A Pilot Study for the Evaluation of Minocycline as a Microglia Inhibitor in the Treatment of Central Retinal Vein Occlusions
Phase: PHASE1
Conditions: Retinal Vein Occlusion
Sponsor: National Eye Institute (NEI)

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page i 
Protocol Title:  A Pilot Study for the Evaluation of Minocycline as a Microglia Inhibitor in the 
Treatment of Central Retinal Vein Occlusions 
NCT Number: NCT01468844 
Date of This Submission/Version: September 19, 2018/v19.0 
Principal Investigator 
Catherine Cukras, MD, 
PhD
NEI/NIH 
Building 10, 
Room 10C438
301-435-5061 
cukrasc@nei.nih.gov 
Principal Investigator – Biomedical Research Centre (BRC) Sites 
Clare Bailey, MD 
BEH/ 
UHB 
Bristol Eye 
Hospital 
+44 (0) 7939- 
152-376 
clare.bailey@bristol.ac.uk 
Bishwanath Pal, 
MBBS, MS, Ophth, 
FRCOphth, FRCSEdin 
MEH 
Moorfields 
Eye Hospital 
+44 (0) 207-
566-2419 
Bishwanath.Pal@moorfiel
ds.nhs.uk 
Lead Associate Investigator 
Wai Wong, MD, PhD 
NEI/NIH 
Building 6, 
Room 217 
301-496-7566 
wongw@nei.nih.gov 
Associate Investigators 
Emily Y. Chew, MD 
NEI/NIH 
Building 10, 
Room 3-2531 
301-496-6583 
echew@nei.nih.gov 
Henry Wiley, MD 
NEI/NIH 
Building 10, 
Room 10D45
301-451-4261 
wileyhe@nei.nih.gov 
Awilda V. Holland, 
DNP, MSHSc, RN, 
CCRP
NIH/NEI 
Building 10, 
Room 10D45 
301-435-1831 
aholland@mail.nih.gov 
Angela Kibiy, MPH, 
BSN, RN 
NEI/NIH 
Building 10, 
Room 10D45
301-435-1833 
angela.kibiy@nih.gov 
Alexander Kaplan, MD 
NIH/NEI 
Building 10, 
Room 10D45 
301-443-8557 
alex.kaplan@nih.gov 
Munir Iqbal, MD, 
FRCSC 
NIH/NEI 
Building 10, 
Room 3-2531 
301-496-6583 
munir.iqbal@nih.gov 
Christopher Hwang, 
MD 
NIH/NEI 
Building 10, 
Room 3-2531 
301-496-6583 
christopher.hwang@nih.gov 
Medically Accountable Investigator 
Emily Y. Chew, MD 
NEI/NIH 
Building 10, 
Room 3-2531 
301-496-6583 
echew@nei.nih.gov 
Research Contact  
Angela Kibiy, MPH, 
BSN, RN 
NEI/NIH 
Building 10, 
Room 10D45
301-435-1833 
angela.kibiy@nih.gov 
 
 
 

MiCRVO 
September 19, 2018 
 
Version 19.0 
CONFIDENTIAL 
Page ii 
Coordinating Center : 
The Emmes Corporation (Emmes) 
401 North Washington St., Suite 700 
Rockville, MD 20850 USA 
Phone: (301) 251-1161 
Facsimile: (202) 478-0243 
 
Participating Site: 
 
Bristol Eye Hospital (BEH) 
Lower Maudlin Street 
Bristol BS1 2LX, UK 
Phone: +4401173424613 
Facsimile: +4401173424721 
 
Moorfields Eye Hospital (MEH) 
The John Saunders Suite 
9-11 Bath Street 
London EC1V 9LF, UK 
Phone: +44 (0) 2075-662-419 
Fax: +44 (0) 2075-662-972 
 
Human Research Protections Program Investigator and Staff Training: 
“Just in time” human subjects protection training courses are required for investigators and staff 
participating on this protocol: None 
 
Total Requested Accrual: 
20 
Participants – A minimum of 10 and a maximum of  
20 participants will be accrued. 
0 
Healthy Volunteers 
 
Project Uses Ionizing Radiation:  
 No 
 Yes 
 
IND/IDE: 
 No  
 Yes 
Drug/Device #: 
108,154 
Sponsor:  
Catherine Cukras, MD, PhD 
 
EudraCT: 
 
 
 
 
 No   
 Yes 
 
Drug/Device #: 
2017-001143-12 
 
Chief Investigator:  
Clare Bailey, MD 
 
Durable Power of Attorney: 
 No  
 Yes 
 
Multi-institutional Project: 
 No  
 Yes 
 
 

MiCRVO 
September 19, 2018 
 
Version 19.0 
CONFIDENTIAL 
Page iii 
Site 
FWA 
Coordinating Center: National Eye Institute (NEI) 
FWA00005897 
Participating Center: Bristol Eye Hospital (BEH) 
Principal Investigator: Clare Bailey, MD
FWA00000523 
Participating Center: Moorfields Eye Hospital (MEH) 
Principal Investigator: Bishwanath Pal, MBBS, MS, Ophth, FRCOphth, 
FRCSEdin 
FWA00010199 
 
Additional sites may be identified and added to this study in future amendments. 
Data and Safety Monitoring Board: 
 No  
 Yes 
 
Technology Transfer Agreement:   
 No   
 Yes 
 
Samples Being Stored for Future Use:  
 No  
 Yes 
 
Flesch-Kincaid Reading Level of Consent Form:  
9.5 

MiCRVO 
September 19, 2018 
 
Version 19.0 
CONFIDENTIAL 
Page iv 
TABLE OF CONTENTS 
PROTOCOL ABBREVIATIONS LIST ................................................................................................ VI 
PRÉCIS ............................................................................................................................................ 1 
1.0 INTRODUCTION/SCIENTIFIC RATIONALE ............................................................................. 3 
1.1 
Central Retinal Vein Occlusions ..................................................................................... 3 
1.2 
Current Treatments of CRVO ......................................................................................... 4 
1.3 
Role of Microglia ............................................................................................................ 4 
1.4 
Role of Microglia in Retinal Vein Occlusions ................................................................ 5 
1.5 
Minocycline as a Microglia Inhibitor ............................................................................. 6 
1.5.1 
Minocycline ................................................................................................................ 6 
1.5.2 
Preclinical Studies with Minocycline ......................................................................... 7 
1.5.3 
Clinical Use and Clinical Studies with Minocycline .................................................. 7 
2.0 STUDY OBJECTIVE ................................................................................................................. 8 
3.0 PARTICIPANTS ....................................................................................................................... 8 
3.1 
Participant Eligibility Criteria ......................................................................................... 8 
3.1.1 
Inclusion Criteria ........................................................................................................ 8 
3.1.2 
Exclusion Criteria ..................................................................................................... 10 
3.2 
Study Eye Eligibility Criteria........................................................................................ 11 
3.2.1 
Study Eye Inclusion Criteria ..................................................................................... 11 
3.2.2 
Study Eye Exclusion Criteria .................................................................................... 12 
3.2.3 
Study Eye Selection Criteria in Cases of Bilateral Disease ...................................... 13 
4.0 STUDY DESIGN AND METHODS ........................................................................................... 13 
4.1 
Study Overview ............................................................................................................ 13 
4.2 
Recruitment ................................................................................................................... 13 
4.3 
Screening....................................................................................................................... 14 
4.4 
Randomization, Masking and Unmasking .................................................................... 15 
4.5 
Study Design and Procedures ....................................................................................... 15 
4.5.1 
Treatment Prior to Month 3 ...................................................................................... 18 
4.5.2 
Treatment Beginning at Month 3 .............................................................................. 18 
4.6 
Ocular and Systemic Evaluations ................................................................................. 21 
4.6.1 
Reporting of Expected Events .................................................................................. 22 
4.7 
Study and Concomitant Therapy .................................................................................. 23 
4.7.1 
Minocycline Formulation at Pine Pharmaceuticals .................................................. 23 
4.7.2 
Minocycline Formulation for BRC Sites .................................................................. 23 
4.7.3 
Placebo Formulation at Pine Pharmaceuticals .......................................................... 23 
4.7.4 
Placebo Formulation for BRC Sites .......................................................................... 24 
4.7.5 
Dosage, Administration and Storage ........................................................................ 24 
4.7.6 
Concomitant Therapy................................................................................................ 24 
4.8 
Investigational Product Accountability ......................................................................... 24 
4.9 
Follow-up/Termination Procedures .............................................................................. 25 
4.10 
Storage of Samples and Data ........................................................................................ 25 
 
 
 

MiCRVO 
May 31, 2018 
 
TABLE OF CONTENTS (CONTINUED) 
Version 19.0 
CONFIDENTIAL 
Page v 
5.0 RISKS/DISCOMFORTS .......................................................................................................... 25 
5.1 
Intravitreal Bevacizumab Risks .................................................................................... 27 
5.2 
Investigational Product Risks ....................................................................................... 27 
5.2.1 
Minocycline-related .................................................................................................. 27 
5.2.2 
Drug Interaction-related ............................................................................................ 29 
5.2.3 
Placebo-related .......................................................................................................... 29 
6.0 PARTICIPANT MONITORING ................................................................................................ 29 
6.1 
Individual Withdrawal Criteria ..................................................................................... 29 
6.2 
Pregnancy Monitoring .................................................................................................. 30 
7.0 OUTCOME MEASURES ......................................................................................................... 31 
7.1 
Primary Outcome .......................................................................................................... 31 
7.2 
Secondary Outcomes .................................................................................................... 31 
7.3 
Safety Outcomes ........................................................................................................... 32 
8.0 STATISTICAL ANALYSIS ...................................................................................................... 32 
9.0 HUMAN PARTICIPANTS PROTECTION ................................................................................. 34 
9.1 
Equitability .................................................................................................................... 34 
9.1.1 
Justification for Exclusion of Children ..................................................................... 34 
9.1.2 
Justification for Exclusion of Pregnant or Lactating Women ................................... 35 
9.2 
Qualifications of Investigators ...................................................................................... 35 
9.2.1 
Professional Licensure .............................................................................................. 37 
10.0 ANTICIPATED BENEFITS ...................................................................................................... 38 
11.0 CLASSIFICATION OF RISK ................................................................................................... 38 
12.0 CONSENT DOCUMENTS AND PROCESS ................................................................................ 38 
12.1 
Unanticipated Enrollment of Non-English Speaking Participants at the NEI .............. 39 
13.0 DATA AND SAFETY MONITORING ....................................................................................... 39 
13.1 
Coordinating Center ...................................................................................................... 40 
13.2 
Data and Safety Monitoring Committee ....................................................................... 40 
13.3 
Criteria for Stopping the Study ..................................................................................... 41 
14.0 QUALITY ASSURANCE ......................................................................................................... 41 
15.0 REPORTING OF UNANTICIPATED PROBLEMS, ADVERSE EVENTS AND PROTOCOL 
DEVIATIONS .................................................................................................................................. 42 
16.0 ALTERNATIVE THERAPIES .................................................................................................. 43 
17.0 PRIVACY .............................................................................................................................. 43 
18.0 CONFIDENTIALITY ............................................................................................................... 43 
19.0 CONFLICT OF INTEREST ...................................................................................................... 44 
20.0 TECHNOLOGY TRANSFER.................................................................................................... 44 
21.0 RESEARCH AND TRAVEL COMPENSATION.......................................................................... 44 
22.0 REFERENCES ........................................................................................................................ 45 
APPENDIX 1: DETERMINING CHILDBEARING POTENTIAL .......................................................... 49 
APPENDIX 2: STUDY FLOWSHEET ................................................................................................ 50 
APPENDIX 3: LIST OF DEFINITIONS ............................................................................................. 52 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page vi 
PROTOCOL ABBREVIATIONS LIST 
AE
Adverse Event 
ALS 
Amyotrophic Lateral Sclerosis 
APD 
Afferent Pupillary Defect
BCVA
Best Corrected Visual Acuity 
BEH 
Bristol Eye Hospital 
BRB 
Blood-Retinal Barrier
BRC 
Biomedical Research Centre 
BRVO
Branch Retinal Vein Occlusion 
BUN
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CC
Clinical Center 
CD
Clinical Director 
CD-68 
Clusters of Differentiation 68 
CFP
Color Fundus Photography
CFR 
Code of Federal Regulation 
CNS 
Central Nervous System
CNS IRB
Combined NeuroScience Institutional Review Board
COX-2 
Cyclooxygenase-2 
CRIS 
Clinical Research Information System
CTCAE
Common Terminology Criteria for Adverse Events
CVA
Cerebral Vascular Event
DME 
Diabetic Macular Edema 
DSMC
Data and Safety Monitoring Committee 
Emmes 
The Emmes Corporation
EMR
Electronic Medical Record 
ETDRS
Early Treatment Diabetic Retinopathy Study
EudraCT 
European Clinical Trials Database 
FA 
Fluorescein Angiogram
FDA 
Food and Drug Administration
FGF
Fibroblast Growth Factor
FSH
Follicle-Stimulating Hormone
HRPP
Human Research Protections Program
HRVO
Hemi-Retinal Vein Occlusion
ICE 
IL-1b-Converting Enzyme 
ICRRC 
Intramural Clinical Research Review Committee 
IL-1b 
Interleukin-1b
IL-6
Interleukin-6 
IL-8
Interleukin-8 
IND
Investigational New Drug 
IOP 
Intraocular Pressure

MiCRVO 
September 19, 2018 
 
PROTOCOL ABBREVIATIONS LIST (CONTINUED) 
 
Version 19.0 
CONFIDENTIAL 
Page vii 
IP 
Investigational Product 
IRB
Institutional Review Board
MCP-1 
Monocyte Chemoattractant Protein 
MEH 
Moorfields Eye Hospital
MHRA 
Medicines & Healthcare products Regulatory Agency
MI 
Myocardial Infarction
MMP 
Matrix Metalloproteinase
MS
Multiple Sclerosis
NEI
National Eye Institute
NGF 
Nerve Growth Factor 
NIH
National Institutes of Health 
NO
Nitric Oxide
OB/GYN 
Obstetrics and Gynaecology
OCT 
Optical Coherence Tomography 
OHSRP
Office of Human Subject Research Protection 
ONL
Outer Nuclear Layer 
PI 
Principal Investigator
PTMS 
Protocol Tracking and Management System 
QA
Quality Assurance 
RVO
Retinal Vein Occlusion
SAE 
Serious Adverse Event 
SOP
Standard Operating Procedure 
SPF
Sun Protection Factor
STZ
Streptozotocin
SUSAR
Serious Unanticipated Serious Adverse Reaction 
TNFa 
Tumor Necrosis Factor-a 
USP
United States Pharmacopeia
UV
Ultraviolet
VA
Visual Acuity 
VEGF 
Vascular Endothelial Growth Factor
YAG
Yttrium Aluminum Garnet 

MiCRVO 
 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 1 
PRÉCIS 
Objective: Retinal vein occlusions (RVOs) are significant sources of vision loss, affecting mostly 
healthy people over 55 years of age. The common source of vision loss is the macular edema 
accompanying the retinal injury. Very recently, studies employing monthly anti-vascular 
endothelial growth factor (VEGF) treatments have demonstrated a benefit to this line of treatment; 
however, the duration of effectiveness appears to be short lived and the length of time needed for 
these monthly injections remains unknown. A histologic study of human retinas with RVOs found 
the presence of activated microglia. Microglia are capable of migrating through the retina to sites 
of inflammation to associate closely with neurons and the vasculature, and are key cellular players 
in the mediation of processes of chronic inflammation. For these reasons, microglia represent a 
promising cellular target for forms of therapy that limit the deleterious inflammatory changes 
found in vein occlusions. Minocycline, a second-generation tetracycline, has been shown to exhibit 
anti-inflammatory properties, including microglial inhibition. The objective of this study is to 
investigate the safety and potential efficacy of minocycline as a microglia inhibitor in participants 
with central retinal vein occlusion (CRVO). 
Study Population: A minimum of 10 and a maximum of 20 participants who meet the eligibility 
criteria may be enrolled. Eligibility criteria include: foveal center-involved macular edema 
secondary to a CRVO, retinal thickness in the central subfield > 350 microns as measured by 
optical coherence tomography (OCT); and visual acuity (VA) between 20/32 and 20/200 in the 
study eye. 
Design: In this pilot, double-masked, randomized multi-center study, participants will receive 
monthly bevacizumab injections for the first three months, followed by PRN dosing. In addition, 
participants will take an oral dose of 100 mg of minocycline or placebo twice daily for 24 months. 
During each monthly visit, participants will have their visual acuity measured and will undergo 
OCT testing to measure retinal thickness. At the Month 3 visit and thereafter, participants will be 
evaluated for “improvement” and “worsening” and will be eligible for additional bevacizumab 
treatment and/or investigational product (IP) depending on which criteria they fulfill.  
Additionally, at Month 12, participants will also be evaluated for “no improvement.” 
 
 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 2 
Outcome Measures: The primary outcome is the difference in mean change in best-corrected 
visual acuity (BCVA), as measured in ETDRS letters, between the minocycline and placebo 
groups in the study eye at 12 months compared to baseline. Secondary outcomes include the 
difference between the minocycline and placebo groups in the number of intravitreal bevacizumab 
injections between 12 and 24 months and baseline, changes in mean macular sensitivity as 
measured by microperimetry at 3, 6, 12, 18 and 24 months compared to baseline, the mean change 
in BCVA at 24 months compared to baseline, changes in retinal thickness as measured by OCT at 
6, 12, 18 and 24 months compared to baseline, number of participants improving ≥ 1 logOCT scale 
step at 12 and 24 months compared to baseline, as well as and changes in fluid leakage in the 
macula as demonstrated by fluorescein angiography at 12 and 24 months compared to baseline. 
Safety outcomes include the number of participant withdrawals, number and severity of systemic 
and ocular toxicities and the number of adverse events (AEs). 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 3 
1.0 
INTRODUCTION/SCIENTIFIC RATIONALE 
1.1 
Central Retinal Vein Occlusions 
Retinal vein occlusions are a significant source of vision loss, affecting mostly healthy people over 
55 years of age. The common source of vision loss is the macular edema accompanying the retinal 
injury. The two main types of retinal vein occlusions are central retinal vein occlusions (CRVO) 
and branch retinal vein occlusions (BRVO). The prevalence of CRVO is approximately 0.1%.1,2 
The standard-of-care for CRVO is even more limited than for BRVO. While optic nerve 
sheathotomy and other invasive measures have been tried, these interventions have not been 
successfully proven in a large randomized clinical trial. Very recently the Central Retinal Vein 
OcclUsIon Study: Evaluation of Efficacy and Safety (CRUISE), a phase III multicenter trial, 
reported six-month outcome results demonstrating efficacy of intravitreal ranibizumab injections 
for the treatment of CRVO.3 The CRUISE study, while encouraging, only has six-month results 
published and requires monthly intravitreal injections with no clear treatment endpoint. 
Ranibizumab has very recently gained FDA approval for the indication of vein occlusions and the 
labeling includes recommendations for monthly intravitreal injections. 
The fundamental cause of macular edema associated with retinal vein occlusions is not understood 
completely, but it is increasingly clear that its pathophysiology extends beyond microvascular 
disease to involve immune mediators in the retina. While hydrostatic stress following the  
break-down of the blood-retinal barrier (BRB) can partly contribute to retinal edema, tissue 
responses to hypoxia are also likely to play a role. In the aftermath of a retinal vein occlusion, 
tissue hypoxia induces the expression of several cytokines, including monocyte chemoattractant 
protein (MCP-1), leading to the activation of inflammatory cells, such as macrophages and 
microglia, which are then attracted to the hypoxic retinal areas.4 Activated microglia release  
TNF-α which triggers the production of interleukin-8 (IL-8), VEGF, basic fibroglast growth factor 
(FGF) and MCP-1 in retinal vascular cells and glial cells adjacent to the microvessels.5 A study on 
patients with BRVO examined the concentrations of VEGF and interleukin-6 (IL-6) in the aqueous 
humor and found that these cytokine levels were increased in the setting of retinal vein occlusion.6  
Further, a histologic study of human retinas with retinal vein occlusions found numerous cluster 
of differentiation-68 (CD-68) positive cells surrounding the vasculature indicating the presence of 
activated microglia.7 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 4 
Inflammation may represent an early adaptive response to metabolic derangements in the ischemic 
retina; over time; however, it leads to progressive vascular damage results, culminating in macular 
edema and neovascularization.8 As such, there may be a feasible therapeutic rationale to broadly 
limit and down-regulate the level of microglia-mediated chronic inflammation in the treatment of 
RVOs. 
1.2 
Current Treatments of CRVO 
Unlike branch retinal vein occlusions, CRVOs did not demonstrate an improvement in visual 
acuity with focal laser photocoagulation.9 Several more invasive therapies have been pursued 
including optic neurotomy and sheathotomy. However, none have shown efficacy in a randomized 
controlled clinical trial. In fact, a review of CRVO intervention treatments in 2007 concluded that 
there was limited evidence for any intervention to improve visual acuity in patients with CRVO.10 
Recently, phase III results of the CRUISE study, have demonstrated efficacy of monthly injections 
of ranibizumab for treatment of central retinal vein occlusions.3 And in late June 2010, the FDA 
approved ranibizumab for use in the treatment of retinal vein occlusions. 
However, while the treatment of monthly injections appears beneficial in the short term, the longer 
term result of this course of treatment is unknown. Also unknown, is the number of injections 
required, and the durability of these injections. While being a major breakthrough in the field of 
treatment of these retinal conditions, monthly anti-VEGF injections still have limitations for 
treating this disease. 
We propose to study minocycline as a microglia inhibitor which can modulate the activation of 
microglia, alter the cytokine profile present, and thus may be useful in the treatment of CRVO. 
1.3 
Role of Microglia 
Retinal microglia, derived from the monocytic lineage, are resident cells in the healthy retina, and 
may be construed as representatives of the immune system in the immune-privileged environment 
of the retina. Microglia are related to macrophages but are a distinct entity11 comprising 
approximately 5% to 20% of the total glial cell population in the central nervous system (CNS).12 
Microglia in the CNS are important sources of inflammatory cytokines and chemokines, and are 
the primary cellular mediators of immune function.13 Most of the factors released by activated 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 5 
microglia are proinflammatory and neurotoxic, including cytokines tumor necrosis factor-a 
(TNFa) and interleukin-1b (IL-1b), free radicals such as NO and superoxide, fatty acid metabolites 
such as eicosanoids, and quinolinic acid.14 The activation of microglia has been implicated in the 
pathogenesis of many neurodegenerative diseases including Alzheimer’s, Parkinson’s disease, 
HIV-related dementia, Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS) and prion 
diseases.15 The cytokines released by activated microglia are thought to speed neurodegeneration. 
Microglia have also been implicated in ischemic and mechanical injury to the brain.16 In the retina, 
retinal glial cells consist of macroglia (Müller cells and astrocytes) and microglia. Microglia are 
able to migrate in various retinal disease states. In photic injury, microglia migrate from the inner 
retinal layers to the outer nuclear layer (ONL) and also into the subretinal space.17,18 In sites of 
inflammation, these cells migrate through the retina to closely associate with neurons and the 
vasculature, and are key cellular players in the mediation of processes of chronic inflammation. 
As such, it is likely that retina microglia play an important role in the inflammatory etiology of 
diabetic retinopathy. 
1.4 
Role of Microglia in Retinal Vein Occlusions 
There is accumulating evidence that retinal microglia are indeed associated with inflammation in 
the retina in conditions such as diabetic retinopathy and RVOs. While diabetic retinopathy is often 
thought of as a vasculopathy, there is a growing body of evidence to suggest that changes in the 
retinal neurons precede vascular changes.19 Microglia function has been investigated in a diabetic 
animal model where diabetes was induced in rats with the injection of streptozotocin (STZ). 
Animal models of diabetes have indicated a role of microglia activation in diabetic retinopathy.  
In a histologic study of microglia in eyes with diabetic retinopathy, Zeng et al. reported that 
microglia increase in number and exhibit hypertrophic features as well as an up-regulation of 
markers in diseased states and marked microglia surrounding the retinal vasculature, labeled 
“microglia perivasculitis” in further stages of disease.20 This may lead to early fluorescein leakage 
present before frank vasculopathy is noticed clinically both in diabetic retinopathy and vein 
occlusion injury. 
 
 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 6 
Animal models of ischemia/reperfusion injury mimics the mechanism of injury occurring in 
RVOs. Shin et al. used both an ischemia/reperfusion model as well as a venous cauterization 
method to demonstrate that microglia become activated under these circumstances and migrate to 
the inner plexiform layer near blood vessels.21 Further research by Lin et al. on an ischemia/ 
reperfusion model in rats have shown that not only are microglia activated in this model, but also 
that they can be inhibited by minocycline.22 In their model, they demonstrated a significant 
treatment effect of treatment in rats with minocycline inhibiting the vascular permeability response 
by inhibiting microglia. 
Indeed, focal laser photocoagulation, the long-time standard-of-care treatment for Diabetic 
Macular Edema (DME) and for branch retinal vein occlusion (BRVO), recently has been found to 
induce prompt changes in the morphology and behavior of retinal microglia, and may thus also 
involve microglia in their therapeutic effect.23 For these reasons, microglia represent a promising 
cellular target for forms of therapy that limit the deleterious inflammatory changes found in vein 
occlusions. While therapeutic agents that specifically inhibit individual pro-inflammatory 
molecules one at a time may have efficacy, an approach that targets the cellular mediator, the 
microglia cell, may have broader and more relevant effects. 
1.5 
Minocycline as a Microglia Inhibitor 
1.5.1 Minocycline 
Minocycline is a second-generation tetracycline, which has anti-inflammatory properties that are 
separate from its anti-microbial properties. Minocycline has high lipophilicity, which leads to both 
excellent bioavailability and ability to cross the blood-brain barrier24 and appears to inhibit the 
activation of microglia, but not astrocytes.25 The mechanism of neuroprotection by minocycline is 
likely several-fold and includes: anti-inflammatory effects, reduction of matrix metalloproteinase 
(MMP) activity,26 and decrease in NO production, ultimately leading to an inhibition of microglia 
and of cell death.27 Minocycline can exert its anti-inflammatory effects on microglia in culture, 
inhibiting their proliferation and release of IL-1B, IL-6, TNF-, NO secretion, and  
NGF-production leading to neuroprotection with the inhibition of cell death.28-32 Minocycline has 
been also found to inhibit induction of IL-1b-converting enzyme (ICE) mRNA25 which means that 
minocycline may function by reducing cytotoxic properties of microglia which can be activated 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 7 
by ischemia and neuroexcitation. In addition, minocycline can also help prevent cytokine-induced 
activation of microglia and prevent further production of proinflammatory stimuli. 
1.5.2 Preclinical Studies with Minocycline 
In animal models of global and focal cerebral ischemia, traumatic brain and spinal injury, 
minocycline treatment showed a reduction in lesion size in conjunction with the inhibition of 
microglial cells.33-36 In rodent models of spinal cord injury, treatment with minocycline not only 
reduced lesion size and improved histological parameters but also improved neurological function 
such as hind limb function and strength.37 
Minocycline has also been studied in the context of ocular diseases. In mouse models of glaucoma, 
minocycline successfully decreased microglial activation and retinal ganglion cell axonal transport 
and improved optic nerve integrity.38 Minocycline was effective in decreasing retinal microglia 
activation in culture.39 In models of inherited and light-induced retinal degeneration, minocycline 
was effective in delaying photoreceptor cell death.39,40 As mentioned above, minocycline reduces 
apoptotic cell death in mouse models of diabetic retinopathy.32 Animal studies have also indicated 
that inhibiting microglia activation with minocycline was useful in decreasing the level of pro-
inflammatory mediators and preventing diabetes-induced cell death in the retina.32 In particular, 
addition of minocycline to TNF-alpha-activated microglia was found to prevent the release of 
COX-2, an enzyme important in prostaglandin synthesis and is a robust marker of inflammation.32  
Ultimately, diabetic rats do demonstrate an increased rate of apoptosis, as evidenced by increased 
caspase-3 activity, and minocycline has been shown to decrease that activation.32 
1.5.3 Clinical Use and Clinical Studies with Minocycline 
Minocycline is a member of the tetracycline family of antibiotics that has good CNS bioavailability 
following oral administration. It is FDA-approved for treating many infections including skin 
infections caused by Staphylococcus aureus and is often used in ophthalmology to treat blepharitis 
and ocular rosacea. It has a favorable side-effect profile, although it should not be used in 
pregnancy as the use of tetracycline class of drugs during tooth development may cause permanent 
discoloration of the teeth. 
 
 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 8 
Minocycline is used widely and has been shown to be well tolerated when used at the  
FDA-approved doses proposed in this study. Based on studies examining the adverse events (AEs) 
reported between 1998 and 2003, and the number of prescriptions for minocycline, the rate of AEs 
has been reported as 72 AEs per million prescriptions averaging to 13 per million per year.41  
The majority of these events were gastrointestinal upset, photosensitivity, hyperpigmentation and 
tooth discoloration.41 
Its application in clinical trials as an anti-microglia agent include a large clinical trial of  
152 patients with acute stroke in which patients treated with 200 mg minocycline for five days had 
a significantly better neurological outcome compared with placebo.27 Other ongoing clinical 
studies include the use of minocycline to decrease symptom progression in Huntington’s disease 
(NCT00277355), and to provide neuroprotective effects in Parkinson’s disease (NCT00063193) 
and in ALS (NCT00047723). 
A current clinical trial, conducted by the Penn State Diabetic Retinopathy Center, is commencing 
recruitment to examine the effects of a related tetracycline, doxycycline, in its ability to slow the 
deterioration or improve retinal function and/or induce regression, or slow progression, of diabetic 
retinopathy (NCT00511875). 
2.0 
STUDY OBJECTIVE 
The study objective is to investigate the safety and potential efficacy of minocycline, a microglia 
inhibitor, in the treatment of CRVO. 
3.0 
PARTICIPANTS 
The accrual ceiling is 20 participants who meet the eligibility criteria. 
3.1 
Participant Eligibility Criteria 
3.1.1 Inclusion Criteria 
To be eligible, the following participant-level inclusion criteria must be met, where applicable. 
1. Participant is 18 years of age or older. 
2. Participant must understand and sign the protocol’s informed consent document. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 9 
3. Female participants of childbearing potential (see Appendix 1 for definition) must not be 
pregnant or breast-feeding and must be willing to undergo serum (BRC sites only) and 
urine pregnancy tests throughout the study. 
4a. For the NEI Site: Female participants of childbearing potential (see Appendix 1 for 
definition) and male participants able to father children must have (or have a partner who 
has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must 
agree to practice two acceptable methods of contraception throughout the course of the 
study and for one week after study medication discontinuation (based on the half life of 
minocycline which is 11-22 hours). Acceptable methods of contraception include: 
 hormonal contraception (i.e., birth control pills*, injected hormones, dermal patch or 
vaginal ring), 
 intrauterine device, 
 barrier methods (diaphragm, condom) with spermicide, or 
 surgical sterilization (hysterectomy or tubal ligation). 
*Oral birth control pills must be used with caution as minocycline decreases the 
effectiveness of some oral contraceptives. Participants already taking oral contraceptives 
may continue to use them, but must agree to use at least one other method of birth control 
while on study. 
4b. For the BRC Sites: Female participants of childbearing potential (see Appendix 1 for 
definition) and male participants able to father children must have (or have a partner who 
has) had a hysterectomy or vasectomy, or be completely abstinent from intercourse.  
Male participants or male partners (of female participants) who have not had a vasectomy 
or are not abstinent are required to use a condom with spermicide throughout the course of 
the study and for one week after study medication discontinuation (based on the half life 
of minocycline which is 11-22 hours). Female participants of childbearing potential or 
female partners (of male participants) of childbearing potential must practice one of the 
below acceptable methods of contraception throughout the course of the study and for one 
week after study medication discontinuation: 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 10 
 hormonal contraception (i.e., birth control pills*, injected hormones, dermal patch or 
vaginal ring), 
 intrauterine device, 
 barrier methods (e.g., diaphragm) with spermicide, or 
 surgical sterilization (hysterectomy or tubal ligation). 
Abstinence is only acceptable when it is the participant’s preferred and usual lifestyle 
choice. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. 
*Oral birth control pills must be used with caution as minocycline decreases the 
effectiveness of some oral contraceptives. Participants already taking oral contraceptives 
may continue to use them, but must agree to use at least one other method of birth control 
while on study. 
It should be noted that two forms of contraception (as specified above) will be used by 
sexually active participants for the duration of the study and for one week after study 
medication discontinuation. 
5. Participants must agree to notify the study investigator or coordinator if any of their doctors 
initiate a new medication during the course of this study. 
6. Participant must have normal renal function and liver function, or have mild abnormalities 
not above grade 1 as defined by the Common Terminology Criteria for AEs v4.0 (CTCAE). 
7. Participant must agree to minimize exposure to sunlight or artificial UV rays and to wear 
protective clothing, sunglasses, and sunscreen (minimum SPF 15) if s/he must be out in the 
sun. 
8. Participant has at least one eye that meets the study eye criteria listed in Section 3.2 below. 
3.1.2 Exclusion Criteria 
A participant is not eligible if any of the following exclusion criteria are present. 
1. Participant is in another investigational study and actively receiving IP for CRVOs. 
2. Participant is unable to comply with study procedures or follow-up visits. 
3. Participant has a known hypersensitivity to sodium fluorescein dye. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 11 
4. Participant has a condition that, in the opinion of the investigator, would preclude 
participation in the study (e.g., unstable medical status including blood pressure and 
glycemic control). 
5. Participant has a history of chronic renal failure requiring dialysis or kidney transplant. 
6. Participant has a history of chronic hepatitis or liver failure. 
7. Participant has an allergy or hypersensitivity to minocycline or any drug in the tetracycline 
family. 
8. Participant is currently taking a tetracycline medication. 
9. Participant is taking any medication that could adversely interact with minocycline such as 
methoxyflurane. 
10. Participant has a blood pressure of > 180/110 (systolic above 180 OR diastolic above 110). 
 If blood pressure is brought below 180/110 by anti-hypertensive treatment, the 
participant can become eligible. 
11. Participant is currently being treated with systemic anti-VEGF agents or systemic steroids. 
12. Participant had a cerebral vascular event (CVA) or myocardial infarction (MI) within three 
months prior study entry. 
13. Participant has a history of thyroid cancer. 
3.2 
Study Eye Eligibility Criteria 
The participant must have at least one eye meeting all inclusion criteria and none of the exclusion 
criteria listed below. 
3.2.1 Study Eye Inclusion Criteria 
1. The study eye has a best-corrected ETDRS visual acuity score between 78 and 34 letters 
(i.e., between 20/32 and 20/200). 
2. The study eye shows definite retinal thickening due to a CRVO based on clinical 
examination involving the center of the macula that is not refractory to further therapy as 
based on the investigator’s clinical judgment. CRVO is defined as an eye that had retinal 
hemorrhage or other biomicroscopic evidence of RVO (e.g., telangiectatic capillary bed) 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 12 
and a dilated (or previously dilated) venous system in at least three quadrants of the retina 
drained by the affected vein. 
3. The study eye has retinal thickness in the central subfield on baseline OCT measurement 
> 350 microns, as measured by Zeiss Cirrus spectral domain OCT, or an equivalent retinal 
thickness on a similar OCT machine. 
4. The study eye has media clarity and pupillary dilation sufficient for adequate fundus 
photographs. Furthermore, the participant must be able to cooperate during the procedure 
for accurate fundus photographs. 
3.2.2 Study Eye Exclusion Criteria 
1. Macular edema is considered to be due to a cause other than CRVO. 
2. An eye should not be considered eligible if: 
 The macular edema is considered to be related to cataract extraction, or 
 Clinical examination and/or OCT suggest that vitreoretinal interface disease (e.g., a 
taut posterior hyaloid or epiretinal membrane) is the primary cause of the macular 
edema, or 
 Clinical examination, medical history and/or fluorescein angiography suggest that 
diabetic retinopathy is the primary cause of the edema. 
3. The study eye has a history of a recurrent RVO. 
4. The study eye has a history of RVO present for >18 months. 
5. A brisk afferent pupillary defect (APD) is present in the study eye. 
6. An ocular condition (other than RVO) is present such that, in the opinion of the 
investigator, visual acuity would not improve from resolution of macular edema  
(e.g., foveal atrophy, pigmentary changes, dense subfoveal hard exudates, laser scar at 
fovea, non-retinal condition). 
7. An ocular condition (other than RVO) is present that, in the opinion of the investigator, 
might affect macular edema or alter visual acuity during the course of the study  
(e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, 
Irvine-Gass Syndrome, etc.). 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 13 
8. A substantial cataract that, in the opinion of the investigator, is likely to be decreasing 
visual acuity by three lines or more (i.e., cataract would be reducing acuity to 20/40 or 
worse if eye was otherwise normal) is present in the study eye. 
9. The study eye has had panretinal or sectoral scatter photocoagulation (PRP) within four 
months prior to study entry. 
10. The study eye has had pars plana vitrectomy within six months prior to study entry. 
11. The study eye has undergone major ocular surgery (including cataract extraction, scleral 
buckle, any intraocular surgery, etc.) within three months prior to study entry. 
12. A yttrium aluminum garnet (YAG) capsulotomy has been performed on the study eye 
within two months prior to study entry. 
13. The study eye has had treatment < 3 months prior to study entry of intravitreal or periocular 
steroid injections. 
14. The study eye has had treatment < 28 days prior to study entry of intravitreal anti-VEGF 
agents. 
3.2.3 Study Eye Selection Criteria in Cases of Bilateral Disease 
If both eyes of a participant meet the criteria described in Sections 3.2.1 and 3.2.2, the study eye 
will be determined at the investigator’s discretion. 
4.0 
STUDY DESIGN AND METHODS 
4.1 
Study Overview 
This is a pilot, double-masked, randomized, multi-center study to investigate the safety and 
potential efficacy of minocycline as a microglia inhibitor in participants with CRVO who are 
concurrently being treated with standard-of-care anti-VEGF (bevacizumab) intravitreal injections. 
This study is designed not to determine efficacy but rather to generate preliminary data to support 
a fully powered phase III study. 
4.2 
Recruitment 
Up to 20 participants will be recruited from the NEI clinic and BRC sites, collectively.  
The recruitment totals are not fixed at either the NEI or BRC sites. 
NIH recruitment will occur by self-referral and referral from outside physicians will be permitted. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 14 
A letter will be provided to local ophthalmologists to assist with recruitment. A recruitment flyer 
will be posted at community gathering places including but not limited to: hospitals, libraries, 
senior centers, senior housing facilities, area metro and bus stops, websites, newspapers and 
throughout the NIH campus. NIH investigators from this study working at the Veterans Affairs 
hospital will provide information to patients in the Veterans Affairs eye clinic, but will not perform 
a formal assessment of eligibility or conduct any part of the informed consent process at the 
Veterans Affairs hospital. Potentially interested patients will contact the investigators at a later 
time. Contact information from Veterans Affairs patients will be provided to the NIH investigators 
only if the patient specifically requests that someone call them to set up the initial visit.  
The interaction will be documented in the medical record at the Veterans Affairs clinic. 
Participants at the BRC sites will be identified following attendance at routine appointments or 
sent a recruitment letter from existing databases of patients diagnosed with CRVO and who 
routinely attend the BRC sites for treatment. 
4.3 
Screening 
Potential participants at the NEI will be screened under the NEI screening (08-EI-0102) or 
evaluation and treatment protocol (08-EI-0169) to establish eligibility. The participant must have 
an active signed consent for one of the above mentioned protocols on file for baseline examinations 
to occur. Baseline examinations will be performed as outlined in Appendix 2. Laboratory measures 
may be performed within 42 days of enrollment. Optical coherence tomography (OCT), color 
fundus photography and fluorescein angiography may be performed within seven days of the 
baseline visit. All other baseline examinations must occur on the day the participant reviews and 
signs this protocol’s consent form, unless specified in Appendix 2. Treatment with the IP 
(minocycline or placebo) cannot occur until the participant has reviewed and signed this protocol’s 
consent form. 
Potential participants from the BRC sites will be screened under this study protocol.  
The participant must have signed this protocols consent form for any study examinations to occur. 
For the BRC sites, it is expected that the baseline examinations can be completed in one clinic visit 
over one day. If the baseline examinations cannot be performed in one clinic visit over one day, it 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 15 
is acceptable that the baseline examinations be completed at subsequent clinic visits, if scheduled 
within fourteen days of the first visit. 
4.4 
Randomization, Masking and Unmasking 
After the participant is determined eligible and has completed the informed consent process, the 
group will be assigned based on a predetermined randomization schedule developed by the 
Coordinating Center. Randomization will be stratified by site. 
Randomization must occur on the same day as the initial administration of IP while the participant 
and the ophthalmologist are present and will not be permitted any time before.  
Participant eligibility must be confirmed before a participant is randomized. Participants will be 
randomized to one of two groups with equal probability of equal numbers of participants in each 
group: minocycline or placebo. Participants must continue to receive the same treatment regimen 
to which they were assigned for the duration of the study. 
All clinic staff and participants will be masked to group assignments. Only designated pharmacy 
personnel, select individuals at the Emmes Corporation, and the NEI Data and Safety Monitoring 
Committee (DSMC) will have access to the group assignments. 
Participants will be unmasked if deemed clinically necessary by the examining physician and if 
the study Principal Investigator (PI) and DSMC Chair are in agreement. In the case of a medical 
emergency, the examining or treating physician will have the final decision and unilateral right for 
unmasking. A request for unmasking, after approval by the PI and the DSMC Chair, will be made 
to the Coordinating Center personnel, who will inform the PI and the DSMC Chair of the group 
assignment. Attempts should be made to maintain the masking of the investigators prior to the 
study-wide unmasking. Unmasking will be recorded on an AE form. All instances of unmasking 
must be reported to the ICRRC, the CNS IRB and the DSMC. 
4.5 
Study Design and Procedures 
For the NEI Site: The study duration will be 24 months. During this period, participants will be 
instructed to take the IP (either placebo or minocycline 100 mg capsule) twice daily. The primary 
outcome will be assessed at Month 12, and secondary outcomes will be assessed at 6, 12, 18 and 24 
months. Visits will occur at baseline, and then monthly or as clinically indicated. The study will 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 16 
require a minimum of 25 appointments (baseline and Months 1-24). All appointments must be 
conducted within a window of ± seven days from the target day. The tests scheduled at each visit 
will be completed in one day. At each visit, the participant will undergo a review of systems and 
an assessment of safety variables. A complete ophthalmologic examination will be performed at 
each visit to measure outcome variables. 
During each clinic visit, participants will have their visual acuity measured and will undergo OCT 
testing to measure retinal thickness. 
For the BRC Sites: The study duration will be approximately 24 months. During this period, 
participants will be instructed to take the IP (either placebo or minocycline 100 mg capsule) twice 
daily. The primary outcome will be assessed at Month 12, and secondary outcomes will be assessed 
at 6, 12, 18 and 24 months. Visits will occur at baseline, and then monthly or as clinically indicated. 
The study will require a minimum of 26 appointments (baseline and Months 1-24 and safety 
follow-up). All appointments must be conducted within a window of ± seven days from the target 
day, except for the safety follow-up visit which must occur at least five days after the cessation of 
IP. The tests scheduled at each visit are expected to be completed in one day, with the exception 
of the Baseline visit, Month 12 visit and Month 24 visit. If the baseline examinations cannot be 
performed in one clinic visit over one day, it is acceptable that the baseline examinations be 
completed at subsequent clinic visits, if scheduled within fourteen days of the first visit. If the 
Month 12 and Month 24 examinations cannot be performed in one clinic visit over one day, it is 
acceptable that the examinations be completed at subsequent clinic visits, if scheduled within 
seven days of the first visit. At each visit, the participant will undergo a review of systems and an 
assessment of safety variables. A complete ophthalmologic examination will be performed at each 
visit (except for the safety follow-up visit) to measure outcome variables. If the Baseline visit, 
Month 12 visit, or Month 24 visit are conducted over more than one day, BCVA, OCT and 
microperimetry testing must be conducted on the day of the injection. 
During each study visit, with the exception of the Month 24 visit and safety follow-up visit at the 
BRC sites, IP will be dispensed to the participant unless the treatment is deemed to be “worsening” 
or to offer “no improvement,” and the participant and investigator decide to stop IP.  
An information sheet outlining instructions on taking the study medication and concomitant 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 17 
medications will be distributed to participants and discussed in detail by study personnel.  
They will be asked to inform any physician who is prescribing new medications that they are 
currently taking minocycline. In addition, the participants will be asked to inform a study team 
member if a new medication is prescribed to them. 
 
 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 18 
Participant compliance with IP will be prompted through ongoing encouragements and reminders 
during study visits and scheduled and unscheduled telephone contacts. Compliance will be 
assessed by pill counts conducted during study visits and the participant’s pill diary.  
Once identified, occurrences in which the computed compliance rate between study visits falls 
below 50% will be reported as a protocol deviation to the CNS IRB within two weeks using PTMS. 
4.5.1 Treatment Prior to Month 3 
At baseline, the participant will receive an injection of 1.25mg bevacizumab, an anti-VEGF agent, 
and also start the randomized IP. At Months 1 and 2, the participant will again receive bevacizumab 
injections in the study eye and continue the randomized IP. 
4.5.2 Treatment Beginning at Month 3 
Visual acuity and macular edema will be evaluated at study visits to determine further treatment. 
Starting at Month 3 and at every visit thereafter, the following scenarios will be considered.  
(Also refer to Figure 1.) The participant will be reinjected with bevacizumab unless the participant 
meets the “improvement,” “worsening,” “new steady state” or “no improvement” criteria defined 
in Appendix 3. 
Scenario 1: If the participant meets the “improvement” criteria defined in Appendix 3, the 
participant will continue to take the IP, but the bevacizumab injection will be withheld at that visit. 
Scenario 2: If the participant meets the “worsening” criteria defined in Appendix 3, the participant 
will be offered any therapy available at the discretion of the treating investigator, including: 
a. Anti-VEGF Treatment 
b. Intravitreal or Periocular Steroid Injections 
Scenario 3: If the participant does not meet the “improvement” or “worsening” criteria, but meets 
the “new steady state” criteria defined when the central subfield thickness remains ≥ 300 microns 
on OCT but has not changed > 25 microns over the last three consecutive injections (also defined 
in Appendix 3), the treating investigator physician will have the discretion to hold bevacizumab 
injections until the OCT changes (worsens) by > 25 microns from this “new steady state” level. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 19 
At the Month 12 visit and at every visit thereafter, Scenarios 1, 2 and 3 will be considered as well 
as the following scenario, which allows for a study physician to determine whether there has been 
“no improvement” in the participant’s condition: 
Scenario 4: If the participant meets the “no improvement” criteria defined in Appendix 3, or if the 
investigator’s clinical impression is that there has been no improvement in the study eye, the 
participant will be offered therapy at the discretion of the treating investigator. The decision to  
re-inject the participant with bevacizumab (the anti-VEGF agent) will be made by the treating 
investigator after consulting with the participant. The decision to continue the IP will also be made 
by the treating investigator after consulting with the participant. 

MiCRVO 
 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 20 
Figure 1. Treatment Scenarios 
 
 
 
Enrollment = Month 0 
- Confirm eligibility 
- Review/sign consent form 
- Give bevacizumab injection 
- Randomize participant to 
investigational product 
Months 1, 2 
- Give bevacizumab injection  
- Dispense randomized 
investigational product to 
participant 
Is this visit Month 12 or after? 
no 
yes 
Does participant meet criteria 
for “no improvement?” 
- Treat participant at the 
discretion of treating investigator 
no 
- Dispense randomized 
investigational product 
- Hold bevacizumab 
injection 
- Treat participant at 
the discretion of 
treating investigator 
no 
Does the participant meet 
criteria for “improvement?” 
yes 
yes 
Does participant meet 
criteria for “worsening?” 
no 
yes 
Months 3 and thereafter 
- Consult decision tree to the 
right 
Does participant meet criteria for “new 
steady state?” 
yes 
-Dispense investigational 
product 
-Investigator physician discretion 
to hold bevacizumab injection 
no 
- Dispense randomized 
investigational product 
- Give bevacizumab 
injection

MiCRVO 
 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 21 
4.6 
Ocular and Systemic Evaluations 
Following is a detailed list of the study procedures. All of the study procedures, with the exception 
of the administration of the IP, are typical components of the clinical care required for a participant 
with macular edema secondary to CRVO. Examinations are performed at the study visits as 
indicated in the study flowsheet (Appendix 2). 
1. Dispense IP and provide an information sheet outlining instructions on taking IP and 
concomitant medications and pill diary 
2. Drug Accountability Review 
3. Evaluation for “improvement,” “worsening” and “no improvement” defined in  
Appendix 3 
4. Medical/Ophthalmic History 
5. Physical Examination 
6. Vital Signs 
7. Review of Systems 
8. Allergies Assessment 
9. Concomitant Medications Assessment 
10. Adverse Event Assessment 
11. Best-Corrected Visual Acuity (BCVA) and Manifest Refraction using Early Treatment 
Diabetic Retinopathy Study (ETDRS) Methods 
12. Slit Lamp Examination 
13. Dilated Fundus Examination 
14. Color Fundus Photography (CFP) 
15. Intraocular Pressure (IOP) 
16. Spectral Domain Optical Coherence Tomography (OCT) 
17. Microperimetry 
18. Fluorescein Angiogram (FA) 
19. Acute Care Panel1 
20. Hepatic Panel1 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 22 
21. Complete Blood Count (CBC)1 
22. Thyroid Function Test1,2  
23. Thyroid Palpation3 
24. Pregnancy Test for Women of Childbearing Potential (serum and urine)1, 4 (see Appendix 
1 for definition) 
1  All abnormal values or positive tests will be reported to the participant’s primary care 
physician, with the participant’s permission. 
2  Participants with abnormal thyroid function test results will be referred to an 
endocrinologist. 
3 Abnormal findings during a thyroid palpation will be followed by a referral to an 
endocrinologist. 
4 Applicable to the BRC sites only: A serum pregnancy test will be performed with  
24 hours prior to initiation of minocycline. After initiation of contraception, urine 
pregnancy tests will be conducted; however, a serum test will be performed anytime a 
urine test result creates doubt. 
If any medications need to be initiated or altered to address any change in lab values, or symptoms, 
the participant’s primary care doctor will be contacted, or the medical consultant team will be 
contacted to evaluate the participant and to prescribe the appropriate medications. 
4.6.1 Reporting of Expected Events 
It is anticipated that participants in this study will occasionally miss or fail to complete an assessment, 
procedure or study visit. These omissions will be considered expected events and not protocol 
deviations provided they are infrequent and do not include data needed to assess safety or the primary 
study outcome. If such an event is identified, the PI will submit a report to the IRB within two weeks 
using PTMS. 
Cumulative proportions of these missed events in the study population will be presented to the IRB 
annually. In addition, these rates will be calculated and monitored biannually by the DSMC. 
The following are considered deviations: 
 An individual misses more than 15% of the required study assessments/procedures, 
 An individual misses more than 15% of the required study visits, 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 23 
 An individual completes more than 15% of the required study visits outside of the visit 
window, 
 Collectively, participants missed more than 15% of a specific assessment/procedure, 
 Collectively, participants missed more than 15% of the required study visits, or 
 Collectively, participants complete more than 15% of the required visits outside the visit 
window. 
If the total number of expected items (study visits or study assessments/procedures) is less than or 
equal to 16, and two or more items are missing, a deviation will be reported. If the total number of 
items expected is greater than 16, and 15% or more items are missing, a deviation will be reported. 
The total number of items (study visits or study assessments/procedures) for an individual and 
collectively will be calculated cumulatively. If a protocol deviation (as defined above) is identified, 
the PI will submit a report to the IRB using PTMS. 
4.7 
Study and Concomitant Therapy 
4.7.1 Minocycline Formulation at Pine Pharmaceuticals 
Pine Pharmaceuticals (100 Colvin Woods Parkway #300, Tonawanda, New York) will supply the 
minocycline hydrochloride capsules for oral administration containing 100 mg of minocycline 
(NDC number 00591-5695-50, manufactured by Actavis Pharma, Inc.). Pine Pharmaceuticals will 
provide the pink opaque capsules to the NIH Pharmacy. 
4.7.2 Minocycline Formulation for BRC Sites 
At the BRC sites, minocycline hydrochloride capsules for oral administration containing the 
equivalent of 100 mg of minocycline will be investigated under European Clinical Trials Database 
(pending EudraCT submission to M.H.R.A.) For the BRC sites, the commercial licensed tablets 
will be overencapsulated by the BEH pharmacy. 
4.7.3 Placebo Formulation at Pine Pharmaceuticals 
Pine Pharmaceuticals will formulate and supply a placebo pill with inactive ingredients in a pink 
opaque capsule. The prepared capsules will be provided to the NIH Pharmacy. The placebo 
capsules are indistinguishable from the minocycline capsules used in this trial. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 24 
4.7.4 Placebo Formulation for BRC Sites 
The BEH pharmacy has formulated a placebo capsule with inactive ingredients. The placebo 
capsules are indistinguishable from the minocycline capsules used in this trial. 
4.7.5 Dosage, Administration and Storage 
Participants will be instructed to take the IP orally two times a day, once in the morning and once in 
the evening approximately 12 hours apart. The exception to this will occur on the day of the baseline 
visit. On the day of the baseline visit at which IP is dispensed, participants will take only the evening 
pill. Minocycline will be administered at an oral dose of 100 mg twice daily. Placebo pills contain 
no active ingredients. 
At the baseline and Months 1-23 study visits, a 37-day supply will be dispensed. Participants will 
be given a pill diary upon which to record the morning and evening doses of the IP. The IP should 
be stored at 15 – 30° C (59 - 86° F). It should be protected from light, moisture and excessive heat. 
Participants will be required to return their bottles of IP to each visit for pill counts for compliance 
monitoring. 
4.7.6 Concomitant Therapy 
If the study eye develops neovascularization warranting panretinal photocoagulation, the 
participant will withdraw from this study because it is known that panretinal photocoagulation 
laser can exacerbate macular edema. This could interfere with the interpretation of the study data 
(see exclusion criteria Section 3.2.2). 
The non-study eye will receive standard care treatment, as appropriate. 
4.8 
Investigational Product Accountability 
The pharmacy and/or unmasked site staff designated to receive IP are responsible for the 
accountability of all used and unused study IP. Adequate drug accountability records include 
documentation of all IP and supplies shipped, received, formulated, dispensed and returned to the 
pharmacy. Participants will be asked to complete a pill diary documenting that they took the IP. 
At each visit, participants will be responsible for the return of a completed pill diary and any 
unused study medication and supplies. The investigator/study staff will review the pill diary with 
the participant for completeness and accuracy, document the number of returned pills and return 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 25 
the unused study medication and supplies to the appropriate pharmacy. Each pharmacy will 
destroy unused IP and supplies following reconciliation by the Coordinating Center. 
4.9 
Follow-up/Termination Procedures 
At the conclusion of the study, the participants will no longer be able to receive the IP under this 
protocol. 
At the NEI, follow-up care will be arranged with an outside ophthalmologist or the participant will 
continue to be seen at the NIH under another protocol, if available, and if the participant is eligible. 
The participants and their physicians, with written consent, will be informed of their disease status 
during this study. Clinical data obtained during participation may be shared with the participants 
and, with written permission from the participants, their private physicians. Results from the 
overall study will be listed on http://www.clinicaltrials.gov once the data have been analyzed. 
4.10 
Storage of Samples and Data 
No samples will be stored for this study. At the NEI, the clinical data will be stored in the NEI’s 
electronic medical record system (EMR), The Emmes Corporation’s database and the Clinical 
Research Information System (CRIS). At the BRC sites, the clinical data will be stored in The 
Emmes Corporation’s database. Some of the baseline data for the NEI may be obtained under the 
NEI screening or evaluation and treatment protocols. 
5.0 
RISKS/DISCOMFORTS 
There are risks associated with the procedures required for participants in this study.  
However, these are all standard procedures that are performed as part of a normal eye and medical 
examination. Some of the discomforts associated with the ocular examination include the 
following: 
1. Dilating drops or anesthetic drops may sting. They can cause an allergic reaction, or if 
contaminated, can cause an infection, but neither of these problems is very likely to occur. 
Dilating drops can also cause a sudden increase of pressure (acute glaucoma) in eyes that 
are already predisposed to develop this condition. There is little risk of glaucoma being 
triggered in this way, but if it is, treatment is available. The participant’s intraocular 
pressure will be obtained at each ophthalmic examination to determine whether there is an 
increased risk of developing glaucoma. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 26 
2. Color fundus photographs involve a bright flash to take pictures of the retina. This brief 
flash may cause temporary discomfort, but it does not damage the eye. 
3. In rare instances, the cornea may be scratched during measurement of intraocular pressure 
or use of a funduscopic contact lens. A corneal abrasion of this sort may be painful, but it 
heals quickly with no lasting effects. 
4. The fluorescein dye used in fluorescein angiography can make a participant’s skin turn 
yellow for several hours. This yellow color is transient and usually disappears in one day. 
Because the dye undergoes renal excretion, the participant’s urine will turn dark orange for 
up to 24 hours after the examination. The study team will educate the participant regarding 
this urine color change. Some participants may be slightly nauseated during the 
examination, but their nausea usually lasts only a few seconds. If the dye extravasates 
during the injection, the skin around the injection site may feel mildly uncomfortable or 
become yellow. The discomfort usually lasts only a few minutes, and the yellow color fades 
in a few days. There is a chance of ecchymosis at the site of injection and a remote 
possibility of cellulitis from the needle track. 
In rare cases, participants may have an allergic reaction to the dye. Treatment typically 
consists of an oral antihistamine medication, but may require intravenous antihistamine 
administration if the symptoms are severe. Very rarely (less than one in one million 
people), a participant experiences anaphylaxis. This would be treated immediately by 
trained personnel with medications or, if necessary, intubation. 
5. OCT and microperimetry are non-invasive tests used to document and analyze retinal 
pathology. Neither test has any known medical risks. 
Possible discomforts associated with non-ocular examinations include: 
1. Blood draws can cause discomfort and bleeding/bruising at the site of venous puncture. 
There is a remote risk of fainting or local infection. If any of these conditions arise, they 
will be treated. 
2. The medical/ophthalmic history, vital signs, review of systems and pregnancy testing entail 
no medical risk. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 27 
5.1 
Intravitreal Bevacizumab Risks 
The following data on the complications of intravitreal injections of bevacizumab were taken from 
a publication on the subject.43 The following event rates were observed as described in Table 1. 
There is no statistically significant difference in event rates between bevacizumab and ranibizumab 
in any of these categories listed below. Risks related to the mechanical injection include 
endophthalmitis, retinal tears, vitreous hemorrhage, intraocular pressure elevation and lens 
damage. Risks related to the pharmacological agent include uveitis and endophthalmitis. 
Table 1. 
Comparison of Ocular Adverse Events Occurred Among Patients Treated 
with Intravitreal Bevacizumab versus Ranibizumab 
Ocular Adverse Event 
Bevacizumab  
(n = 1,275) 
(%) 
Ranibizumab 
(n = 725) 
(%) 
P 
Retinal detachment  
1 (0.08) 
0 
1.0 
Injection-site redness 
821 (64.39) 
474 (65.38) 
>0.6 
Corneal abrasion 
6 (0.47) 
3 (0.41) 
1.0 
Anterior uveitis 
20 (1.57) 
10 (1.38) 
>0.6 
Posterior or anterior-posterior 
uveitis 
5 (0.39) 
3 (0.41) 
1.0 
Subconjuctival hemorrhage 
125 (9.80) 
75 (10.35) 
>0.6 
Subconjuctival hemorrhage  
(> 1 quadrant)
6 (0.47) 
5 (0.69) 
>0.5 
 
5.2 
Investigational Product Risks 
5.2.1 Minocycline-related 
Due to oral minocycline’s virtually complete absorption, side effects to the lower bowel, 
particularly diarrhea, have been infrequent. The following adverse reactions have been observed 
in patients receiving tetracyclines. 
Gastrointestinal: Anorexia, nausea, vomiting, diarrhea, glossitis, dysphagia, enterocolitis, 
pancreatitis, inflammatory lesions (with monilial over growth) in anogenital region and increases 
in liver enzymes. Rarely, hepatitis and liver failure have been reported. Rare instances of 
esophagitis and esophageal ulcerations have been reported in patients taking the tetracycline-class 
antibiotics in capsule and tablet form. Most of these patients took the medication immediately 
before going to bed. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 28 
Skin: Maculopapular and erythematous rashes. Exfoliative dermatitis has been reported but is 
uncommon. Fixed drug eruptions, including balanitis, have been rarely reported.  
Erythema 
multiforme 
and 
rarely 
Stevens-Johnson 
syndrome 
have 
been 
reported.  
Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some 
individuals taking tetracyclines. This has been reported with minocycline. Pigmentation of the skin 
and mucous membranes has been reported. 
Renal toxicity: Elevations in BUN have been reported and are apparently dose related. While this 
is not a problem in those with normal renal function, in patients with significantly impaired 
function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia and 
acidosis. If renal impairment exists, even usual oral or parenteral doses may lead to excessive 
systemic accumulations of the drug and possible liver toxicity. 
Hypersensitivity reactions: Urticaria, angioneurotic edema, polyarthralgia, anaphylaxis, 
anaphylactoid purpura, pericarditis, exacerbation of systemic lupus erythematosus and rarely 
pulmonary infiltrates with eosinophilia have been reported. A transient lupus-like syndrome has 
also been reported. 
Blood: Hemolytic anemia, thrombocytopenia, neutropenia and eosinophilia have been reported. 
Central Nervous System: Central nervous side effects including light-headedness, dizziness, or 
vertigo have been reported with minocycline therapy. Serious neurologic events reported include 
bulging fontanels in infants and benign intracranial hypertension (Pseudotumor cerebri) in adults. 
Headache and blurred vision have also been reported. 
Other: When given over prolonged periods, tetracyclines have been reported to produce  
brown-black microscopic discoloration of the thyroid glands. Very rare cases of abnormal thyroid 
function have been reported. Thyroid cancer has been reported in the post-marketing setting in 
association with minocycline products. Decreased hearing has been rarely reported in patients on 
minocycline hydrochloride. Tooth discoloration in children less than eight years of age and also, 
rarely, in adults has been reported. Use is not recommended for individuals of either gender 
attempting child conception. There is a risk of impaired spermatogenesis. Because tetracycline can 
reduce the amount of beneficial forms of bacteria in the body, participants will be counseled to 
include probiotics in their diet while participating in the study. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 29 
Pregnant and Nursing Women: Minocycline is in Pregnancy Category D and is excreted in human 
milk. Minocycline can cause fetal harm when administered to a pregnant woman. The use of drugs 
of the tetracycline class during tooth development (last half of pregnancy, infancy and childhood 
to the age of eight years) may cause permanent discoloration of the teeth (yellow-grey-brown). 
5.2.2 Drug Interaction-related 
Because tetracyclines have been shown to depress plasma prothrombin activity, participants who 
are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. 
Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to 
avoid giving tetracycline-class drugs in conjunction with penicillin. Absorption of tetracyclines is 
impaired by antacids containing aluminum, calcium, or magnesium, and preparations that contain 
iron. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal 
renal toxicity. Concurrent use of tetracyclines with oral contraceptives may render oral 
contraceptives less effective. 
5.2.3 Placebo-related 
There are no medical risks associated with the placebo capsules. 
6.0 
Participant Monitoring 
Participants will be monitored during all study visits for AEs by the study investigators. At each 
visit, the participant will be asked about any new ocular or systemic symptoms including rashes, 
hospitalizations or new/changed medications. General and ophthalmic assessments will be 
performed according to Appendix 2. Stopping guidelines for individual participants and the entire 
study are outlined below. 
6.1 
Individual Withdrawal Criteria 
Participants may choose to withdraw from this study for any reason at any time without penalty, 
without loss of benefits, and without prohibition from enrolling in other clinical protocols. 
Participants may stop the study at any time. The investigators will ask all study participants to 
continue to return for study visits even if they stop using the IP. However, participants are free to 
withdraw from the study at any time. Also, investigators may withdraw a participant from IP if the 
investigator determines that the study is not in the participant’s best interest. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 30 
Reasons for participant discontinuation may include, but are not limited to, the following: 
 Investigator determination that it is not in the best medical interest of the participant to 
continue participation; 
 Findings during the course of the trial that may affect willingness to participate; 
 Participant requires additional medicines or intravitreal injections that may interfere with 
the IP; 
 Serious suspected adverse reaction; 
 VA loss of  15 letters from baseline; 
 Any other safety concerns; 
 Inability to keep study visits or to comply with study requirements; or 
 Participant requires ocular surgery which cannot safely be postponed until the end of the 
study. 
Discontinuation of IP does not require participant withdrawal from the study. If the participant 
agrees to continue in the study after discontinuing IP, s/he will continue to return for his/her 
subsequent study visits and undergo the required examinations. Otherwise, the participant will exit 
the study and continue his/her ophthalmic care either with an outside ophthalmologist or at the 
NEI. Participants will be monitored by study investigators and clinical staff at each visit to the 
clinic. 
6.2 
Pregnancy Monitoring 
If the staff becomes aware that a female study participant has become pregnant during the study, 
the investigator will advise the participant to stop taking the IP immediately. The investigator 
and participant will determine whether to continue any remaining study visits or to exit the study. 
If the staff becomes aware that a male study participant has impregnated his partner during the 
study, the investigator will remind the participant of the potential risks to the unborn fetus. 
For the NEI site, in either case of reported pregnancy, the NEI participant (and/or partner) will 
be referred to the NIH OB/GYN consultation service for evaluation and counseling.  
The investigator must follow the participant (or partner) until the pregnancy outcome. The data 
must be recorded on the Confirmed Pregnancy & Outcome case report form, which is also 
reported to the Coordinating Center. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 31 
7.0 
OUTCOME MEASURES 
7.1 
Primary Outcome 
The primary outcome is the difference in mean change of BCVA, as measured in ETDRS letters, 
between the minocycline and placebo groups in the study eye at 12 months compared to baseline. 
7.2 
Secondary Outcomes 
Secondary outcomes include the difference between the minocycline and placebo groups in the: 
 Number of bevacizumab injections from baseline to 12 months and from baseline to 
24 months, 
 Changes in mean macular sensitivity as measured by microperimetry at 3, 6, 12, 18 and 24 
months compared to baseline, 
 Mean change in the ETDRS BCVA in the study eye at 24 months compared to baseline, 
 Changes in retinal thickness as measured by OCT at 6, 12, 18 and 24 months compared to 
baseline, 
 Number of participants improving > 1 logOCT scale step at 12 and 24 months compared 
to baseline, 
 Changes in fluid leakage in the macula as demonstrated by fluorescein angiography at  
12 and 24 months compared to baseline. 
Also, a decrease of ≥ 1-step on the logOCT scale, where Change in logOCT = log (follow-up 
thickness/300) – log(baseline thickness/300) is considered clinically significant.42 A one-step 
decrease is equivalent to at least a 20% improvement of central macular thickness and represents 
greater than twice the variability of retinal thickness measurements (approximately 25-30 
microns). Table 2 presents examples of OCT measurements with their corresponding LogScore, 
where LogScore = 10xlogOCT. 
 
 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 32 
Table 2. OCT and Corresponding LogScores42 
LogScore 
OCT (µm) 
0 
300 
0.5 
337 
1 
378 
1.5 
424 
2 
475 
2.5 
533 
3 
599 
3.5 
672 
4 
754 
4.5 
846 
5 
949 
5.5 
1064 
6 
1194 
6.5 
1340 
7.3 
Safety Outcomes 
Safety outcomes will be the number and severity of systemic and ocular toxicities and AEs.  
The number of participants withdrawn from the study therapy due to vision loss or AEs and the 
number of participants deemed to have worsening disease will also contribute to the assessment of 
safety. 
8.0 
STATISTICAL ANALYSIS 
As this is a pilot study, analyses will be primarily descriptive and by eye. Additionally, all 
exploratory analyses carried out may be stratified by site. No formal sample size calculation has 
been performed. The accrual ceiling for this study is 20 participants (10 per group) with a minimum 
of 10 participants (five per group). This number was selected to obtain at least five participants in 
each group reaching the final study visit in order to obtain preliminary data to potentially support 
a larger trial if promising results are revealed. 
 
 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 33 
BCVA will be evaluated at each scheduled visit, and the primary outcome is defined as the 
difference between groups (those randomized to placebo and those randomized to minocycline) in 
mean change in BCVA in the study eye at 12 months compared to baseline. This study will be 
unable to determine whether there is a statistically significant difference in mean change in BCVA 
between placebo and minoycline groups. Difference in mean change (± standard deviation) in 
BCVA across the two groups will be presented, and interval estimates of mean change in BCVA 
will also be constructed. Exploratory nonparametric statistical analyses will be conducted where 
appropriate. Mean (per group) and individual BCVA will be plotted against time. 
The number of bevacizumab injections required by participants will be assessed as a secondary 
outcome. The number of bevacizumab injections will be summarized for each participant from 
baseline to 12 months and from baseline to 24 months in each group (those randomized to 
minocycline versus placebo) and the means will be compared. 
Changes in mean macular sensitivity as measured by microperimetry will also be assessed as a 
secondary outcome at months 3, 6, 12, 18 and 24 as compared to baseline. A number of recent 
publications have demonstrated the usefulness of microperimetry in assessing macular function in 
vein occlusions.44-55 In addition, some of these studies have found that retinal sensitivity as 
measured by microperimetry correlates more precisely with macular edema thickness 
measurements than with visual acuity measurements.51-52 
Additional secondary outcome measures include changes in retinal thickness in the study eye as 
measured by OCT. Individual and mean changes in retinal thickness will be summarized and 
plotted against time. Other secondary outcomes include change in BCVA in the study eye at 12 
and 24 months compared with baseline, proportion of participants improving ≥ 1 logOCT scale 
step, and change in fluid leakage in the macula of the study eye as demonstrated by fluorescein 
angiography at 12 and 24 months compared to baseline. In general, changes in BCVA, changes in 
retinal thickness, and changes in fluid leakage in the macula will be monitored throughout the 
study period in both the study and fellow eyes. Analyses pertaining to these outcomes will be 
descriptive and will include tabulations with point and interval estimates and plots of outcome 
values over the study period for all participants. Exploratory nonparametric statistical analyses will 
be conducted where appropriate. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 34 
Participants who were exposed to recent (< three months) systemic steroid or systemic  
anti-VEGF prior to enrolling will also be analyzed separately to assess for any possible 
confounding effects for treatment benefit. Safety outcomes, including the number and severity of 
systemic and ocular toxicities and AEs will be summarized by severity, type and assessed 
relatedness to the IP throughout the study period. The number of participants withdrawn from the 
IP due to vision loss or AEs and the number of participants deemed to have worsening disease will 
also be summarized. Worsening disease is defined as loss of 15 or more ETDRS letters of vision 
compared to baseline OR a ≥ 1-step increase in the logOCT scale. These safety analyses will use 
data of all participants who were exposed to IP regardless of adherence to the protocol. 
Participants’ compliance with IP administration will be assessed through capsule counts during 
study visits. If study IP compliance falls below 80% of the level prescribed for any participant, the 
participant will be queried by the site about the reasons for decreased compliance and counseled 
on the importance of compliance for study integrity. The level of compliance will be reported to 
the IRB on annual review and taken into account in the analyses of study outcomes. When IP 
compliance cannot be determined for a participant during any visit due to missing capsule counts, 
IP compliance will be imputed by taking the median of all available capsule counts recorded at 
previous study visits. 
9.0 
HUMAN PARTICIPANTS PROTECTION 
9.1 
Equitability 
Accrual for this study will be equitable among participants with RVOs meeting the enrollment 
criteria. All participants will have received the standard care therapy prior to enrollment. 
9.1.1 Justification for Exclusion of Children 
Children are not eligible for this study as minocycline has not been fully studied in children and is 
not indicated for use in children. 
 
 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 35 
9.1.2 Justification for Exclusion of Pregnant or Lactating Women 
Pregnant or lactating women are not eligible for this study because of the known and unknown 
risks of minocycline. One of the known risks of minocycline is that it can cause permanent 
discoloration of the teeth (yellow-grey-brown) of a fetus when given to a pregnant woman during 
the last half of pregnancy. Minocycline also passes into breast milk and can cause permanent 
discoloration of the teeth of a nursing infant. Given the known and unknown effects on pregnancy 
outcomes, two forms (one form for BRC sites) of contraception will be required for female 
participants of childbearing potential (see Appendix 1 for definition). In addition, female 
participants of childbearing potential will undergo urine pregnancy tests throughout the study. 
9.2 
Qualifications of Investigators 
The following physicians who will be treating the participants are experienced in caring for 
patients with RVOs. In addition, they are experienced in conducting studies similar to this protocol. 
Credentialed NEI staff physicians may also conduct procedures under the direction of these 
investigators. 
The NEI PI has verified that all individuals working on this protocol at the NEI site required to 
take HRPP training under OHSRP SOP 25 (Training requirements for the NIH Human Research 
Protections Program) have completed all required training. 
The BRC site PIs have verified that all individuals working on this protocol at their site are 
sufficiently trained to complete the tasks delegated to them on the study Authorized Staff Signature 
log. 
Catherine Cukras, MD, PhD is the PI with the ability to obtain informed consent. She is responsible 
for 
obtaining 
medical 
history, 
performing 
scheduled 
ophthalmic 
study 
visits, 
dispensing/administering medication, maintaining regulatory documentation, submitting IRB 
materials, generating clinical source documents, resolving data queries and overseeing the 
protocol. Dr. Cukras is currently a staff clinician at NEI. She completed the medical retina clinical 
fellowship at NEI and has mentored medical students in the NEI retina clinic. Dr. Cukras currently 
serves as the PI on a protocol investigating minocycline for the treatment of macular edema.  
She has also served as an Associate Investigator on other clinical research studies on related ocular 
diseases. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 36 
Clare Bailey, MD is the PI for the Bristol Eye Hospital with the ability to obtain informed consent 
at the UK sites. She is responsible for obtaining medical history, performing scheduled ophthalmic 
study visits, administering and dispensing medication, completing regulatory documentation and 
regulatory submissions, generating clinical source documents, resolving data queries and the 
overall oversight of the protocol for the BEH site. Dr. Bailey is a consultant ophthalmologist in 
medical and surgical retina at the BEH and a member of the Royal College of Ophthalmologists. 
Bishwanath Pal, MBBS, MS, Ophth, FRCOphth, FRCSEdin, is the PI for Moorfields Eye Hospital 
with the ability to obtain informed consent from patients at the MEH site. He is responsible for 
obtaining medical history, performing scheduled ophthalmic study visits, administering and 
dispensing medication, completing, generating clinical source documents, resolving data queries 
and the overall oversight of the protocol for the Moorfields site. Dr. Pal is a consultant 
ophthalmologist in medical retina at Moorfields Eye Hospital and a member of the Royal College 
of Ophthalmologists. 
Wai Wong, MD, PhD is the Lead Associate Investigator with the ability to obtain informed 
consent. He is responsible for obtaining medical history, performing scheduled ophthalmic study 
visits, dispensing/administering medication and generating clinical source documents. Dr. Wong 
is a staff clinician and the head of the unit of neuron-glial interactions in retinal diseases at NEI. 
Dr. Wong currently serves as an Associate Investigator on another protocol for the treatment of 
macular edema targeting microglia. Dr. Wong has clinical experience and conducted research 
studies on related ocular diseases as a Principal and Associate Investigator. 
Emily Chew, MD is an Associate Investigator and Accountable Investigator with the ability to 
obtain informed consent. She is responsible for obtaining medical history, performing scheduled 
ophthalmic study visits, dispensing/administering medication and generating clinical source 
documents. Dr. Chew is the deputy clinical director (CD) and director of the medical retina 
fellowship program at NEI. Dr. Chew is on the editorial board of a diabetic journal and serves on 
several committees focused on the care of patients with diabetes. Dr. Chew has conducted 
numerous research studies as a Principal and Associate Investigator on related ocular diseases. 
 
 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 37 
Henry Wiley, MD is an Associate Investigator with the ability to obtain informed consent. He is 
responsible for obtaining medical history, performing scheduled ophthalmic study visits, 
dispensing/administering medication and generating clinical source documents. Dr. Wiley has 
clinical experience and has conducted research studies as a Principal and Associate Investigator 
on related ocular diseases. 
Alexander Kaplan, MD, Christopher Hwang, MD and Munir Iqbal, MD, FRCSC are Associate 
Investigators with the ability to obtain informed consent. They are responsible for obtaining 
medical history, performing scheduled ophthalmic study visits, dispensing/administering 
medication and generating clinical source documents. They are currently clinical fellows at the 
NEI. 
Angela Kibiy, MPH, BSN, RN is an Associate Investigator and the Research Contact without the 
ability to obtain informed consent. She is responsible for providing assistance to the PI with study 
procedures, generating clinical source documents, entering data and resolving data queries.  
Ms. Kibiy has been involved in clinical research studies on ocular diseases as an Associate 
Investigator and primary study coordinator/research contact. 
Awilda V. Holland, DNP, MSHSc, RN, CCRP is an Associate Investigator and back-up 
coordinator without the ability to obtain informed consent. She is responsible for providing 
assistance to the PI with study procedures, generating clinical source documents, entering data and 
resolving data queries. Dr. Holland is the NEI Clinical Trials Coordinating Section Chief and has 
been involved in clinical research studies on ocular diseases. 
Prior to screening or enrolling potential participants, the PI will verify all individuals working on 
this protocol have met the following training and certification requirements as applicable to their 
indicated role: 
9.2.1 Professional Licensure 
Physicians must provide evidence of current medical licensure applicable to the study location(s) 
if they are practicing medicine and undertake to diagnose and/or treat participants (including 
administration of the IP) in this study. A physician who is a site PI must also provide satisfactory 
evidence of ophthalmology training before study initiation. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 38 
10.0 
ANTICIPATED BENEFITS 
During this study, all participants will be eligible to receive intravitreal bevacizumab (Avastin®, 
an anti-VEGF agent. Additionally, participants who are randomized to minocycline may benefit 
directly from this study, as we hypothesize that minocycline may result in resolution or reduction 
of macular edema or improved visual acuity or need for fewer intravitreal bevacizumab injections. 
The study will also lead to generalizable knowledge regarding macular edema associated with 
CRVO. 
11.0 
CLASSIFICATION OF RISK 
Risk is classified as more than minimal risk. The risks will be minimized with careful monitoring and 
are reasonable given that the participants are experiencing visual loss due to CRVO. 
12.0 
CONSENT DOCUMENTS AND PROCESS 
Applicable study investigators with consenting privileges will obtain informed consent. All NIH 
study investigators obtaining informed consent have completed the National Institute of Mental 
Health (NIMH) Human Subject’s Protection Unit (HSPU) “Elements of Successful Informed 
Consent” training. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures and potential risks of the study. The participants must 
have the ability to understand and sign an informed consent form, which must be signed prior to 
enrollment. The participants will have an opportunity to carefully review the consent and ask 
questions regarding this study prior to signing and they will be informed that they may withdraw 
from the study at any time without penalty to themselves or benefits lost. 
If the participant requires the consent to be in larger font in order to read it well, this will be 
provided. If participants are visually impaired to the point of being unable to read the consent, they 
can take the consent back with them to read it over with a family member or with the use of 
magnifying devices. If the participant chooses, the investigator can also read the consent verbatim 
to the participant and answer any questions that may arise. 
An investigator present during the consent process will document the consent process in the 
participant’s medical record. A signed copy of the informed consent form will be provided to the 
participant to take home. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 39 
12.1 
Unanticipated Enrollment of Non-English Speaking Participants at the NEI 
If a non-English speaking participant is eligible for enrollment at the NIH Clinical Center (CC), 
the participant will be provided with the CC Short Written Consent Form for Non-English 
Speaking Research Subjects in the participant’s native language and a verbal explanation of the 
purpose, procedures and risks of the study. The IRB-approved English consent form will serve as 
basis for the verbal explanation of the study. The investigator will obtain an interpreter unless the 
investigator is fluent in the prospective participant’s language. Preferably, the interpreter will be 
someone who is not related to the participant (i.e., not a family member). Interpreters provided by 
the CC will be used whenever possible. The interpreters will interpret the IRB-approved English 
consent form and facilitate discussion between the participant and investigator. 
The IRB-approved English consent form will be signed by the investigator obtaining consent and 
a witness to the oral presentation. The CC Short Written Consent Form will be signed by the 
participant and a witness who observed the presentation of information. The interpreter may sign 
the consent document as the witness and, in this case, will note “Interpreter” with his/her signature. 
If not also serving as the witness, the interpreter will be separately identified on the short form in 
the space provided. A copy of both signed forms (the long form serving as the script and the short 
form) will be provided to the participant. The short form process, including the use of an 
interpreter, will be documented in the medical record in accordance with NIH policy. 
All instances of use of the CC Short Written Consent Form will be reported to the IRB at the time 
of annual review. If the CC Short Written Consent Form is used three times or more for the same 
language within an IRB approval period, this will be reported to the IRB immediately. 
Interpreters will also be present for other protocol procedures as necessary. 
13.0 
DATA AND SAFETY MONITORING 
The NEI Data and Safety Monitoring Committee (DSMC) is responsible for monitoring data and 
safety, and will exercise oversight of the clinical investigation independently from the study 
investigators. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 40 
13.1 
Coordinating Center 
The Emmes Corporation has been assigned as the coordinating center for this trial to conduct data 
collection, protocol monitoring, data analysis and reporting. The coordinating center provides 
routine monitoring of study participants’ data. Monitoring visits will occur on a schedule 
depending on the status of the study. More frequent monitoring visits will be performed at the 
beginning of the study when enrollment is open. Monitoring will decrease as enrollment closes 
and as participant follow-up continues. The protocol monitor will monitor documentation for the 
informed consent process. In addition, the protocol monitor will review source documentation for 
the data collected throughout the trial to ensure that the data points are collected and reported. 
Communications between the investigational site and the Coordinating Center will be maintained 
through regular telephone and e-mail contacts between the Coordinating Center Protocol Monitor 
and the site PI and/or Coordinator. Substantive communications must be maintained both at the 
site and at the Coordinating Center containing the date and a summary of communications where 
instructions are given or received, an interpretation of protocol requirements is made, 
recommendations for corrections to study documentation are made, or where the reporting of 
possible AEs is discussed. 
Although the Coordinating Center advises the NEI CD and PI on data and statistical activities, the 
Coordinating Center staff does not have direct access to or interaction with participants. 
13.2 
Data and Safety Monitoring Committee 
The NEI DSMC is responsible for reviewing and approving the study design and, as appropriate, 
recommending design changes. In addition, the DSMC assesses study data with particular 
consideration of participant safety. The DSMC will convene prior to the initiation of the trial to 
review the protocol. Emmes will provide accumulated data from all study sites to the NEI DSMC 
for review. The Committee will review accumulated data on a biannual basis, but will convene ad 
hoc meetings to address any significant problems related to participant safety brought to its 
attention by any study participant or investigator. The Committee will review the accumulated data 
and consider whether a protocol modification is necessary and approve protocol modifications.  
If changes in protocol are indicated, recommendations will be made to the NEI Director and 
Clinical Center Director who will consider and act on such recommendations in a timely manner. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 41 
All protocol amendments must be reviewed and approved by the NEI DSMC prior to submission 
to the IRB. 
13.3 
Criteria for Stopping the Study 
The DSMC may recommend temporarily suspending or closing enrollment, or stopping the study 
at any time due to safety concerns, demonstration of efficacy or lack of efficacy, or slow 
recruitment. Criteria for stopping the study include the following: 
 A sufficiently large number of dropouts occurs as to make the trial likely to be 
uninformative; 
 A participant experiences a drop in BCVA in the study eye of  30 letters from baseline 
attributed to the IP; 
 A participant experiences a serious adverse event (SAE), drug reaction or complication, 
whether attributed to the IP or not, which has an impact on visual function or any other 
body system or precludes continuation of the IP. This would include the development of 
hypersensitization, allergic responses or other potentially serious drug reactions to 
medications required by the protocol. 
Following premature IP discontinuation, not due to an AE, participants will continue to be 
followed as per the protocol. 
14.0 
QUALITY ASSURANCE 
The NEI and Emmes maintain quality control by adhering to standard operating procedures  
(NEI QA program and NEIS standard operating procedures). These procedures cover the full 
protocol cycle beginning with staff credentialing and training, and protocol development and 
approval, through database development, data collection, monitoring and analysis, and finally 
manuscript preparation at the conclusion of the study. Data quality assurance is of the utmost 
importance to the NEI and Emmes. The two groups use a quality assurance system that relies on 
real-time data checks and reports throughout the course of a study to ensure the accuracy of 
information. This system is a secure and confidential data management system that stores data and 
provides quality assurance and reporting. Emmes has developed a number of routine reports 
specifically designed for monitors (e.g., listings of SAEs, etc.). 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 42 
Additionally, Emmes has developed summary reports of discrepancies, as well as reports of the 
exceptions databases, which include requests and reasons for exceptions. The results of the reports 
are communicated back to site staff, and, along with protocol compliance issues, to the DSMC (if 
applicable). 
Following the monitoring plan for this study, Emmes will perform monitoring activities, including 
on-site audits, review of database entries and the resolution of study issues. In addition to 
monitoring, Emmes performs various detailed automated and manual data quality checks.  
The results from these checks and any protocol compliance issues are communicated back to site 
staff and to the NEI Project Officer, NEI CD and applicable regulatory bodies. 
15.0 
REPORTING OF UNANTICIPATED PROBLEMS, ADVERSE EVENTS AND PROTOCOL 
DEVIATIONS 
The PI is responsible for detecting, documenting, and reporting unanticipated problems, AEs, 
including SAEs, and deviations in accordance with NIH policy, IRB requirements, and federal 
regulations. For the BRC sites, site PI is responsible for detecting, documenting, and reporting 
unanticipated problems, AEs, including SAEs, and deviations, occurring at their site.  
Relatedness to the research of all SAEs will be determined by the PI in consultation with the CD. 
Additionally, both the Sponsor and Investigator will report AEs (SAEs/SUSARs) from the sites in 
accordance with the European Directive 2001/20/EC. SAEs must be reported to the Sponsor by 
the Investigators within 24 hours of awareness. Non-SAEs that are expected as part of the natural 
history of the underlying disease will be summarized at the time of annual review to the IRB. 
Serious unanticipated problems, SAEs (including deaths) that are not unanticipated problems, and 
serious protocol deviations at the NIH will be reported to the CNS IRB and CD as soon as possible 
and in writing not more than seven days after the PI first learns of the event, unless immediate 
reporting is waived for specific SAEs as noted below. Not serious unanticipated problems and not 
serious deviations at the NIH will be reported to the CNS IRB and CD as soon as possible and in 
writing on the NIH Problem Report Form not more than 14 days after the PI first learns of the 
event. Written reports will be submitted in PTMS. For the BRC sites, the site PI is responsible for 
reporting events, including SAEs and protocol deviations to Emmes and the Sponsor, and then 
further reporting to regulatory authorities if reporting requirements are met. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 43 
All unanticipated problems, SAEs, and protocol deviations at the BRC sites will be monitored and 
reported per local regulations. These events will be reported to the NEI DSMC and unanticipated 
problems will be reported to the CNS IRB in the timeframes specified above. 
All AEs, deviations, and unanticipated problems will be summarized and reported to the CNS IRB 
at the time of Continuing Review. 
16.0 
ALTERNATIVE THERAPIES 
Alternatives to participation include further repeat treatment with intraocular injections of  
anti-VEGF agents such as bevacizumab (Avastin®) or ranibizumab (Lucentis®) without 
randomization to minocycline or placebo. Ranibizumab (Lucentis®) recently has been 
demonstrated to improve vision and edema, but the durability of the injections remains unknown. 
Other alternatives include the use of periocular and intraocular corticosteroids. Another approach 
would be observation. Other therapies have been administered with varying rates of success.  
All of these options are associated with significant side effects and complications if the treatment 
is extended and increased. Participants can alternatively receive minocycline outside of the study 
if prescribed off-label by their own physician. 
17.0 
PRIVACY 
All research activities will be conducted in as private a setting as possible. 
18.0 
CONFIDENTIALITY 
No blood, tissue or other samples will be stored in this study. All medical records will be kept 
confidential and will only be reviewed by the participating investigators. Data will be kept in 
password-protected computers held at the NEI and the Coordinating Center. Only study 
investigators and authorized Coordinating Center staff will have access to the study data.  
The participants’ names will not appear on any of the data forms reported to the Coordinating 
Center. A unique identifier will identify the participant if their information is shared with the 
Coordinating Center for research purposes. The participants’ names will not appear in any 
publication of the study results. Participants’ personal information will be kept as private as 
possible. However, records can be inspected by organizations for quality assurance and data 
analysis. Potential inspectors include the members of the FDA, IRB, DSMC and the Coordinating 
Center. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 44 
19.0 
CONFLICT OF INTEREST 
The NIH guidelines were distributed to all the investigators, and none of the investigators had any 
conflicts of interest. 
20.0 
TECHNOLOGY TRANSFER 
There are no technology transfer agreements for this study. 
21.0 
RESEARCH AND TRAVEL COMPENSATION 
For this study, there is no compensation for participation. This protocol does not include 
reimbursement for travel and subsistence. Participants needing financial assistance will be able to 
receive supplemental reimbursement based upon need. Requests for supplemental reimbursement 
will be evaluated on a case-by-case basis for valid financial and/or medical need through a 
standardized process. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 45 
22.0 
References 
1. Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in 
Australia. The Blue Mountains Eye Study. Archives of ophthalmology 1996; 114(10): 1243-
1247. 
2. Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein occlusion: the 
Beaver Dam Eye Study. Transactions of the American Ophthalmological Society 2000; 98: 
133-141; discussion 141-133. 
3. Brown DM, Campochiaro PA, Singh RP et al. Ranibizumab for macular edema following 
central retinal vein occlusion: six-month primary end point results of a phase III study. 
Ophthalmology; 117(6): 1124-1133 e1121. 
4. Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: Basic 
concepts, clinical features and management. Progress in retinal and eye research 2008. 
5. Yoshida S, Yoshida A, Ishibashi T. Induction of IL-8, MCP-1, and bFGF by TNF-alpha in 
retinal glial cells: implications for retinal neovascularization during post-ischemic 
inflammation. Graefe's archive for clinical and experimental ophthalmology = Albrecht von 
Graefes Archiv fur klinische und experimentelle Ophthalmologie 2004; 242(5): 409-413. 
6. Noma H, Funatsu H, Yamasaki M et al. Pathogenesis of macular edema with branch retinal 
vein occlusion and intraocular levels of vascular endothelial growth factor and interleukin-6. 
American journal of ophthalmology 2005; 140(2): 256-261. 
7. Bek T. Capillary closure secondary to retinal vein occlusion. A morphological, 
histopathological, and immunohistochemical study. Acta ophthalmologica Scandinavica 1998; 
76(6): 643-648. 
8. Antonetti DA, Barber AJ, Bronson SK et al. Diabetic retinopathy: seeing beyond glucose-
induced microvascular disease. Diabetes 2006; 55(9): 2401-2411. 
9. Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein 
Occlusion Study Group. American journal of ophthalmology 1984; 98(3): 271-282. 
10. Mohamed Q, McIntosh RL, Saw SM, Wong TY. Interventions for central retinal vein 
occlusion: an evidence-based systematic review. Ophthalmology 2007; 114(3): 507-519, 524. 
11. Giulian D, Li J, Bartel S, Broker J, Li X, Kirkpatrick JB. Cell surface morphology identifies 
microglia as a distinct class of mononuclear phagocyte. J Neurosci 1995; 15(11): 7712-7726. 
12. Lawson LJ, Perry VH, Dri P, Gordon S. Heterogeneity in the distribution and morphology of 
microglia in the normal adult mouse brain. Neuroscience 1990; 39(1): 151-170. 
13. Flaris NA, Densmore TL, Molleston MC, Hickey WF. Characterization of microglia and 
macrophages in the central nervous system of rats: definition of the differential expression of 
molecules using standard and novel monoclonal antibodies in normal CNS and in four models 
of parenchymal reaction. Glia 1993; 7(1): 34-40. 
14. Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: 
mechanisms and strategies for therapeutic intervention. The Journal of pharmacology and 
experimental therapeutics 2003; 304(1): 1-7. 
15. Dickson DW, Lee SC, Mattiace LA, Yen SH, Brosnan C. Microglia and cytokines in 
neurological disease, with special reference to AIDS and Alzheimer's disease. Glia 1993; 7(1): 
75-83. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 46 
16. McMillian MK, Thai L, Hong JS, O'Callaghan JP, Pennypacker KR. Brain injury in a dish: a 
model for reactive gliosis. Trends Neurosci 1994; 17(4): 138-142. 
17. Zeiss CJ, Johnson EA. Proliferation of microglia, but not photoreceptors, in the outer nuclear 
layer of the rd-1 mouse. Investigative ophthalmology & visual science 2004; 45(3): 971-976. 
18. Gupta N, Brown KE, Milam AH. Activated microglia in human retinitis pigmentosa, late-onset 
retinal degeneration, and age-related macular degeneration. Exp Eye Res 2003; 76(4): 463-
471. 
19. Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Levison SW. Diabetic retinopathy: more 
than meets the eye. Surv Ophthalmol 2002; 47 Suppl 2: S253-262. 
20. Zeng HY, Green WR, Tso MO. Microglial activation in human diabetic retinopathy. Archives 
of ophthalmology 2008; 126(2): 227-232. 
21. Shin JM, Quan FS, Lee JH, Chun MH, Oh SJ. Neural Cell Attitudes in Ischemic Retinas 
Evoked by Ischemia/Reperfusion and by Venous Cauterization. Invest Ophthalmol Vis Sci; 
51(5): 2243-A423. 
22. Lin CM, Wolpert EB, Shanmugam S, Antonetti DA, Gardner TW, Abcouwer SF. Different 
Effects of Minocycline and Doxycycline on Retinal Vascular Permeability and 
Neurodegeneration in Ischemia-Reperfusion. Invest Ophthalmol Vis Sci; 51(5): 3648-A298. 
23. Lee JE, Liang KJ, Fariss RN, Wong WT. Ex vivo dynamic imaging of retinal microglia using 
time-lapse confocal microscopy. Investigative ophthalmology & visual science 2008; 49(9): 
4169-4176. 
24. Zemke D, Majid A. The potential of minocycline for neuroprotection in human neurologic 
disease. Clin Neuropharmacol 2004; 27(6): 293-298. 
25. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline 
derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation 
of microglia. J Neurosci 2001; 21(8): 2580-2588. 
26. Ryan ME, Usman A, Ramamurthy NS, Golub LM, Greenwald RA. Excessive matrix 
metalloproteinase activity in diabetes: inhibition by tetracycline analogues with zinc reactivity. 
Curr Med Chem 2001; 8(3): 305-316. 
27. Lampl Y, Boaz M, Gilad R et al. Minocycline treatment in acute stroke: an open-label, 
evaluator-blinded study. Neurology 2007; 69(14): 1404-1410. 
28. Pi R, Li W, Lee NT et al. Minocycline prevents glutamate-induced apoptosis of cerebellar 
granule neurons by differential regulation of p38 and Akt pathways. Journal of neurochemistry 
2004; 91(5): 1219-1230. 
29. Shimazawa M, Yamashima T, Agarwal N, Hara H. Neuroprotective effects of minocycline 
against in vitro and in vivo retinal ganglion cell damage. Brain research 2005; 1053(1-2): 185-
194. 
30. Seabrook TJ, Jiang L, Maier M, Lemere CA. Minocycline affects microglia activation, Abeta 
deposition, and behavior in APP-tg mice. Glia 2006; 53(7): 776-782. 
31. Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, Trauger JW. Antioxidant 
properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-
scavenging activity. Journal of neurochemistry 2005; 94(3): 819-827. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 47 
32. Krady JK, Basu A, Allen CM et al. Minocycline reduces proinflammatory cytokine expression, 
microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. 
Diabetes 2005; 54(5): 1559-1565. 
33. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline 
derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia 
with a wide therapeutic window. Proceedings of the National Academy of Sciences of the 
United States of America 1999; 96(23): 13496-13500. 
34. Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit 
microglial activation and are neuroprotective in global brain ischemia. Proceedings of the 
National Academy of Sciences of the United States of America 1998; 95(26): 15769-15774. 
35. Sanchez Mejia RO, Ona VO, Li M, Friedlander RM. Minocycline reduces traumatic brain 
injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. 
Neurosurgery 2001; 48(6): 1393-1399; discussion 1399-1401. 
36. Festoff BW, Ameenuddin S, Arnold PM, Wong A, Santacruz KS, Citron BA. Minocycline 
neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal 
cord injury. Journal of neurochemistry 2006; 97(5): 1314-1326. 
37. Wells JE, Rice TK, Nuttall RK et al. An adverse role for matrix metalloproteinase 12 after 
spinal cord injury in mice. J Neurosci 2003; 23(31): 10107-10115. 
38. Bosco A, Inman DM, Steele MR et al. Reduced retina microglial activation and improved optic 
nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. 
Investigative ophthalmology & visual science 2008; 49(4): 1437-1446. 
39. Yang LP, Zhu XA, Tso MO. A possible mechanism of microglia-photoreceptor crosstalk. 
Molecular vision 2007; 13: 2048-2057. 
40. Leung DW, Lindlief LA, Laabich A et al. Minocycline protects photoreceptors from light and 
oxidative stress in primary bovine retinal cell culture. Investigative ophthalmology & visual 
science 2007; 48(1): 412-421. 
41. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther 
2005; 27(9): 1329-1342. 
42. Ferris FL 3rd, Miller KM, Glassman AR, Beck RW; Diabetic Retinopathy Clinical Research 
Network. A proposed method of logarithmic transformation of optical coherence tomography 
data for use in clinical research. Ophthalmology 2010 Aug; 117(8):1512-6. 
43. Ladas ID, Karagiannis DA, Rouvas AA, Kotsolis AI, Liotsou A, Vergados I. Safety of repeat 
intravitreal injections of bevacizumab versus ranibizumab: our experience after 2,000 
injections. Retina 2009; 29(3): 313-318. 
44. Yamaike N, Tsujikawa A, Sakamoto A, et al. Retinal sensitivity after intravitreal injection of 
bevacizumab for the treatment of macular edema secondary to retinal vein occlusion. Retina 
2009; 29: 757-767. 
45. Winterhalter S, Lux A, Maier AK, et al. Microperimetry as a routine diagnostic test in the 
follow-up of retinal vein occlusion? Graefes Arch Clin Exp Ophthalmol 2011; 
doi:10.1007/s00417-011-1784-8 
46. Senturk F, Ozdemir H, Karacorlu M, Karacorlu SA, Uysal O. Microperimetric changes after 
intravitreal triamcinolone acetonide injection for macular edema due to central retinal vein 
occlusion. Retina 2010; 30: 1254-1261. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 48 
47. Schneider U, Inhoffen W, Grisanti S, Bartz-Schmidt KU. Characteristics of visual field defects 
by scanning laser ophthalmoscope microperimetry after radial optic neurotomy for central 
retinal vein occlusion. Retina 2005; 25: 704-712. 
48. Schmidt B, Krummenauer F, Losche CC. [Evaluation of Possible Prognostic Factors for the 
Course of Visual Acuity after Intravitreal Ttriamconolone Acetonide.]. Klin Monbl 
Augenheilkd 2011; 229(1), 56-61. doi: 10.1055/s-0031-1281586. 
49. Ogino K, Tsujikawa A, Murakami T, et al. Evaluation of macular function using focal macular 
electroretinography in eyes with macular edema associated with branch retinal vein occlusion. 
Investigative Ophthalmology & Visual Science 2011; 52(11): 8047-8055.  
50. Noma H, Funatsu H, Mimura T, Shimada K. Visual function and serous retinal detachment in 
patients with branch retinal vein occlusion and macular edema: a case series. BMC Ophthalmol 
2011; 11, 29. 
51. Noma H, Funatsu H, Mimura T, Harino S, Shimada K. Functional-morphologic correlates in 
patients with branch retinal vein occlusion and macular edema. Retina 2011; 31(10), 2102-
2108. 
52. Kriechbaum K, Prager F, Geitzenauer W, et al. Association of retinal sensitivity and 
morphology during antiangiogenic treatment of retinal vein occlusion over one year. 
Ophthalmology 2009; 116(12): 2415-2421. 
53. Fujii GY, de Juan E, Jr., Humayun MS. Improvements after sheathotomy for branch retinal 
vein occlusion documented by optical coherence tomography and scanning laser 
ophthalmoscope. Ophthalmic Surg Lasers Imaging 2003; 34(1): 49-52. 
54. Chalam KV, Shah VA. Resolution of macular scotoma after radial optic neurotomy in central 
retinal vein occlusion. Ophthalmic Surg Lasers Imaging 2006; 37(1): 72-75. 
55. Barbazetto IA, Schmidt-Erfurth UM. [Quantification of functional retinal damage in branch 
retinal vein thromboses]. Ophthalmologe 1999; 96(3): 159-165. 
 
 
 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 49 
APPENDIX 1: 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 CNS IRB/NIH Ob-Gyn 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. 
 
 
 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 50 
APPENDIX 2: STUDY FLOWSHEET 
Study Visit Number* (Month) 
0 
1 
2 
3-11 
12 
13-23 
24 
SFTY13 
Visit Number
00
01
02
03-11
12
13-23
24
SFTY
Target Day from Baseline Visit
000
030
060
090-334
365
395-699
730
735
Treatment14 
Dispense Investigational Product1 
(taken twice daily2) 
X 
X 
X 
X3 
X3 
X3 
 
 
Drug Accountability Review
X
X
X
X
X
X
Bevacizumab Injection
X
X
X
X3
X3
X3
General Assessments14 
 
 
 
 
 
 
 
 
Medical/Ophthalmic History
X
Vital Signs
X
Physical Examination
X6
Thyroid Palpation4
X
X
X
X
X
X
X
Review of Systems
X
X
X
X
X
X
X
Allergies Assessment
X
Concomitant Medications 
Assessment
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment
X
X
X
X
X
X
X
Ophthalmic Assessments14
BCVA (ETDRS)
X
X
X
X
X
X
X
X
Manifest Refraction5
X
X
X
Slit Lamp Examination 
X 
X
X
X
X
X
X
X
Dilated Fundus Examination 
X
X
X
X
X
X
X
Intraocular Pressure (IOP)
X
X
X
X
X
X
X
X
Color Fundus Photography (CFP) 
X6
X
X
Spectral Domain Optical 
Coherence Tomography (OCT) 
X6 
X 
X 
X 
X 
X 
X 
X 
Microperimetry
X6
X7
X
X7
X
Fluorescein Angiogram (FA) 
X6
X
X
Laboratory Assessments8, 14 
Acute Care Panel
X9
X
X10
X10
X
X
Hepatic Panel
X9
X
X10
X10
X
X
Complete Blood Count (CBC)
X9
X
Thyroid Function Test11 
X9
X
X10
X10
X
Pregnancy Test (urine)12 
X
X
X
X
X
X
X
 
* These visit numbers correspond with the protocol visit numbers. All follow-up visits will be conducted within a window 
of 7 days of the target day, with the exception of the safety follow-up visit at the BRC sites, which can only occur at 
least five days following IP cessation. 
1 At the time the study medication is dispensed, participants will be provided a pill diary and an information sheet outlining 
instructions on taking study medication and concomitant medications.  
2 Participants will take an oral pill two times a day, once in the morning and once in the evening, approximately  
12 hours apart. The exception to this will occur on the day of the baseline visit, in which participants will take only the 
evening pill.  
3 The decision to continue dispensing IP or injecting bevacizumab is determined by the scenarios described in Section 
4.5.2. 
4  Abnormal findings during a thyroid palpation will be followed by a referral to an endocrinologist.  
5 BCVA with manifest refraction must also be performed when scheduled and when there is a change in VA of  
>10 ETDRS letters (> 0.20 logMAR) as compared with relevant baseline. 
6 These procedures may be completed under another NEI protocol if performed within 1-7 days prior to the baseline visit. 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 51 
7 Microperimetry will be performed at baseline and at Months 3, 6, 12, 18 and 24. 
8 All abnormal values or positive tests will be reported to the participant’s primary care physician, with the participant’s 
permission. 
9 These procedures may be completed under another NEI protocol if performed within 42 days prior to the baseline visit. 
10  The acute care and hepatic panels and thyroid function testing are performed at baseline, Month 2 and every four months 
thereafter (Months 6, 10, 14, 18 and 22), as well as the final visit at Month 24. 
11  Participants with abnormal thyroid function test results will be referred to an endocrinologist. 
12 For women of childbearing potential only and they must have a negative test within 24 hours prior to initiation of IP. 
For the BRC sites, for women of childbearing potential only and they must have a negative serum pregnancy test within 
24 hours prior to initiation of IP. After initiation of contraception, urine pregnancy tests will be conducted; however, a 
serum test will be performed anytime a urine test result creates doubt. See Appendix 1 for guidance on determining 
whether a female is considered to be of childbearing potential. Some women may require a follicle-stimulating hormone 
(FSH) test to determine childbearing potential.  
13 Applicable to the BRC sites only: This visit must be conducted at least five days after the last study drug administration. 
Additional assessments may be performed if deemed necessary by the investigator. 
14 Applicable to the BRC sites only: In the event that the baseline testing was not completed within one day, subsequent 
clinic visits may be scheduled within 14 days of the first visit to complete the scheduled evaluations and treatments. If 
the Month 12 or Month 24 visit was not completed within one day, subsequent visits may be scheduled within 7 days of 
the first visit. If the baseline visit, Month 12 visit or Month 24 visit are conducted over more than one day, BCVA, OCT 
and microperimetry testing must be completed on the day of the injection. 
 
 
 

MiCRVO 
September 19, 2018 
Version 19.0 
CONFIDENTIAL 
Page 52 
APPENDIX 3: LIST OF DEFINITIONS 
 
Improvement: Visual acuity in the study eye of > 84-88 letters (20/20) OR OCT central 
subfield thickness < 300 microns. 
 
Worsening: A decrease in visual acuity of ≥15 or more letters in the study eye compared 
to baseline, AND an increase in OCT central subfield thickness ≥ 1-step log unit compared 
to baseline for at least two consecutive visits. 
 
New Steady State: Improvement and worsening criteria not met and central subfield 
thickness remains ≥ 300 microns on OCT but thickness is stable and has not changed  
> 25 microns over the last three consecutive injections. 
 
No improvement: Improvement and worsening criteria are not met and visual acuity failed 
to increase by ≥ 10 letters in the study eye compared to baseline AND OCT central subfield 
thickness failed to decrease by ≥ 1-step log unit compared to baseline.