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

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Protocol Title:  A Pilot Study for the Evaluation of Minocycline as a Microglia Inhibitor in the 
Treatment of Branch Retinal Vein Occlusions 
Protocol Number: 11-EI-0263 
Date of This Submission/Version: May 6, 2021/20.0 
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 
 
Coordinating Center : 
The Emmes Company, LLC (Emmes) 
401 North Washington St., Suite 700 
Rockville, MD 20850 USA 
Phone: (301) 251-1161 
 
 
 
 
 
 
Participating Sites: 
Bristol Eye Hospital (BEH) 
Lower Maudlin Street 
Bristol BS1 2LX, UK 
Phone: +4401173424613 
Facsimile: +4401173424721 
 
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 #: 
2017-001179-21 
 
Chief Investigator:  
Clare Bailey, MD 
 
Durable Power of Attorney: 
 
 No  
 Yes 
 
Multi-institutional Project: 
 
No  
Yes 

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Data and Safety Monitoring Board: 
 
 No  
 Yes 
 
Technology Transfer Agreement:   
 
 
 No  
 Yes 
 
Samples Being Stored for Future Research:  
 No  
 Yes 
 
Flesch-Kincaid Reading Level of Consent Form:  
9.5 

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TABLE OF CONTENTS 
PROTOCOL ABBREVIATIONS LIST ................................................................................................. V 
PRÉCIS ............................................................................................................................................1 
1.0 
INTRODUCTION/SCIENTIFIC RATIONALE .......................................................................... 3 
1.1 
Branch Retinal Vein Occlusions ..................................................................................... 3 
1.2 
Current Treatments of BRVO ......................................................................................... 4 
1.3 
Role of Microglia ............................................................................................................ 5 
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 .................................................. 8 
2.0 
STUDY OBJECTIVE .............................................................................................................. 8 
3.0 
PARTICIPANTS .................................................................................................................... 9 
3.1 
Participant Eligibility Criteria ......................................................................................... 9 
3.1.1 
Inclusion Criteria ........................................................................................................ 9 
3.1.2 
Exclusion Criteria ..................................................................................................... 11 
3.2 
Study Eye Eligibility Criteria........................................................................................ 12 
3.2.1 
Study Eye Inclusion Criteria ..................................................................................... 12 
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 ........................................................................................ 14 
4.1 
Study Overview ............................................................................................................ 14 
4.2 
Recruitment ................................................................................................................... 14 
4.3 
Screening....................................................................................................................... 15 
4.4 
Randomization, Masking and Unmasking .................................................................... 15 
4.5 
Study Design and Procedures ....................................................................................... 16 
4.5.1 
Treatment Prior to Month 3 ...................................................................................... 17 
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 Therapies ................................................................................ 23 
4.7.1 
Minocycline Formulation at Pine Pharmaceuticals .................................................. 23 
4.7.2 
Minocycline Formulation at the 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 
5.0 
RISKS/DISCOMFORTS ....................................................................................................... 25 

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5.1 
Intravitreal Bevacizumab Risks .................................................................................... 27 
5.2 
Focal Laser Photocoagulation Treatment Risks ........................................................... 27 
5.3 
Investigational Product Risks ....................................................................................... 28 
5.3.1 
Minocycline-related .................................................................................................. 28 
5.3.2 
Drug Interaction-related ............................................................................................ 29 
5.3.3 
Placebo-related .......................................................................................................... 30 
6.0 
PARTICIPANT MONITORING ............................................................................................. 30 
6.1 
Individual Withdrawal Criteria ..................................................................................... 30 
6.2 
Pregnancy Monitoring .................................................................................................. 31 
7.0 
OUTCOME MEASURES ...................................................................................................... 31 
7.1 
Primary Outcome .......................................................................................................... 31 
7.2 
Secondary Outcomes .................................................................................................... 31 
7.3 
Safety Outcomes ........................................................................................................... 33 
8.0 
STATISTICAL ANALYSIS ................................................................................................... 33 
9.0 
HUMAN PARTICIPANTS PROTECTION .............................................................................. 35 
9.1 
Equitability .................................................................................................................... 35 
9.1.1 
Justification for Exclusion of Children ..................................................................... 35 
9.1.2 
Justification for Exclusion of Pregnant or Lactating Women ................................... 35 
10.0 
ANTICIPATED BENEFITS ................................................................................................... 35 
11.0 
CLASSIFICATION OF RISK ................................................................................................ 35 
12.0 
CONSENT DOCUMENTS AND PROCESS ............................................................................. 36 
12.1 
Unanticipated Enrollment of Non-English Speaking Participants at the NEI .............. 36 
13.0 
DATA AND SAFETY MONITORING .................................................................................... 37 
13.1 
Coordinating Center ...................................................................................................... 37 
13.2 
Data and Safety Monitoring Committee ....................................................................... 38 
13.3 
Criteria for Stopping the Study ..................................................................................... 38 
14.0 
QUALITY ASSURANCE ...................................................................................................... 39 
15.0 
REPORTABLE EVENTS ...................................................................................................... 40 
16.0 
ALTERNATIVE THERAPIES ............................................................................................... 40 
17.0 
PRIVACY ........................................................................................................................... 40 
18.0 
CONFIDENTIALITY ............................................................................................................ 40 
19.0 
CONFLICT OF INTEREST ................................................................................................... 41 
20.0 
TECHNOLOGY TRANSFER................................................................................................. 41 
21.0 
RESEARCH AND TRAVEL COMPENSATION....................................................................... 41 
22.0 
REFERENCES ..................................................................................................................... 42 
APPENDIX 1: DETERMINING CHILDBEARING POTENTIAL .......................................................... 46 
APPENDIX 2: STUDY FLOWSHEET ................................................................................................ 47 
APPENDIX 3: LIST OF DEFINITIONS ............................................................................................. 49 
 

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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 
NIH 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 

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IOP 
Intraocular Pressure 
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 

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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 microglia inhibition. The objective of this study is to 
investigate the safety and efficacy of minocycline as a microglia inhibitor in participants with 
branch retinal vein occlusion (BRVO). 
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 BRVO, 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.” 
 
 

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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 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, the number and severity of 
systemic and ocular toxicities and the number of adverse events (AEs). 

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1.0 
INTRODUCTION/SCIENTIFIC RATIONALE 
1.1 
Branch Retinal Vein Occlusions 
RVOs 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 RVOs are central retinal vein occlusions (CRVO) and BRVO. Prevalence of  
BRVO, including hemi-retinal vein occlusions (HRVO), range between 0.6%-1.2%.1, 2  
The standard-of-care for BRVO was previously limited to laser photocoagulation, which was the 
only evidence-based treatment for patients with macular edema secondary to BRVO3 until just 
recently when the Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety Study 
(BRAVO) reported six-month outcome results demonstrating efficacy of intravitreal ranibizumab 
injections for the treatment of BRVO. While the BRVO study did show some success of laser 
treatment in the population studied, it excluded patients with parafoveal capillary non-perfusion, 
a progressive decrease in visual acuity, or marked cystoid macular edema. The BRAVO study, 
while encouraging, only has six-month results published and requires monthly intravitreal 
injections with no clear endpoint of this treatment. 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 RVOs is not completely understood, 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 RVO, 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 fibroblast 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 RVO.6 Further, a histologic study of human retinas with RVOs found 

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numerous clusters of differentiation 68 (CD-68) positive cells surrounding the vasculature 
indicating the presence of activated microglia.7 
Inflammation may represent an early adaptive response to metabolic derangements in the ischemic 
retina; over time; however, it leads to progressive vascular damage 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 BRVO 
From 1984 to 2010, the only proven method to treat edema associated with BRVOs was focal laser 
photocoagulation.3 Clinical trials have demonstrated that laser therapy reduces the risk of moderate 
visual loss by 50%, but in some patients, visual loss progresses despite laser treatment. In some 
cases, laser treatment is not safe because the leaking microaneurysms are too close to the fovea. 
Additionally, laser photocoagulation does not typically improve visual acuity.9, 10  
Recently, phase III results of the BRAVO study, have demonstrated efficacy of monthly injections 
of ranibizumab for treatment of BRVOs.11 And in late June 2010, the FDA approved ranibizumab 
for use in the treatment of RVOs. 
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 BRVO. 
 
 

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1.3 
Role of Microglia 
Retinal microglia, derived from the monocytic lineage, are resident cells in the healthy retina that 
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 entity12 comprising 
approximately 5% to 20% of the total glial cell population in the central nervous system (CNS).13 
Microglia in the CNS are important sources of inflammatory cytokines and chemokines, and are 
the primary cellular mediators of immune function.14 Most of the factors released by activated 
microglia are proinflammatory and neurotoxic, including cytokines tumor necrosis factor-a 
(TNFa) and interleukin-1b (IL-1b), free radicals such as nitric oxide (NO) and superoxide, fatty 
acid metabolites such as eicosanoids, and quinolinic acid.15 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.16 The cytokines released by activated microglia are 
thought to speed neurodegeneration. Microglia have also been implicated in ischemic and 
mechanical injury to the brain.17 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.18, 19 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 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.20 Microglia function has been investigated in a diabetic 
animal model where diabetes was induced in rats with the injection of streptozotocin (STZ). 
 
 

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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.21 This may lead to early fluorescein leakage 
present before frank vasculopathy is noticed in diabetic retinopathy and vein occlusion injury. 
Animal models of ischemia/reperfusion injury mimic 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.22 Further research by Lin et al. on an ischemia/reperfusion 
model in rats has shown not only that microglia are activated in this model, but also that they can 
be inhibited by minocycline.23 In their model, they demonstrated a significant treatment effect 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 BRVO, 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.24 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 barrier25 and appears to inhibit the 
activation of microglia but not astrocytes.26 The mechanism of neuroprotection by minocycline is 
likely several-fold and includes anti-inflammatory effects, reduction of matrix metalloproteinase 
(MMP) activity,27 and decrease in NO production, ultimately leading to an inhibition of microglia 

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and of cell death.28 Minocycline can exert its anti-inflammatory effects on microglia in culture, 
inhibiting their proliferation and release of IL-1B, IL-6, TNF-α, NO secretion, and  
NGF-production leading to neuroprotection with the inhibition of cell death.29-33 Minocycline has 
been also found to inhibit induction of IL-1b-converting enzyme (ICE) mRNA,26 which means 
that minocycline may function by reducing cytotoxic properties of microglia which can be 
activated 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.34-37 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.38 
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.39 Minocycline was effective in decreasing retinal microglia 
activation in culture.40 In models of inherited and light-induced retinal degeneration, minocycline 
was effective in delaying photoreceptor cell death.40, 41 As mentioned above, minocycline reduces 
apoptotic cell death in mouse models of diabetic retinopathy.33 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.33  
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.33 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.33 
 
 

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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. 
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 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.42  
The majority of these events were gastrointestinal upset, photosensitivity, hyperpigmentation and 
tooth discoloration.42 
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.28 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 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 BRVO. 
 
 

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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 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. 
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. 
 
 

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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: 
• 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 the 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). 

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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. 
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 BRVO. 
2. Participant is unable to comply with study procedures or follow-up visits. 
3. Participant has a known hypersensitivity to sodium fluorescein dye. 
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 to study entry. 
13. Participant has a history of thyroid cancer. 

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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 evidence of definite retinal thickening due to a BRVO 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. BRVO is defined as an eye that 
had retinal hemorrhage or other biomicroscopic evidence of RVO (e.g., telangiectatic 
capillary bed) and a dilated (or previously dilated) venous system in one or two quadrants 
or less of the retina drained by the affected vein. HRVO is an RVO that involves two 
altitudinal quadrants. In this study, eyes with a HRVO will be considered a BRVO and are 
given the same treatment as BRVO eyes. 
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. The study eye has macular edema considered to be due to a cause other than BRVO. 
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. 

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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 is present in the study eye 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., uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass 
Syndrome, etc.). 
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 < three 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. 
 
 

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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 BRVO 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. 
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 outpatient 
appointments or sent a recruitment letter from existing databases of patients diagnosed with BRVO 
and who routinely attend the BRC sites for treatment. 
 
 
 

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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. 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) cannot occur until the 
participant has reviewed and signed this protocol’s consent form. 
Potential participants at the BRC sites will be screened under this study protocol. The participant 
must have signed this protocol’s 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 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 for equal numbers of participants in each 
group: minocycline or placebo. Participants must continue to receive the same IP 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, the NEI Data and Safety Monitoring Committee (DSMC) and select individuals at 
Emmes will have access to the group assignments. 

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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 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 NIH 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 require a minimum of 25 appointments (baseline and Months 1-24). All visits 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 visits 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 

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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 multiple days, 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 the 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 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 to them that they may be currently taking 
minocycline. In addition, the participants will be asked to inform a study team member if a new 
medication is prescribed to them. 
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 NIH IRB within two weeks using PTMS. 
4.5.1 
Treatment Prior to Month 3 
At baseline, the participant will receive an injection of 1.25 mg 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. 
 
 

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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 re-injected 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. Focal Laser Treatment - If, based on fluorescein angiography, there is leakage into the 
fovea and insufficient focal laser treatment (i.e., extension of extra-foveal leakage beyond 
the lasered area), the participant may qualify for focal laser treatment. If the participant 
meets retreatment for focal laser, they can be retreated according to Branch Vein Occlusion 
Study (BVOS) guidelines if they have not been treated with focal laser in the past four 
months. 
b. Anti-VEGF Treatment. 
c. 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. 
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: 
 
 

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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. 

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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 
discretion of treating 
investigator 
no 
Does the participant meet 
criteria for “improvement?” 
yes 
yes 
Does participant meet 
criteria for “worsening?” 
no 
yes 
- Dispense randomized 
investigational product 
- Give bevacizumab 
injection 
Months 3 and thereafter 
- Consult decision tree to the 
right 
Does participant meet criteria for “new 
steady state?” 
yes 
no 
-Dispense investigational 
product 
-Investigator physician discretion 
to hold bevacizumab injection 

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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 BRVO. 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,” as 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. AE 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 

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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, 
 
 

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• 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 Therapies 
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 the equivalent of 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 at the 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 pills 
are indistinguishable from the minocycline capsules used in this trial. 

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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 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 IP 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 the unused IP 

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and supplies to the appropriate pharmacy. Each pharmacy will destroy returned 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), Emmes’ database and the Clinical Research Information 
System (CRIS). At the BRC sites, the clinical data will be stored in The Emmes Company, LLC’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. 

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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. 
5. 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. 
6. 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. 

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5.1 
Intravitreal Bevacizumab Risks 
The following data on the complications of intravitreal injections of bevacizumab were taken from 
a publication on the subject.44 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 
Focal Laser Photocoagulation Treatment Risks 
There are risks associated with the standard-of-care treatment, laser photocoagulation. If a laser 
burn occurs too near the center of vision, a scotoma or “blind spot” could develop. After several 
years, the scars caused by the laser may enlarge and cause vision to decrease.  
Serious complications from laser treatment are very rare. They occur in less than 1 in 1,000 cases. 
These include damage to the macula, bleeding inside the eye, damage to the optic nerve, damage 
to the iris, damage to the lens or an intraocular lens, retinal hole, and vision loss. 

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Anesthetic drops and a contact lens may be used as a part of the laser procedure. Risks include 
allergic reaction, infection and corneal abrasion. If any of these problems occur, they usually clear 
up rapidly. 
Participants will sign the separate focal laser photocoagulation procedural consent if they receive 
laser therapy under this protocol. 
5.3 
Investigational Product Risks 
5.3.1 
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. 
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. 

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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. 
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). 
5.3.2 
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 also preparations that 

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include 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. 
5.3.3 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. 
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 in the course of the trial that may affect willingness to participate, 
• Participant requires additional medicines or intravitreal injections that will interfere with 
the IP, 
• Serious suspected adverse reaction, 
• VA loss of ≥ 15 letters from baseline, 
• Participant requires ocular surgery which cannot safely be postponed until the end of the 
study, 
• Any other safety concerns, or 
• Inability to keep study visits or to comply with study requirements. 

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Discontinuation of IP does not require participant withdrawal from the protocol. 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. 
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 placebo and minocycline 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, 

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• 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 ≥ one-step on the logOCT scale, where Change in logOCT = log (follow-up 
thickness/300) – log(baseline thickness/300) is considered clinically significant.43 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. 
Table 2. OCT and Corresponding LogScores43 
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 

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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 IP 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 has been 
calculated. 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. 
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 minocycline 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.45-56 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.52-53 

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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 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 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. 
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 ≥ one-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. 

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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 and will 
be eligible to receive adjuvant laser therapy during the study if necessary. 
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. 
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. 
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, improved visual acuity, or need for fewer intravitreal bevacizumab injections. 
The study will also lead to generalizable knowledge regarding macular edema associated with 
BRVO. 
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 BRVO. 

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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. 
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. 

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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.  
13.1 
Coordinating Center 
Emmes 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 

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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. 
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; 
 
 

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• 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.). 
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. 

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15.0 
REPORTABLE EVENTS 
Reportable events will be tracked and submitted to the NIH IRB as outlined in Policy 801.  
16.0 
ALTERNATIVE THERAPIES 
Alternatives to participation include further repeat treatment with the current standard-of-care  
laser photocoagulation, as well as intraocular injections of anti-VEGF agents such as  
bevacizumab (Avastin®) or ranibizumab (Lucentis®) without randomization to minocycline.  
Ranibizumab (Lucentis®) has recently been demonstrated to improve vision and edema, but the 
durability of the injections remains unknown. Other alternatives include commonly employed 
treatments such as the use of periocular and intraocular corticosteroids. 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. 

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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. 
 
 

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22.0 
REFERENCES 
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15. Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: 
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47. 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 
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48. Schneider U, Inhoffen W, Grisanti S, Bartz-Schmidt KU. Characteristics of visual field defects 
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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 NIH 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. 
 

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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 
 
 
 
 
 
 
 
Physical Examination 
X6 
 
 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
 
 
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 (serum/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. 
1At 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 a 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 to relevant baseline. 
6 These procedures may be completed under another NEI protocol if performed within 1-7 days prior to the baseline visit. 

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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 panel, hepatic panel, 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 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. 
 

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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.