followed until an outcome is known. The outcome of all such 
pregnancies (i.e., spontaneous miscarriage, elective termination, still births, normal birth or 
congenital abnormality) must be documented and followed-up on a case report form that will be 
provided by the DCC. The pregnancy will be followed until an outcome, including any premature 
termination, must be reported to the DCC. All live births must be followed for a minimum of 30 
days or to the first well-baby visit. All reports of congenital abnormalities/birth defects and 
spontaneous abortions/miscarriages should be reported as an SAE for this study. Elective 
abortion procedures, without complications, should not be considered as AEs unless they require 
hospitalization. 
8.3 Vision Threatening Adverse Events 
An adverse event will be considered vision-threatening and reported as an SAE if it has one of 
the following features: 
• 
A vision loss of > 30 letters on the ETDRS chart compared to the last measurement 
provided the vision loss lasts > 1 hour. 
• 
Resulting BCVA is light perception or worse for > 1 hour. 
• 
Surgical intervention (including ocular procedures such as laser or cryopexy, intraocular 
injections, or aspiration of fluid) is required to prevent permanent loss of vision. 
• 
There is severe intraocular inflammation (4+ cell in the anterior chamber or vitreous). 
• 
Medical intervention is required to prevent permanent vision loss in the opinion of the 
investigator. 
8.4 Causality 
The Investigator will use the following question when assessing causality of any adverse event to 
study treatment: Is there a reasonable possibility that the administered cellular product caused 
the event? An affirmative answer designates the event as a suspected adverse reaction. 
In addition, each adverse event will be assessed for its relationship to study procedures, including 
the injection itself. The Investigator will use the following question when assessing causality of an 
adverse event to study procedure: Is there a reasonable possibility that the intravitreal injection 
procedure caused the event? 
The Medical Monitor at the DCC is available for consultation on assessing causality. For SAEs, 
the Medical Monitor will evaluate all reported SAEs against all accumulating knowledge regarding 
the study treatment. If the Medical Monitor’s causality determination differs from the Investigator’s 
assessment, the Medical Monitor’s determination will prevail for regulatory reporting purposes. 

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8.5 Naming and Grading of Adverse Events 
Each adverse event will be graded for severity based on the severity grading outlined below: 
Grade 1 
(Mild) An AE that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities. 
Grade 2 
(Moderate) An AE that is sufficiently discomforting to interfere with normal everyday 
activities. 
Grade 3 
(Severe) An AE that prevents normal, everyday activities. In adults, such an AE 
would, for example, prevent attendance at work/school and would necessitate the 
administration of corrective therapy. 
All adverse events will be followed by the Investigator until resolution or up to one month after 
study termination or until the study participant is lost to follow-up. The Investigator will treat or 
observe participants with adverse events as appropriate for standard of care and follow the 
participants at regular intervals until resolution or stabilization of the adverse event. 
8.6 Adverse Event Reporting 
Each adverse event will be recorded in the participant’s medical record and the adverse event 
source document will be completed by the Study Coordinator and Investigator. The Study 
Coordinator completing the adverse event documentation form will be the study coordinator 
assigned to the visit and may be masked or unmasked depending on the visit. The information 
will be transmitted to the DCC using Advantage eClinical. All serious adverse events will be 
reported to the DCC within 24 hours of its occurrence and/or the site’s knowledge of the event. 
All other adverse events will be reported to the DCC within 7 days of the site becoming aware of 
the event. 
8.7 Regulatory Reporting 
Death or life-threatening serious adverse events that are related to therapy and unexpected will 
be reported to the FDA and local regulatory agencies within 7 days. All other adverse events that 
are serious, related to therapy, and unexpected will be reported to the FDA in 15 days. The initial 
notification may be via a telephone call or a fax. A written IND Safety Report will be written and 
submitted within 15 days following the notification of the event. 
 

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9.0 
REFERENCES 
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3. Booth C, Veys P. T cell depletion in paediatric stem cell transplantation. Clin Exp Immunol. 
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4. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for 
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5. Vrtovec B, Poglajen G, Sever M, et al. CD34+ stem cell therapy in nonischemic dilated 
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6. Quyyumi AA, Vasquez A, Kereiakes D, et al. PreSERVE-AMI: A randomized, double-blind, 
placebo-controlled clinical trial of intracoronary administration of autologous CD34+ cells in 
patients with left ventricular dysfunction post STEMI. Circ Res. 2016; Epub ahead of print. 
7. Rafii S, Meeus S, Dias S, et al. Contribution of marrow-derived progenitors to vascular and 
cardiac regeneration. Semin Cell Dev Biol. 2002; 13: 61-67. 
8. Schmeisser A, Strasser RH. Phenotypic overlap between hematopoietic cells with suggested 
angioblastic potential and vascular endothelial cells. J Hematother Stem Cell Res. 2002; 11: 
69-79. 
9. Zhang QH, She MP. Biological behaviour and role of endothelial progenitor cells in vascular 
diseases. Chin Med J (Engl). 2007; 120: 2297-2303. 
10. Sheridan CM, Pate S, Hiscott P, Wong D, Pattwell DM, Kent D. Expression of hypoxia-
inducible factor-1alpha and -2alpha in human choroidal neovascular membranes. Graefes 
Arch Clin Exp Ophthalmol. 2009; 247: 1361-1367. 
11. Sidney LE, Branch MJ, Dunphy SE, Dua HS, Hopkinson A. Concise review: Evidence for 
CD34 as a common marker for diverse progenitors. Stem Cells. 2014; Epub ahead of print. 
12. Masuda H, Asahara T. Clonogenic assay of endothelial progenitor cells. Trends Cardiovasc 
Med. 2013; 23: 99-103. 
13. Harris JR, Brown GA, Jorgensen M, et al. Bone marrow-derived cells home to and regenerate 
retinal pigment epithelium after injury. Invest Ophthalmol Vis Sci. 2006; 47: 2108-2113. 
14. Li Y, Reca RG, Atmaca-Sonmez P, et al. Retinal pigment epithelium damage enhances 
expression of chemoattractants and migration of bone marrow-derived stem cells. Invest 
Ophthalmol Vis Sci. 2006; 47: 1646-1652. 
15. Otani A, Dorrell MI, Kinder K, et al. Rescue of retinal degeneration by intravitreally injected 
adult bone marrow-derived lineage-negative hematopoietic stem cells. J Clin Invest. 2004; 
114: 765-774. 
16. Caballero S, Sengupta N, Afzal A, et al. Ischemic vascular damage can be repaired by 
healthy, but not diabetic, endothelial progenitor cells. Diabetes. 2007; 56: 960-967. 
17. Park SS, Caballero S, Bauer G, et al. Long-term Effects of Intravitreal Injection of GMP-grade 
Bone Marrow Derived CD34+ Cells in NOD-SCID Mice with Acute Ischemia-Reperfusion 
Injury. Invest Ophthalmol Vis Sci. 2012; 53, 986-994. 

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18. Calzi L, Kent DL, Change KH, et al. Labeling of stem cells with monocrystalline iron oxide for 
tracking and localization by magnetic resonance imaging. Microvasc Res. 2009; 78: 132-139. 
19. Moisseiev E, Smit-McBride Z, Oltjen S, et al. Intravitreal administration of human bone marrow 
CD34+ stem cells in a murine model of retinal degeneration. Invest Ophthalmol Vis Sci. 2016; 
57: 4125-4135. 
20. Siqueira RC, Messias A, Voltarelli JC, Scott IU, Jorge R. Intravitreal injection of autologous 
bone marrow-derived mononuclear cells for hereditary retinal dystrophy: a phase I trial. 
Retina. 2011; 31: 1207-1214. 
21. Jonas JB, Witzens-Harig M, Arseniev L, Ho AD. Intravitreal autologous bone-marrow-derived 
mononuclear cell transplantation. Acta Ophthalmologica. 2010; 88: e131. 
22. Park SS, Moisseiev E, Bauer G, et al. Advances in bone marrow stem cell therapy for retinal 
dysfunction. Prog Retin Eye Res. 2016; Epub ahead of print. 
23. Park SS, Bauer G, Abedi M, et al. Intravitreal autologous bone marrow-derived CD34+ cells 
for ischemic and degenerative retinal disorders: preliminary phase 1 clinical trials findings. 
Invest Ophthalmol Vis Sci. 2014; 56: 81-89. 
24. Mitchell P, Smithe W, Chang A. Prevalence and association of retinal vein occlusion in 
Australia: The Blue Mountain Eye Study. Arch Ophthalmol. 1996; 114: 1243-1247. 
25. Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein occlusion: the Beaver 
Dame Eye Study. Trans Am Ophthalmol Soc. 2000; 98: 133-141. 
26. Rogers S, MoIntosh RL, Cheung N, et al. The prevalence of retinal vein occlusion: pooled 
data from population studies from the United States, Europe, Asia, and Australia. 
Ophthalmology. 2010; 117: 313-319. 
27. Central Vein Occulsion Study Group. Natural history and clinical management of central 
retinal vein occlusion. The Central Retinal Vein Occlusion Group. Arch Ophthalmol. 1997; 
115: 486-491. 
28. The SCORE Study Research Group. SCORE Study Report 5. A randomized trial comparing 
the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss 
associated with macular edema secondary to central retinal vein occlusion. Arch Ophthalmol. 
2009; 127: 1101-1114. 
29. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following 
central retinal vein occlusion. Six-month prmary end point results of a phase III study. 
Ophthlamology. 2010; 117: 1124-1133. 
30. McIntosh RL, Rogers SL, Lim L, et al. Natural history of central retinal vein occlusion: an 
evidence-based systematic review. Ophthalmology. 2010; 117:1113–1123. 
 
 

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APPENDIX A: Ethnic Distribution of Patients Seen at the University of California 
Davis Eye Center Eye Clinic between 11/1/12 to 10/31/13 
Based on Patients’ Response 
Afghan 
0.0% 
American Indian/Alaskan 
0.0% 
Black 
1.4% 
Cambodian 
0.0% 
Caucasian 
7.3% 
Chinese 
0.1% 
Declined to state 
2.2% 
Filipino 
0.0% 
Hispanic or Latino 
8.4% 
Indo-Chinese Non-Spec 
0.0% 
Iranian 
0.0% 
Japanese 
0.0% 
Korean 
0.1% 
Laotian/Hmong 
0.0% 
Mexican American 
1.0% 
N. African Non-Spec 
0.0% 
No Response 
16.5% 
Not Hispanic or Latino 
58.6% 
Other 
2.7% 
Other Asian/Mideastern 
0.5% 
Other Hispanic 
0.0% 
Other Pacific Island 
0.0% 
Pakistani 
0.0% 
Unknown 
0.9% 
Vietnamese 
0.1% 
Total: 
100.0% 
 
 

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APPENDIX B: Determining Childbearing Potential 
A female participant who is considered non-childbearing due to a medical condition (i.e., 
participant has previously undergone a hysterectomy) does not need a pregnancy test, Follicle-
stimulating Hormone (FSH) test, or contraception. 
If a female participant is considered non-childbearing due to menopause, it must be in accordance 
with the following guidance on the definition of menopause. This guidance defines menopause 
as: 
Women over age 55 who have not had a period for one year will be considered menopausal 
and do not need a pregnancy test, FSH test, or contraception. 
Women between 50 and 55 who have not had a period for one year should have an FSH test. 
If their FSH level is ≥ 20 mIU/mL, they will be considered menopausal and do not need 
pregnancy testing or contraception. If their FSH level is < 20 mIU/mL, they will need pregnancy 
testing and contraception as required by the protocol. 
Women between 45 and 50 who have not had a period for one year will need both an FSH 
test and a pregnancy test. If they are not pregnant and their FSH level is ≥ 20 mIU/mL, they 
will be considered menopausal and will not require contraception or additional pregnancy 
testing. If their FSH test is < 20 mIU/mL, they will need pregnancy testing and contraception 
as required by the protocol.