Clinical trial NCT01468831
Conditions: Retinal Vein Occlusion
Keywords: Minocycline Macular Edema
Sponsor: National Eye Institute (NEI)
Start date: 2012-03-28; Completion date: 2021-03-18
Enrollment: 9 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

\- Branch retinal vein occlusion (BRVO) is a blockage of the small veins that carry blood away from the retina in the back of the eye. It often leads to macular edema, a swelling of the retina that is a common source of vision loss. Studies suggest that inflammation might be a cause. Minocycline is a drug that might help prevent cells involved in inflammation from becoming activated. It is approved for use as an antibiotic, but it has not yet been tested to see if it can treat BRVO.

Objectives:

\- To test the safety and effectiveness of minocycline as a treatment for branch retinal vein occlusion.

Eligibility:

\- Individuals at least 18 years of age who have branch retinal vein occlusion in at least one eye, with vision between 20/32 and 20/200.

Design:

* This study lasts 2 years, with at least 25 visits.
* Participants will be screened with a physical exam and medical history. They will also have blood tests and an eye exam. One eye will be selected as the study eye to receive the medicine.
* Those in the study will take minocycline or a placebo pill twice a day, about 12 hours apart, for 2 years.
* Participants will have monthly visits for blood tests and full eye exams to study the effect of the treatment. Other exams may include thyroid tests and eye imaging studies. Those in the study may also receive injections of a drug to prevent the growth of new blood vessels in the eye.

Detailed description:
Objective:

Retinal vein occlusions (RVO) 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 ten and a maximum of 20 participants who meet the eligibility criteria may be enrolled. Eligibility criteria include: foveal center-involved macular edema secondary to a BRVO, retinal thickness in the central subfield greater than 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.

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, the changes in retinal thickness as measured by OCT at 6, 12, 18 and 24 months compared to baseline, number of participants improving greater than or equal to 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.

Arms: arm 1: Participants injected with bevacizumab for three months followed by PRN dosing and placebo twice daily for 24 months arm 2: Participants injected with bevacizumab for three months followed by PRN dosing and 100mg minocycline twice daily for 24 months
Interventions: intervention 1: Minocycline intervention 2: Placebo intervention 3: Bevacizumab
Intervention descriptions: intervention 1: 100 mg of minocycline in a pink opaque capsule intervention 2: Pill with inactive ingredients in a pink opaque capsule intervention 3: 1.25 mg bevacizumab injection

Protocol documents:
ICF_002.pdf: 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Eye Institute 
 
 
STUDY NUMBER: 
11-EI-0263 
 
 
PRINCIPAL 
INVESTIGATOR:  
Catherine Cukras, MD, PhD 
 
 
STUDY TITLE: 
A Pilot Study for the Evaluation of Minocycline as a Microglia 
Inhibitor in the Treatment of Branch Retinal Vein Occlusions 
 
 
Continuing Review Approved by the IRB on 01/16/19 
Amendment Approved by the IRB on 01/09/19 (P) 
Date Posted to the Web: 02/09/19 
Standard 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health 
(NIH). 
 
First, we want you to know that: 
 
Taking part in NIH research is entirely voluntary. 
 
You may choose not to take part, or you may withdraw from the study at any 
time. In either case, you will not lose any benefits to which you are otherwise 
entitled. However, to receive care at the NIH, you must be taking part in a 
study or be under evaluation for study participation. 
 
You may receive no benefit from taking part. The research may give us 
knowledge that may help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds 
of medical or research treatments they would want to receive (such as blood 
transfusions). If you have such beliefs, please discuss them with your NIH doctors or 
research team before you agree to the study. 


 
 
  
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CONTINUATION:  page  2  of  14  pages 
 
 
 
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Now we will describe this research study. Before you decide to take part, please take 
as much time as you need to ask any questions and discuss this study with anyone at 
NIH, or with family, friends or your personal physician or other health professional. 
1) Why is this research being done?  
The purpose of this study is to see if a drug, minocycline, can help patients with 
Branch Retinal Vein Occlusion (BRVO). 
BRVO often leads to macular edema, a swelling of the retina in the back of the eye 
that is a common source of vision loss. Studies have suggested that inflammation 
might be a cause. Thus, if it can be controlled, vision may be kept intact.  
Minocycline is a drug that might help prevent cells involved in inflammation from 
becoming activated. If it can, it might help treat macular edema.  
Minocycline is approved by the FDA as an antibiotic. Minocycline has not been studied 
before to see if it can help alleviate the effects of BRVO. Those who participate in this 
study will be given either minocycline or placebo. A placebo is a harmless sugar pill 
that will have no effect. Neither you nor your study doctors will choose or know 
whether you are taking minocycline or placebo. Whether you receive minocycline or 
placebo will be chosen at random – like rolling dice. The type of pill you take will stay 
the same throughout the study. The FDA has approved the experimental use of 
minocycline for this study.  
2) Why are you being invited to participate?  
You have been asked to participate in this study because you have BRVOs in at least 
one eye. We will choose the affected eye as the “study eye”.  
To be eligible for this study, you must: 
 Be 18 years of age or older. 
 Be able to understand and sign this consent form for yourself. 
 Agree to inform us if you start a new medication while you are in this study. 
 Agree to protect yourself from sunlight or artificial UV rays while in this study. 
 Have vision between 20/32 and 20/200 in the study eye. 


 
 
  
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CONTINUATION:  page  3  of  14  pages 
 
 
 
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 Not be pregnant. If you are a woman who is able to get pregnant or if you are a 
man able to father children, you (or your partner) must have had a hysterectomy 
or a vasectomy, be completely abstinent from intercourse or be willing to use 
two effective methods of birth control while in this study and for one week after 
you stop taking the study pills. 
Please be aware that minocycline can make hormonal contraceptives 
less effective and thus increase the risk of pregnancy. Acceptable 
methods of birth control for this study include the combined use of TWO of the 
following methods: 
1. hormonal contraception (birth control pills, injected hormones, skin patch or 
vaginal ring),  
2. intrauterine device  
3. diaphragm with spermicide or a condom with spermicide 
4. tubal ligation. 
You cannot participate in this study if: 
 You have had BRVOs in your study eye for longer than 18 months. 
 You are in another research study and are taking investigational study drugs for 
BRVO. 
 You are allergic to the dye used for fluorescein angiography. 
 You are allergic to minocycline or any drug in the tetracycline family. 
 You have any illness or condition that might make it unsafe for you to participate, 
such as high blood pressure that is not controlled with medicine. 
 You have a history of chronic hepatitis or liver failure. 
 You are currently taking a tetracycline medication. 
 You are taking systemic anti-VEGF medication such as Avastin® (bevacizumab) 
or systemic steroids. 
 You have had thyroid cancer. 


 
 
  
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 You are taking any medication that is unsafe to take with minocycline, such as 
methoxyflurane. Methoxyflurane is used for general anesthesia and can cause 
serious or fatal kidney damage if used with minocycline. If you need general 
anesthesia or sedation at any time while you are in this study, please 
make sure that you inform your doctors that you may be taking 
minocycline for this study. 
You are not eligible now, but you may be able to enroll at some later date if: 
 You have a blood pressure that is above 180/110. If your blood pressure is 
brought below 180/110 by treatment, you may become eligible for this study. 
 You have had eye injections in your study eye within the past 28 days with anti-
VEGF agents such as Avastin® (bevacizumab), Lucentis® (ranibizumab) or 
Macugen® (pegaptanib sodium)  
 You had a steroid eye injection within the past three months. 
 You had a stroke or heart attack within three months prior to study entry. 
 You had photocoagulation in your study eye within four months prior to study 
entry. 
 You had eye surgery in your study eye within six months of study entry. 
 You had a YAG treatment in your study eye within two months of study entry 
3) How many people will take part in this research study?  
Up to twenty participants with BRVO will be enrolled in this study. 
4) How long will you take part in this research study?  
This study lasts two years (24 months). The study requires at least 25 visits to the NEI 
outpatient clinic. Each visit will last about three hours. 
You will have an initial visit followed by monthly visits for 24 months. You may need to 
return to the clinic for additional appointments as medically needed.  
You will stay under the care of your own doctors for your general medical care while 
you are in this study. You should tell all of your own doctors about this study and that 
you may be taking minocycline so that they can avoid drug interactions that might be 
dangerous. 


 
 
  
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5) What do we do to decide if you are eligible for this research study?  
At your first visit, we will ask you about your medical and eye disease history, perform 
a physical examination, and examine your eyes. If only one of your eyes has macular 
edema from BRVO, we will call that the “study eye.” If both of your eyes have macular 
edema from BRVO, we will choose one of your eyes to be the “study eye.” We will test 
your vision and measure the thickness of your retina. We will draw blood by placing a 
needle in a vein in your arm to test blood count and blood chemistries. If you are a 
woman who is able to get pregnant, you will have a pregnancy test.  
6) What procedures, drugs, or other treatments are involved in this research 
study?  
If you are eligible to participate, you will be assigned to take either minocycline or 
placebo. The minocycline and placebo pills will look the same. Both the minocycline 
and placebo pills will be prepared by Pine Pharmaceuticals (Tonawanda, New York). 
Neither you nor your doctor will know which you are taking. The placebo pills will be 
made of inactive ingredients and will have no medical effect. You will start taking the 
study pills, minocycline, or a placebo, the evening after your first study visit. You will 
take one pill twice a day for two years. You should take one pill in the morning and 
one pill in the evening, at about the same time each day, about 12 hours apart. You 
will need to record the morning and evening doses of pills taken in a diary that we will 
give you.  
You will return for an outpatient visit once a month for 24 months. You will need to 
bring the diary and your pill bottle with any unused study pills with you to each visit. 
At each visit, we will ask you about your health and what medications you are taking. 
Please tell us about any changes in your medications that your own doctors may have 
made. 
At each study visit, you will have some or all of the following tests:  
Eye Examination: The eye examination includes testing how well you see, measuring 
your eye pressure and checking your eye movements. To examine the inside of your 
eyes, we will use eye drops to dilate your pupils. While your eyes are dilated, we will 


 
 
  
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measure the thickness of your retina. Photographs of the inside of the eyes may be 
taken during the eye examination and while your eyes are dilated.  
Thyroid Gland Examination: We will examine the thyroid gland in your neck. We will 
feel your thyroid gland while you swallow. If the examination suggests a possible 
problem with your thyroid gland, you will be referred to an endocrinologist. 
Fluorescein Angiography: For fluorescein angiography, an intravenous line will be 
placed in a vein in your arm. The intravenous line will be used to inject a dye called 
“fluorescein.” The dye will travel through your veins and into the blood vessels in your 
eyes. A camera will be used to take pictures of the dye as it flows through the blood 
vessels in your eyes. 
Microperimetry: We will test how well you can detect different levels of light. You will 
be seated in front of a computer screen and asked to press a button when you see a 
light on the screen.  
Blood Tests: Blood will be drawn for blood chemistries, blood cell counts, thyroid tests, 
and tests of your blood sugar level. Blood will be drawn at several study visits. We will 
draw no more than ½ cup of blood at one time and no more than five cups of blood 
during the entire study. 
Urine Tests: Women who are able to get pregnant will have a urine pregnancy test. 
Eye Injection: You will receive bevacizumab (Avastin®) treatment in your study eye at 
your baseline, Month 1 and Month 2 visits. You may continue to receive this treatment 
at later visits if needed. 
In this study, bevacizumab is being used for “off-label” use, meaning that the drug has 
not been FDA-approved for the treatment of macular edema due to retinal vein 
occlusions. However, bevacizumab is similar in structure to the anti-VEGF drug, 
ranibizumab, which has FDA-approval for macular edema due to retinal vein 
occlusions. There are insufficient data at this time to determine definitively if one anti-
VEGF drug be preferred over the other in this situation. Because of this, it is standard 
practice to use either bevacizumab or ranibizumab to treat this condition. At this time, 
we do not know whether one anti-VEGF is better than the other. 


 
 
  
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In your third month of taking the study medication, you will be able to get focal laser 
treatment in your “study eye,” if it is needed. You can receive treatment for the non-
study eye at the NIH or from your own physician.  
7) What are the risks and discomforts of this research study?  
Risks of Minocycline: Minocycline is an antibiotic. It is widely used to treat infections. 
The most common side effects of minocycline are diarrhea, upset stomach or 
abdominal pain.  
Minocycline can make your skin and eyes sensitive to sunlight and can cause dark 
patches on the skin. Exposure to sunlight, even for brief periods of time, may cause a 
skin rash, itching, redness or other discoloration of the skin, or severe sunburn. When 
you take this medicine, you should:  
 Wear protective clothing, including a hat and sunglasses whenever you are 
outside.  
 Apply a sun block product that has a skin protection factor (SPF) of at least 15 to 
your skin and a sun block lipstick to your lips. Some participants may require a 
product with a higher SPF number, especially if they have a fair complexion. 
 Use extra caution near water, snow, and sand because they reflect and intensify 
the damaging rays of the sun. 
 Not use a sunlamp or tanning bed or booth. 
You may still be more sensitive to sunlight or sunlamps for two weeks to several 
months or more after stopping this medicine. If you have a severe reaction, see your 
doctor immediately. 
Light-headedness, dizziness and vertigo have been reported with minocycline. 
A potentially fatal reaction called “Drug Rashes with Eosinophilia and Systematic 
Symptoms (DRESS)” has been reported with minocycline use. You should contact the 
study team or your own doctors immediately if you develop a new rash.  
Some cases of thyroid cancer have been reported in people taking minocycline. We will 
monitor you for signs of thyroid cancer by examining your thyroid and by blood tests. 
If needed, we will refer you to an endocrinologist for further evaluation. 


 
 
  
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Other rare but potentially severe side effects of minocycline include allergic reactions 
(rash, hives, itching, difficulty breathing, tightness in the chest, swelling of the mouth, 
face, lips or tongue), bleeding or discharge from the gums, bloody stools, blurred 
vision, decreased hearing, fever, headache, inflammation of the pancreas (which can 
cause stomach tenderness, nausea, vomiting, increased pulse rate), joint pain, muscle 
pain or weakness, or liver toxicities. We will treat these if they occur. 
If you develop side effects, including, but not limited to those listed above, or have to 
stop taking minocycline for any reason, we ask that you notify us immediately. Even if 
you stop the minocycline, we ask that you continue to come for the remaining study 
visits so that we can follow your macular edema. 
Minocycline can interfere with helpful bacteria in your body, such as those living in 
your intestines that help with digestion. Therefore, we recommend including live 
culture yogurts in your diet or taking probiotic dietary supplements, which can help 
maintain these bacteria, while you are participating in this study. 
CAUTION: MINOCYCLINE CAN HARM A FETUS. Both men and women need 
to use contraception while in this study. 
Minocycline can lower sperm count. We do not know if a child fathered by a man 
taking minocycline could be affected.  
Minocycline can harm a fetus when taken by a pregnant woman. It can cause 
permanent discoloration of the child’s teeth. Minocycline passes into breast milk and 
can cause permanent discoloration of the teeth of a nursing infant. Therefore, women 
who are pregnant, nursing, or wishing to become pregnant, cannot participate in this 
study. Men should avoid fathering a child while in this study. 
Women who are able to get pregnant will have a urine pregnancy test done at each 
study visit. If you or your partner becomes pregnant while participating in this study or 
suspect that you might be pregnant, you must tell us immediately. The doctor will 
advise you of the possible risks to your unborn child and options available to you. If 
you become pregnant, we will stop the minocycline immediately and you will be 
withdrawn from the study. 


 
 
  
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Risks of Eye Examination, Dilation and Photography: There is minimal medical risk 
from the tests of vision, measuring eye pressure and eye photography. During the 
exam, the eye drops used to dilate your eyes may sting. You may have glare and 
blurry vision for several hours while your eyes are dilated. Some people are allergic to 
eye drops, while others experience a temporary increase in eye pressure. Your eye 
could become red or painful. These problems will be treated if they occur.  
Risks of Physical Examination: Please note that this physical examination is for 
research purposes only and does not replace any examination you may receive from 
your own physicians. 
Risks of Microperimetry and Urine Pregnancy Tests: There are no medical risks from 
these tests. 
Risks of Fluorescein Angiography: The risks of an intravenous catheter include 
bleeding, infection, or inflammation of the skin and vein with pain and swelling. These 
will be treated if they occur. The dye may cause your skin to turn yellow for several 
hours. Because the dye passes through your kidneys, your urine will turn dark orange 
for up to 24 hours after the exam. Some people feel nauseous for a few seconds 
during the fluorescein angiogram. The fluorescein dye can leak out of your vein during 
the injection and cause the skin to feel mildly uncomfortable or become yellow. The 
mild discomfort usually lasts only a few minutes, and the yellow color goes away in a 
few days. In rare cases, there is an allergic reaction to the dye, which causes a rash 
and itching. Allergic reactions are treated by antihistamines, given by pills or a shot if 
needed. Severe allergic reactions that cause difficulty breathing and a drop in blood 
pressure can be life-threatening but are very rare. This would be treated immediately. 
Please let your doctors know if you have ever had an allergic reaction to fluorescein. 
Risks of Drawing Blood: You may have some discomfort and bruising at the site of 
needle entry. There is a very small risk of fainting. Infection in the area of the needle 
insertion is rare.  
Risks of Bevacizumab Injection: There are risks related to the eye injection itself. As 
with any injection in the eye, there is a risk of infection and tears or detachment in the 
retina at the back of the eye. We will lessen the risk of infection by cleaning your eye 
prior to injection and using sterile instruments to give you the injection. If you develop 


 
 
  
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an infection, we will treat you with antibiotics. If you develop a tear in the retina, we 
will seal the tear with laser. If you develop a retinal detachment, you will require an 
operation to fix the retina. In previous studies with bevacizumab injection, the chance 
of developing an infection or retinal tear or detachment was less than 1%. There is a 
risk of elevated eye pressure which would be treated with eye drops if this occurred. If 
the pressure does not decrease with eye drops, we may need to drain eye fluid by 
placing a small needle in the eyeball. Another risk of injections into the eyeball is 
cataract formation, which may require surgery to treat. 
Bevacizumab is given intravenously (IV) for other diseases. When given by IV, side 
effects of bevacizumab include stroke, high blood pressure, and an irregular heartbeat. 
Allergic reactions to bevacizumab can occur but are rare. Allergic reactions may be 
mild, such as skin rash or hives, or severe, such as breathing difficulties or shock. A 
severe allergic reaction could result in permanent disability or death and requires 
immediate medical treatment. If you develop serious symptoms, go to your nearest 
emergency room immediately. Do not wait to call us. 
An uncommon but potentially serious side effect that some patients treated with 
intravenous bevacizumab have is gastrointestinal (GI) perforation, or a tear in the 
stomach or intestines. Symptoms of a GI perforation include abdominal pain, nausea, 
vomiting, constipation and fever. 
Intravenous bevacizumab treatment can lead to slow or incomplete wound healing. 
Bevacizumab can also cause severe bleeding, such as bleeding in the stomach, 
bleeding in the brain, coughing up blood, vomiting blood, nosebleeds, and vaginal 
bleeding. If you experience any of the symptoms described here, you should seek 
immediate medical attention, in our clinic or from your own doctors. 
There is a chance your vision may worsen while you are in this study. Worsened vision 
could occur because of the progression of your eye disease, as a side effect of 
bevacizumab, or for other reasons. 
8) Are there any benefits to you if you take part in this research study? 
You may benefit from participating in this study if you receive minocycline and it helps 
treat macular edema secondary to BRVO. In addition, your participation will help us 


 
 
  
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learn more about BRVO and macular edema that might help you or others in the 
future.  
9) What other choices do you have?  
You may choose not participate in this study but to pursue other therapy under the 
care of your own physician. Such treatments include laser treatment, or eye injections 
of steroids, bevacizumab (Avastin®), ranibizumab (Lucentis®), or pegaptanib sodium 
(Macugen®). Your doctors will discuss these options with you before you enroll in this 
study.  
If you participate, you will be able to receive bevacizumab (Avastin®) eye injections or 
laser treatment during the study, if you need it. 
Minocycline is an FDA-approved antibiotic. You may not have to participate in this 
study to receive minocycline. Your own doctor may be able to prescribe minocycline 
for you as an “off-label” use. 
10) Are there reasons that your research participation may end early? 
You can withdraw from this study at any time without losing any of the benefits to 
which you may otherwise be entitled. We may remove you from the study if medical 
problems develop or if you are unable to comply with the requirements of the study. 
We will remove you from the study if you need to start a medication that cannot be 
taken safely with minocycline. We will remove you from the study if you require a 
treatment that is not permitted in this study. 
This study is under review by a Data and Safety Monitoring Committee (DSMC). A 
DSMC is an independent group of doctors, scientists and ethicists. The DSMC can 
stop or change the study early if they determine that the study medications are not 
working, or that the study’s goals have been met or cannot be met. If the study is 
stopped, your participation will end. 
11) What will happen when the research study is over? 
When the research study is over, you will stop taking the study pills. You will continue 
to receive care from your regular eye doctor during and after this study. You may be 
offered participation in another NIH study, if one is available. 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-EI-0263 
CONTINUATION:  page  12  of  14  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
12) Will your clinical and other test results be shared with you? 
We will give you the results of all of your examinations. With your written request, we 
will send reports to your own doctors.  
We will share with you in a timely manner any information we learn that may affect 
your willingness to continue to participate in the study. 
13) Will the results of this research study be shared with you?  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this Web 
site at any time. 
14)  Will any of your blood, tissue, or other samples be stored and used for 
research in the future? 
None of your blood will be stored or used for future research.  
15)  Will you receive any compensation (money or other) for taking part in 
this research study?  
The amount of payment to research volunteers is guided by the National Institutes of 
Health policies. In general, patients are not paid for taking part in research studies at 
the National Institutes of Health. Reimbursement of travel and subsistence will be 
offered consistent with NIH guidelines. 
You will not be paid to be in this study. We can assist you if you have problems related to 
transportation to the NIH. 
16)  Do any of the researchers or the NIH have a financial interest related to 
this research study? 
None of the doctors in this study receives money or has a conflict-of-interest related to 
this research study. 
 
 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
11-EI-0263 
CONTINUATION:  page  13  of  14  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
17) What privacy and confidentiality procedures apply to the information 
gathered about you in this study? 
When results of an NIH research study are reported in medical journals or at scientific 
meetings, the people who take part are not named or identified. In most cases, the 
NIH will not release any information about your research involvement without your 
written permission. However, if you sign a release of information form, for example, 
for an insurance company, the NIH will give the insurance company information from 
your medical record. This information might affect (either favorably or unfavorably) the 
willingness of the insurance company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records. 
However, you should know that the Act allows release of some information from your 
medical record without your permission, for example, if it is required by the Food and 
Drug Administration (FDA), members of Congress, law enforcement officials, or other 
authorized persons. 
18)  What is the NIH's policy regarding research-related injuries?  
The Clinical Center will provide short-term medical care for any injury resulting from 
your participation in research here. In general, no long-term medical care or financial 
compensation for research-related injuries will be provided by the National Institutes of 
Health, the Clinical Center, or the Federal Government. However, you have the right to 
pursue legal remedy if you believe that your injury justifies such action. 
19)  Who can answer your questions about the research and your rights as 
a research subject?  
If you have any problems or questions about this study, or about your rights as a 
research participant, or about any research-related injury, contact the Principal 
Investigator, Catherine Cukras, MD, PhD; Building 10-CRC, Room 10C438, E-mail: 
cukrasc@nei.nih.gov. You may also call the NEI Clinic Coordinator Angela Kibiy, MPH, 
BSN, RN, at (301) 435-1833 or the Clinical Center Patient Representative at (301) 
496-2626. 
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
11-EI-0263 
CONTINUATION:  page  14  of  14  pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for  
Minor Patient. 
I have read the explanation about this 
study and have been given the 
opportunity to discuss it and to ask 
questions.  I hereby consent to take part 
in this study. 
I have read the explanation about this 
study and have been given the 
opportunity to discuss it and to ask 
questions.  I hereby give permission for 
my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal 
Date 
 Representative 
Signature of Parent(s)/Guardian 
Date 
 
  
 
  
Print Name 
 
Print Name 
 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees 
to participate in the study. 
 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JANUARY 16, 2019 THROUGH FEBRUARY 14, 2020. 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
  
 
 
Print Name 
 
Print Name 
 
 

Prot_000.pdf: 
MiBRVO 
 May 6, 2021 
 
Version 20.0 
CONFIDENTIAL 
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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 


MiBRVO 
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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 


MiBRVO 
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Version 20.0 
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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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PROTOCOL ABBREVIATIONS LIST (CONTINUED) 
Version 20.0 
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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 
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retinal degeneration, and age-related macular degeneration. Exp Eye Res 2003; 76(4): 463-
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20. Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Levison SW. Diabetic retinopathy: more 
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23. Lin CM, Wolpert EB, Shanmugam S, Antonetti DA, Gardner TW, Abcouwer SF. Different 
Effects of Minocycline and Doxycycline on Retinal Vascular Permeability and 
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24. Lee JE, Liang KJ, Fariss RN, Wong WT. Ex vivo dynamic imaging of retinal microglia using 
time-lapse confocal microscopy. Investigative ophthalmology & visual science 2008; 49(9): 
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25. Zemke D, Majid A. The potential of minocycline for neuroprotection in human neurologic 
disease. Clin Neuropharmacol 2004; 27(6): 293-298. 
26. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline 
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27. Ryan ME, Usman A, Ramamurthy NS, Golub LM, Greenwald RA. Excessive matrix 
metalloproteinase activity in diabetes: inhibition by tetracycline analogues with zinc reactivity. 
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28. Lampl Y, Boaz M, Gilad R et al. Minocycline treatment in acute stroke: an open-label, 
evaluator-blinded study. Neurology 2007; 69(14): 1404-1410. 
29. Pi R, Li W, Lee NT et al. Minocycline prevents glutamate-induced apoptosis of cerebellar 
granule neurons by differential regulation of p38 and Akt pathways. Journal of neurochemistry 
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30. Shimazawa M, Yamashima T, Agarwal N, Hara H. Neuroprotective effects of minocycline 
against in vitro and in vivo retinal ganglion cell damage. Brain research 2005; 1053(1-2): 185-
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31. Seabrook TJ, Jiang L, Maier M, Lemere CA. Minocycline affects microglia activation, Abeta 
deposition, and behavior in APP-tg mice. Glia 2006; 53(7): 776-782. 
32. Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, Trauger JW. Antioxidant 
properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-
scavenging activity. Journal of neurochemistry 2005; 94(3): 819-827. 
33. Krady JK, Basu A, Allen CM et al. Minocycline reduces proinflammatory cytokine expression, 
microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. 
Diabetes 2005; 54(5): 1559-1565. 
34. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J. A tetracycline 
derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia 
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United States of America 1999; 96(23): 13496-13500. 
35. Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit 
microglial activation and are neuroprotective in global brain ischemia. Proceedings of the 
National Academy of Sciences of the United States of America 1998; 95(26): 15769-15774. 
36. Sanchez Mejia RO, Ona VO, Li M, Friedlander RM. Minocycline reduces traumatic brain 
injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction. 
Neurosurgery 2001; 48(6): 1393-1399; discussion 1399-1401. 
37. Festoff BW, Ameenuddin S, Arnold PM, Wong A, Santacruz KS, Citron BA. Minocycline 
neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal 
cord injury. Journal of neurochemistry 2006; 97(5): 1314-1326. 
38. Wells JE, Rice TK, Nuttall RK et al. An adverse role for matrix metalloproteinase 12 after 
spinal cord injury in mice. J Neurosci 2003; 23(31): 10107-10115. 
39. Bosco A, Inman DM, Steele MR et al. Reduced retina microglial activation and improved optic 
nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. 
Investigative ophthalmology & visual science 2008; 49(4): 1437-1446. 
40. Yang LP, Zhu XA, Tso MO. A possible mechanism of microglia-photoreceptor crosstalk. 
Molecular vision 2007; 13: 2048-2057. 
41. Leung DW, Lindlief LA, Laabich A et al. Minocycline protects photoreceptors from light and 
oxidative stress in primary bovine retinal cell culture. Investigative ophthalmology & visual 
science 2007; 48(1): 412-421. 
42. Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther 
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43. Ferris FL 3rd, Miller KM, Glassman AR, Beck RW; Diabetic Retinopathy Clinical Research 
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44. Ladas ID, Karagiannis DA, Rouvas AA, Kotsolis AI, Liotsou A, Vergados I. Safety of repeat 
intravitreal injections of bevacizumab versus ranibizumab: our experience after 2,000 
injections. Retina 2009; 29(3): 313-318. 
45. Yamaike N, Tsujikawa A, Sakamoto A, et al. Retinal sensitivity after intravitreal injection of 
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46. Winterhalter S, Lux A, Maier AK, et al. Microperimetry as a routine diagnostic test in the 
follow-up of retinal vein occlusion? Graefes Arch Clin Exp Ophthalmol 2011; 
doi:10.1007/s00417-011-1784-8 
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 
occlusion. Retina 2010; 30: 1254-1261. 
48. Schneider U, Inhoffen W, Grisanti S, Bartz-Schmidt KU. Characteristics of visual field defects 
by scanning laser ophthalmoscope microperimetry after radial optic neurotomy for central 
retinal vein occlusion. Retina 2005; 25: 704-712. 
49. Schmidt B, Krummenauer F, Losche CC. [Evaluation of Possible Prognostic Factors for the 
Course of Visual Acuity after Intravitreal Ttriamconolone Acetonide.]. Klin Monbl 
Augenheilkd 2011; 229(1), 56-61. doi: 10.1055/s-0031-1281586. 
50. Ogino K, Tsujikawa A, Murakami T, et al. Evaluation of macular function using focal macular 
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Investigative Ophthalmology & Visual Science 2011; 52(11): 8047-8055.  
51. Noma H, Funatsu H, Mimura T, Shimada K. Visual function and serous retinal detachment in 
patients with branch retinal vein occlusion and macular edema: a case series. BMC Ophthalmol 
2011; 11, 29. 
52. Noma H, Funatsu H, Mimura T, Harino S, Shimada K. Functional-morphologic correlates in 
patients with branch retinal vein occlusion and macular edema. Retina 2011; 31(10): 2102-
2108. 
53. Kriechbaum K, Prager F, Geitzenauer W, et al. Association of retinal sensitivity and 
morphology during antiangiogenic treatment of retinal vein occlusion over one year. 
Ophthalmology 2009; 116(12): 2415-2421. 
54. Fujii GY, de Juan E, Jr., Humayun MS. Improvements after sheathotomy for branch retinal 
vein occlusion documented by optical coherence tomography and scanning laser 
ophthalmoscope. Ophthalmic Surg Lasers Imaging 2003; 34(1): 49-52. 
55. Chalam KV, Shah VA. Resolution of macular scotoma after radial optic neurotomy in central 
retinal vein occlusion. Ophthalmic Surg Lasers Imaging 2006; 37(1): 72-75. 
56. Barbazetto IA, Schmidt-Erfurth UM. [Quantification of functional retinal damage in branch 
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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. 
 

SAP_001.pdf: 
Statistical Analysis Plan 
For 
A Pilot Study for the Evaluation of Minocycline as a  
Microglia Inhibitor in the Treatment of Branch Retinal Vein Occlusions 
 
NCT01468831 
 
Version 1.0 
February 18, 2021 
 
Prepared by Megan Wall 
 
 
 
Original Author Signature: 
 
__________________________________________ 
 
 
 
 
 
Megan Wall, MS 
 
Reviewer Signature:  
 
__________________________________________ 
 
 
 
 
 
Supriya Menezes, MS 
 
Principal Investigator Signature: 
__________________________________________ 
 
 
 
 
 
Catherine Cukras, MD, PhD 


MiBRVO SAP 
February 18, 2021 
 
TABLE OF CONTENTS 
Version 1.0 
Confidential 
Page i 
LIST OF ABBREVIATIONS ..................................................................................................................... 3 
1.0 
INTRODUCTION ............................................................................................................................. 4 
1.1 
Branch Retinal Vein Occlusions (BRVO) ...................................................................................... 4 
2.0 
DATA SOURCE ............................................................................................................................... 5 
3.0 
GENERAL REVIEW OF STUDY DESIGN ......................................................................................... 5 
3.1 
Randomization, Masking and Unmasking ...................................................................................... 5 
3.2 
Study Design .................................................................................................................................. 6 
3.2.1 
Treatment Prior to Month 3 ..................................................................................................... 7 
3.2.2 
Treatment Beginning at Month 3 ............................................................................................ 7 
3.2.3 
Criteria for Stopping the Study ............................................................................................... 9 
3.3 
Study Objective .............................................................................................................................. 9 
3.4 
Study Population .......................................................................................................................... 10 
3.4.1 
Inclusion Criteria ................................................................................................................... 10 
3.4.2 
Exclusion Criteria .................................................................................................................. 12 
3.5 
Study Eye Eligibility Criteria ....................................................................................................... 13 
3.5.1 
Study Eye Inclusion Criteria ................................................................................................. 13 
3.5.2 
Study Eye Exclusion Criteria ................................................................................................ 13 
3.5.3 
Choice of Study Eye in Cases of Bilateral Eligibility ........................................................... 15 
3.6 
Outcome Measures ....................................................................................................................... 15 
3.6.1 
Primary Study Outcome ........................................................................................................ 15 
3.6.2 
Secondary Study Outcomes .................................................................................................. 15 
3.6.3 
Safety Outcomes ................................................................................................................... 15 
4.0 
STATISTICAL CONSIDERATIONS ................................................................................................ 16 
4.1 
Sample Size .................................................................................................................................. 16 
4.2 
Analysis Population ...................................................................................................................... 16 
4.3 
Descriptive Statistics .................................................................................................................... 16 
4.4 
Handling of Missing Values ......................................................................................................... 16 
4.5 
Handling Duplicate Assessments ................................................................................................. 17 
4.6 
Software for Analyses .................................................................................................................. 17 
5.0 
PARTICIPANT DISPOSITION ........................................................................................................ 17 
6.0 
PARTICIPANT CHARACTERISTICS .............................................................................................. 18 
6.1 
Participant Demographics ............................................................................................................ 18 
6.2 
Medical and Ophthalmic History ................................................................................................. 18 
7.0 
PARTICIPANT COMPLIANCE ....................................................................................................... 18 
7.1 
Protocol Deviations and Unanticipated Problems ........................................................................ 18 
7.1.1 
IP Compliance Deviations ..................................................................................................... 18 
7.2 
Study Procedure Deviations ......................................................................................................... 19 
7.3 
Visit Schedule Deviations ............................................................................................................ 20 
8.0 
TREATMENT ................................................................................................................................ 20 
9.0 
STOPPING THE STUDY ................................................................................................................. 20 
10.0 
PRIMARY OUTCOME ANALYSIS .................................................................................................. 20 
11.0 
SECONDARY OUTCOMES ANALYSIS ............................................................................................ 22 
11.1 Number of Bevacizumab Injections ............................................................................................. 23 
11.2 Macular Sensitivity ....................................................................................................................... 23 
11.3 Best-Corrected Visual Acuity (BCVA) ........................................................................................ 23 
11.4 Optical Coherence Tomography (OCT) ....................................................................................... 23 


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11.5 Improvement of ≥ 1 logOCT Scale Step ...................................................................................... 24 
11.1 Changes in Fluid Leakage ............................................................................................................ 25 
12.0 
SAFETY ANALYSIS ....................................................................................................................... 25 
12.1 Adverse Events (AEs) .................................................................................................................. 25 
12.2 Withdrawal from IP Due to Vision Loss and Adverse Events and Participants with Worsening 
Disease .................................................................................................................................................... 25 
12.3 Best-Corrected Visual Acuity (BCVA) ........................................................................................ 26 
12.4 Optical Coherence Tomography (OCT) ....................................................................................... 26 
12.5 Intraocular Pressure (IOP) ............................................................................................................ 26 
12.6 Thyroid Palpation Assessment and Review of Systems ............................................................... 26 
12.7 Laboratory Assessments ............................................................................................................... 27 
12.8 Other Safety Outcomes ................................................................................................................. 27 
13.0 
QUALITY ASSURANCE PLANS ..................................................................................................... 27 
14.0 
REFERENCES ............................................................................................................................... 28 
15.0 
MOCK SHELLS ............................................................................................................................. 29 
 
LIST OF TABLES 
 
Table 1: Participant Disposition .................................................................................................................. 29 
Table 2: Demographic Information by Site and Treatment Arm ................................................................ 30 
Table 3: Medical and Ocular History .......................................................................................................... 31 
Table 4: Protocol Deviations and Unanticipated Problems ........................................................................ 32 
Table 5: Missed Study Procedures .............................................................................................................. 32 
Table 6: Missed and Out of Window Study Visits ..................................................................................... 33 
Table 7: Analysis of Primary Outcome of Change in BCVA of the Study Eye from Baseline at Month 12
 ..................................................................................................................................................... 33 
Table 8: Analysis of Secondary Outcome of Number of Bevacizumab Injections by Participant from 
Baseline to Month 12 and from Baseline to Month 24 ............................................................... 34 
Table 9: Analysis of Secondary Outcome of Summary of Bevacizumab Injections by Treatment Arm 
from Baseline to Month 12 and from Baseline to Month 24 ....................................................... 34 
Table 10: Analysis of Secondary Outcome of Change in Macular Sensitivity as Measured by 
Microperimetry from Baseline at Months 3, 6, 12, 18 and 24 .................................................... 35 
Table 11: Analysis of Secondary Outcome of Change in BCVA of the Study Eye from Baseline at Month 
24 ................................................................................................................................................. 35 
Table 12: Analysis of Secondary Outcome of Change in Central Retinal Thickness of the Study Eye from 
Baseline at Months 6, 12, 18 and 24 ........................................................................................... 35 
Table 13: Analysis of Secondary Outcome of Number of Participants Improving ≥ 1 logOCT Scale Step 
in the Study Eye at 12 and 24 Months Compared to Baseline .................................................... 35 
Table 14: Analysis of Secondary Outcome of Change in Fluid Leakage in the Macula in the Study Eye at 
12 and 24 Months Compared to Baseline ................................................................................... 35 
Table 15: Summary of Adverse Events ...................................................................................................... 36 
Table 16: Summary of Adverse Events by System Organ Class (SOC) and Preferred Term (PT) ............ 37 
Table 17: Summary of Visual Acuity Over Time ....................................................................................... 38 
Table 18: Summary of Central Retinal Thickness Over Time .................................................................... 39 
Table 19: Summary of IOP Over Time ....................................................................................................... 39 


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Table 20: Results of Thyroid Palpation Assessment and Review of Systems Over Time .......................... 39 
Table 21: Summary of Laboratory Assessments Over Time ...................................................................... 40 
 
LIST OF FIGURES 
 
Figure 1: Consort Diagram ......................................................................................................................... 41 
Figure 2: Mean Best-Corrected Visual Acuity Over Time by Treatment Arm .......................................... 42 
Figure 3: Best-Corrected Visual Acuity Over Time by Participant ............................................................ 43 
Figure 4: Mean Central Retinal Thickness Over Time by Treatment Arm ................................................ 43 
Figure 5: Central Retinal Thickness Over Time by Participant .................................................................. 43 
 
 
LIST OF LISTINGS 
 
Listing 1: Demographic Information by Participant ................................................................................... 44 
Listing 2: IP Compliance ............................................................................................................................ 44 
 
Listing A1. Visit Schedule Deviations Due to COVID-19 ......................................................................... 45 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
APD 
Afferent Pupillary Defect 
BCVA 
Best-Corrected Visual Acuity 
BEH 
Bristol Eye Hospital 
BRC 
Biomedical Research Centre 
BRVO 
Branch Retinal Vein Occlusion 
BVOS 
Branch Vein Occlusion Study 
CFP 
Color Fundus Photography 
COVID-19 
Coronavirus Disease 2019  
CRVO 
Central Retinal Vein Occlusion 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
Cerebral Vascular Event 
DSMC 
Data and Safety Monitoring Committee 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FA 
Fluorescein Angiography  
FDA 
Food and Drug Administration 
HRVO 
Hemi-Retinal Vein Occlusions 
ICRRCC 
Intramural Clinical Research Review Committee 
IOP 
Intraocular Pressure 
IP 
Investigational Product  
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction  
NEI 
National Eye Institute 
OCT 
Optical Coherence Tomography 
PI 
Principal Investigator 
PRP 
Panretinal Photocoagulation 
PT 
Preferred Term 
RVO 
Retinal Vein Occlusion 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Software 
SOC 
System Organ Class 
VEGF 
Vascular Endothelial Growth Factor 
YAG 
Yttrium Aluminum Garnet 


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1.0 
INTRODUCTION 
This statistical analysis plan (SAP) provides the proposed analyses for the MiBRVO protocol titled  
“A Pilot Study for the Evaluation of Minocycline as a Microglia Inhibitor in the Treatment of 
Branch Retinal Vein Occlusions”. This document contains fifteen sections: (1) background of the 
study (2) data sources for analyses, (3) an overview of the study design, (4) statistical 
considerations, (5) participant disposition, (6) participant characteristics, (7) participant 
compliance, (8) treatment, (9) criteria for stopping the study, (10) statistical analysis for the 
primary outcome, (11) statistical abalysis for the secondary outcomes, (12) review of safety 
analyses, (13) quality assurance plans, (14) references, and (15) proposed data tables, figures and 
listings. This document is based on version 22.0 of the protocol dated December 10, 2019. 
1.1 
Branch Retinal Vein Occlusions (BRVO) 
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 branch retinal vein occlusions 
(BRVO) and central retinal vein occlusions (CRVO). Prevalence of BRVO, including hemi-retinal 
vein occlusions (HRVO), range between 0.6%-1.2% (1, 2). 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, 
such as 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. There is accumulating evidence that retinal microglia are 
associated with inflammation in the retina in conditions such as diabetic retinopathy and the RVOs. 
Therefore, 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 with anti-inflammatory properties and high lipophilicity, appears to inhibit the 
activation of microglia as has been observed in animal studies and culture (3-6). Minocycline is 
used widely clinically and has been shown to be well tolerated when used as the FDA-approved 
doses proposed in this study. The objective of this study is to investigate the safety and potential 
efficacy of minocycline, a microglia inhibitor, in the treatment of BRVO.  


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2.0 
DATA SOURCE 
Data received from the National Eye Institute (NEI) will be collected via their electronic data 
capture system (EMR), and uploaded on a daily basis to the Coordinating Center’s database, 
Advantage EDC. Data received from the Bristol Eye Hospital (BEH) will be collected directly 
through Advantage EDC. Aligned OCT and microperimetry data collected for all participants will 
be provided directly to the Coordinating Center.  
3.0 
GENERAL REVIEW OF STUDY DESIGN 
3.1 
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 investigational product 
(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, select individuals at the Emmes Company, LLC, and the NEI Data and Safety 
Monitoring Committee (DSMC) will have access to the group assignments.  
Participants will be unmasked if deemed clinically necessary by the examining physician and if 
the study Principal Investigator (PI) and DSMC Chair are in agreement. In the case of a medical 
emergency, the examining or treating physician will have the final decision and unilateral right for 
unmasking. A request for unmasking, after approval by the PI and the DSMC Chair, will be made 
to 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 adverse event (AE) form. All instances 
of unmasking must be reported to the ICRRC, the NIH IRB, and the DSMC. At the conclusion of 
the study, all investigators will be unmasked. 


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3.2 
Study Design 
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 3, 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 visits (baseline and Months 1-24). All appointments must be 
conducted within a window of ± seven days from the target day. The tests scheduled at each visit 
will be completed in one day. At each visit, the participant will undergo a review of systems and 
an assessment of safety variables. A complete ophthalmologic examination will be performed at 
each visit to measure outcome variables.  
During each clinic visit, participants will have their visual acuity measured and will undergo 
optical coherence tomography (OCT) testing to measure retinal thickness.  
For the Biomedical Research Centre (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 3, 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 the safety follow-up visit which must occur at least 
five days after the cessation of IP. The tests scheduled at each visit are expected to be completed 
in one day, with the exception of the baseline visit, Month 12 visit and Month 24 visit. If the 
baseline examinations cannot be performed in one clinic visit over one day, it is acceptable that 
the baseline examinations be completed at subsequent clinic visits, if scheduled within fourteen 
days of the first visit. If the Month 12 and Month 24 examinations cannot be performed in one 
clinic visit over one day, it is acceptable that the examinations be completed at subsequent clinic 
visits, if scheduled within seven days of the first visit. At each visit, the participant will undergo a 
review of systems and an assessment of safety variables. A complete ophthalmologic examination 
will be performed 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, best-
corrected visual acuity (BCVA), OCT and microperimetry testing must be conducted on the day 


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of the injection. If a participant or site is unable to complete microperimetry testing, the testing 
may be waived and the investigator will specify the reason the test could not be completed. 
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 the investigator decide to stop 
IP. An information sheet outlining instructions on taking the study medication and concomitant 
mediations will be distributed to participants and discussed in detail by study personnel. They will 
be asked to inform any physician who is prescribing new medications that they are currently taking 
minocycline. In addition, the participants will be asked to inform a study team member if a new 
medication is prescribed to them.  
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 iRIS.  
3.2.1 Treatment Prior to Month 3 
At baseline, the participant will receive an injection of 1.25 mg bevacizumab, an anti-vascular 
endothelial growth factor (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.  
3.2.2 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. The 
participant will be re-injected with bevacizumab unless the participant meets the “improvement,” 
“worsening,” “new steady state” or “no improvement” criteria defined below.  
Scenario 1: If the participant meets the “improvement” criteria, 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, the participant will be offered any 
therapy available at the discretion of the treating investigator, including: 


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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, 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: 
Scenario 4: If the participant meets the “no improvement” criteria 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. 
The “improvement,” “worsening,” “new steady state,” and “no improvement” criteria are defined 
as follows: 
• 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 ≥ 15 or more letters in the study eye compared to 
baseline, AND an increase in OCT subfield thickness ≥ 1-step log unit compared to 
baseline for at least two consecutive visits.  


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• 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.  
3.2.3 Criteria for Stopping the Study 
The DSMC may recommend temporarily suspending or closing enrollment, or stopping the study 
at any time due to safety concerns, demonstration of efficacy or lack of efficacy, or slow 
recruitment. Criteria for stopping the study include the following: 
• A sufficiently large number of dropouts occurs as to make the trial likely to be 
uninformative; 
• A participant experiences a drop in BCVA in the study eye of ≥ 30 letters from baseline 
attributed to the IP; 
• A participant experiences a serious adverse event (SAE), drug reaction or complication, 
whether attributed to the IP or not, which has an impact on visual function or any other 
body system or precludes continuation of the IP. This would include the development of 
hypersensitization, allergic responses or other potentially serious drug reactions to 
medications required by the protocol. 
Following premature IP discontinuation, not due to an AE, participants will continue to be 
followed as per the protocol.  
3.3 
Study Objective 
The objective of this study is to investigate the safety and potential efficacy of minocycline, a 
microglia inhibitor, in the treatment of BRVO. 


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3.4 
Study Population 
A minimum of 10 and a maximum of 20 participants who meet the eligibility criteria may be 
enrolled from the NEI clinic and BEH sites, collectively. The recruitment totals are not fixed at 
either the NIH or BEH sites.   
3.4.1 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 must not be pregnant or breast-feeding and 
must be willing to undergo serum (BRC sites only) and urine pregnancy tests throughout 
the study. 
4. For the NEI Site: Female participants of childbearing potential 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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5. For the BRC Sites: Female participants of childbearing potential 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. 
6. 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. 


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7. 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 Adverse Events 
v4.0 (CTCAE). 
8. Participant has at least one eye that meets the study eye criteria listed in Section 3.4. 
3.4.2 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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3.5 
Study Eye Eligibility Criteria 
The participant must have at least one eye meeting all inclusion criteria and none of the exclusion 
criteria listed below. 
3.5.1  Study Eye Inclusion Criteria 
1. The study eye has a best-corrected Early Treatment Diabetic Retinopathy Study 
(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. 
3.5.2 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 


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• Clinical examination, medical history and/or fluorescein angiography suggest that 
diabetic retinopathy is the primary cause of the edema. 
3. The study eye has a history of a recurrent RVO. 
4. The study eye has a history of RVO present for > 18 months. 
5. A brisk afferent pupillary defect (APD) is present in the study eye. 
6. An ocular condition 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. 


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3.5.3 Choice of Study Eye in Cases of Bilateral Eligibility 
If both eyes of a participant meet the criteria described in Sections 3.5.1 and 3.5.2, the study eye 
will be determined at the investigator’s discretion.  
3.6 
Outcome Measures 
3.6.1 Primary Study 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. 
3.6.2 Secondary Study Outcomes 
Secondary outcomes include the difference between the minocycline and placebo groups in the: 
• Number of bevacizumab injections from baseline to 12 months and from baseline to 24 
months,  
• Changes in mean macular sensitivity as measured by microperimetry at 3, 6, 12, 18 and 24 
months compared to baseline,  
• Mean change in the ETDRS BCVA in the study eye at 24 months compared to baseline, 
• Changes in the retinal thickness in the study eye 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 macular as demonstrated by fluorescein angiography at 12 
and 24 months compared to baseline. 
3.6.3 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. 


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4.0 
STATISTICAL CONSIDERATIONS 
4.1 
Sample Size 
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 possible if promising results are revealed.  
4.2 
Analysis Population 
The following analysis populations will be considered for this study: 
Enrolled population: Includes all participants enrolled in the study, regardless of compliance, 
follow-up or treatment received.  
Safety population: Includes all participants who were exposed to IP, regardless of adherence to the 
protocol. 
Primary outcome analysis population: Includes those participants who were exposed to IP and 
were followed up for at least 12 months. 
4.3 
Descriptive Statistics 
For continuous parameters, such as visual acuity, central retinal thickness as measured by OCT, 
and macular sensitivity as measured by microperimetry, descriptive statistics will include number 
of observations, mean, standard deviation, median, minimum and maximum. For categorical 
parameters, such as changes in fluid leakage as demonstrated by fluorescein angiography, 
frequency and percentage of participants will be summarized.  
4.4 
Handling of Missing Values 
If IP compliance cannot be determined for a participant due to missing capsule counts, IP 
compliance will be imputed by taking the median of all available capsule counts recorded at 
previous study visits.  
If there are missing values for outcome data, then sensitivity analyses will be conducted as 
appropriate.  


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4.5 
Handling Duplicate Assessments 
If participants completed assessments as both scheduled and supplementary visits, the assessments 
from the scheduled visit will be considered in the analysis and tabular summaries. However, if an 
assessment is completed only at supplementary visits, then the assessments from the most recent 
supplementary visit will be included in the analysis and tabular summaries. Results of all 
assessments, including those performed during supplementary visits, will be included in the 
listings.  
4.6 
Software for Analyses 
Statistical analyses will be performed using SAS version 9.4 or higher or R v3.6.1 or higher.  
All tables, listings and figures presented in the analysis will be created using either SAS v9.4 or 
Rv3.6.1 or higher. 
5.0 
PARTICIPANT DISPOSITION 
Overall participant disposition including the number and percentage of participants enrolled, 
completed 12 months of treatment, completed the study and discontinued the study early will be 
summarized. Reasons for study discontinuation will also be summarized (Table 1). The number 
and percentage of participants who withdraw from IP due to safety, including due to vision loss 
(manually identified based on investigator’s comments for those participants with reason for 
withdrawal from IP indicated as “safety withdrawal”) and AEs (reason for withdrawal from IP 
indicated as “safety withdrawal” for the occurrence of AEs assessed as being related to study IP 
that preclude further administration of IP) will be included. Further, the number and percentage of 
participants deemed to have worsening disease will be included. Worsening disease is defined as 
loss of 15 or more ETDRS letters of vision compared to baseline OR a ≥ 1-step increase in the 
logOCT scale. This table will be based on the enrolled population. Data will be presented by 
treatment and site.  
Participant flow as outlined in Figure 1 will also be presented.  
If a participant terminates from the study at Month 12 but completes the ophthalmic assessments 
as the Month 12 visit, they will be counted as having completed follow-up through Month 12. 
Similarly, if a participant discontinues IP or is deemed to have worsening disease at the Month 12 
visit, the event will be considered to have occurred after Month 12. 


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6.0 
PARTICIPANT CHARACTERISTICS 
These presentations will be based on the enrolled population. 
6.1 
Participant Demographics 
Demographic characteristics including baseline age, sex, race and ethnicity. Demographic data will 
be summarized by treatment and site as outlined in Table 2 and listed in Listing 1. This table will be 
based on the enrolled population. The listing will include the registration date of participants as well 
as the eye that was selected to be the study eye and the treatment participants were randomized to. 
6.2 
Medical and Ophthalmic History 
The total number and percentage of participants with a history of medical and ocular conditions, 
medications, and ocular procedures will be summarized. History of ocular conditions and procedures 
will also be summarized by eye (study eye and fellow eye) and treatment (Table 3). Medical and 
ocular history will also be listed; the listing will include the date of diagnosis and/or time since 
diagnosis at baseline for select conditions and procedures.  
Any findings from the physical examination at baseline will be included in a listing. 
7.0 
PARTICIPANT COMPLIANCE 
These presentations will be based on the enrolled population.  
7.1 
Protocol Deviations and Unanticipated Problems 
The total number of protocol deviations and unanticipated problems and the number and percentage 
of participants with deviations and unanticipated problems will be summarized. The number of 
events per participant and type (serious or not serious) and outcome of events will also be 
summarized (Table 4). Listings of participant specific and non-participant specific protocol 
deviations and unanticipated problems will be presented.  
7.1.1 IP Compliance Deviations 
This listing will present the number of doses taken, the number of doses missed, the expected number 
of doses taken and the compliance rate for each participant (Listing 2). For each participant, the 
number of expected overall doses will be calculated as follows: 
𝑁 𝐷𝑜𝑠𝑒𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑= (𝐷𝑎𝑡𝑒 𝐿𝑎𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑣𝑖𝑠𝑖𝑡 𝑎𝑡𝑡𝑒𝑛𝑑𝑒𝑑−𝐷𝑎𝑡𝑒 𝐹𝑖𝑟𝑠𝑡 𝑑𝑎𝑡𝑒 𝐼𝑃 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑) ∗2 


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If participants took IP on the date they withdrew from the study or completed the study, the number 
of expected doses overall will be calculated as follows: 
𝑁 𝐷𝑜𝑠𝑒𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑= (𝐷𝑎𝑡𝑒 𝐿𝑎𝑠𝑡 𝑠𝑡𝑢𝑑𝑦 𝑣𝑖𝑠𝑖𝑡 𝑎𝑡𝑡𝑒𝑛𝑑𝑒𝑑−𝐷𝑎𝑡𝑒 𝐹𝑖𝑟𝑠𝑡 𝑑𝑎𝑡𝑒 𝐼𝑃 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑+ 1) ∗2 
If a participant disconinues IP between visits but continues in the study, the number of expected 
doses will be calculated as: 
𝑁 𝐷𝑜𝑠𝑒𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑= (𝐷𝑎𝑡𝑒 𝐿𝑎𝑠𝑡 𝑑𝑎𝑡𝑒 𝐼𝑃 𝑡𝑎𝑘𝑒𝑛−𝐷𝑎𝑡𝑒 𝐹𝑖𝑟𝑠𝑡 𝑑𝑎𝑡𝑒 𝐼𝑃 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑+ 1) ∗2 
The sites will report the number of pills taken based on self-reported information as recorded in 
the pill diary. The number of doses taken and missed will be calculated for each participant as: 
𝑁 𝐷𝑜𝑠𝑒𝑠 𝑡𝑎𝑘𝑒𝑛= 𝑁 𝑃𝑖𝑙𝑙𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑁 𝑃𝑖𝑙𝑙𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑 
𝑁 𝐷𝑜𝑠𝑒𝑠 𝑚𝑖𝑠𝑠𝑒𝑑= 𝑁 𝐷𝑜𝑠𝑒𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑−𝑁 𝐷𝑜𝑠𝑒𝑠 𝑡𝑎𝑘𝑒𝑛 
Negative values will indicate participants who took excess IP.  
Compliance rates will be calculated as: 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 𝑟𝑎𝑡𝑒= (𝑁 𝐷𝑜𝑠𝑒𝑠 𝑡𝑎𝑘𝑒𝑛/𝑁 𝐷𝑜𝑠𝑒𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑) ∗100 
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.  
Participants with compliance rates less than 80% will be flagged. 
7.2 
Study Procedure Deviations 
This table will present the number of procedures not completed, the expected number of 
procedures completed, and the percentage of procedures missed by participant, procedure and 
collectively for all participants, cumulatively throughout the study (Table 5). Number of 
procedures not completed is defined when the site reports a missed procedure or when the protcol 
monitors note a missed procedure at a site, and will be presented as a sum. Expected number of 
procedures completed is defined based on the study flowsheet included in the protocol, and will 
also be presented as a sum. Percentage of procedures missed will be calculated as follows: 
(𝑁 𝑝𝑟𝑜𝑐𝑒𝑑𝑢𝑟𝑒𝑠 𝑛𝑜𝑡 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑒𝑑/𝑁 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑝𝑟𝑜𝑐𝑒𝑑𝑢𝑟𝑒𝑠 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑒𝑑) ∗100   


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7.3 
Visit Schedule Deviations 
This table will present the number of expected visits, number of missed study visits, the percentage 
of missed study visits, the number of out of window visits, and the percentage of out of window 
visits for each individual participant and collectively for all participants, cumulatively throughout 
the study (Table 6). Number of expected, missed and out of window study visits will be calculated 
from the study flowsheet and will all be presented as sums. The percentage of missed study visits 
will be calculated as: 
(𝑁 𝑣𝑖𝑠𝑖𝑡𝑠 𝑚𝑖𝑠𝑠𝑒𝑑/𝑁 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑣𝑖𝑠𝑖𝑡𝑠) ∗100   
Similarily, the percentage of out of window study visits will be calculated as: 
(𝑁 𝑣𝑖𝑠𝑖𝑡𝑠 𝑜𝑢𝑡 𝑜𝑓 𝑤𝑖𝑛𝑑𝑜𝑤/𝑁 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑣𝑖𝑠𝑖𝑡𝑠) ∗100   
Missed and out-of-window visits with the reason indicated as COVID-19 will also be presented 
by participant (Listing A1). 
8.0 
TREATMENT 
Information related to injections administered at each visit will be listed. 
9.0 
STOPPING THE STUDY 
If a participant meets one of the criteria for stopping the study listed in Section 3.2.3, a listing 
containing site, participant ID, date of last contact, visit number, reason for termination and 
comments related to termination will be constructed. 
10.0 
PRIMARY OUTCOME ANALYSIS 
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. 
BCVA at baseline as well as change from baseline at Month 12 will be summarized for both 
treatment arms (Table 7). Interval estimates of mean change in BCVA will also be constructed as 
described below. The difference in mean change between the two groups at Month 12 will be 
calculated as the mean change from baseline at Month 12 for the Minocycline group minus the 
mean change from baseline at Month 12 for the Placebo group. Manifest refraction values for 
BCVA will be used when available. 


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Due to the small (N < 30) sample size, interval estimates for BCVA at baseline and Month 12 and 
change from baseline at Month 12 for each treatment group will be calculated as follows: 
𝐶𝑜𝑛𝑓𝑖𝑑𝑒𝑛𝑐𝑒 𝐼𝑛𝑡𝑒𝑟𝑣𝑎𝑙= 𝑥̅ ± 𝑡𝑛−1,1−𝛼/2 ∗√𝜎2
𝑛 
Where: 
𝑥̅ is the mean.  
t n-1, 1 – α/2 is the t-value with n-1 degrees of freedom at a confidence level of α.  
n is the number of observations.  
𝜎  is the standard deviation.  
 
Additionally, due to the small (N < 30) sample size, interval estimates for the mean difference in 
BCVA at baseline and Month 12 between the two groups as well as the difference in the mean 
change in BCVA from baseline at Month 12 bewteen the two groups will be calculated as follows: 
𝐶𝑜𝑛𝑓𝑖𝑑𝑒𝑛𝑐𝑒 𝐼𝑛𝑡𝑒𝑟𝑣𝑎𝑙= (𝑥1
̅̅̅ −𝑥2
̅̅̅) ± 𝑡𝑑,1−𝛼/2 ∗√𝜎𝑇1−𝑇2
2
 
Where: 
 𝑥1
̅̅̅ and 𝑥2
̅̅̅ are the means for the Minocycline and Placebo groups, respectively. 
t d, 1 – α/2  is the t-value with d degrees of freedom at a confidence level of α. d will be determined 
using the below equation. 
𝜎𝑇1−𝑇2 is the standard deviation of the difference between the means of the Minocycline and 
Placebo groups and will be calculated using the below equation. 
The degrees of freedom, d, for the t-value used to calculate the confidence interval of the difference 
between the two groups will be determined as follows:  
𝑑=
(𝜎1
2
𝑛1 + 𝜎2
2
𝑛2)
2
1
𝑛1 −1 (𝜎1
2
𝑛1)
2
+
1
𝑛2 −1 (𝜎2
2
𝑛2)
2 


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Where: 
𝜎1 and 𝜎2 are the standard deviations for the Minocycline and Placebo groups, respsectively. 
n1 and n2 are the number of observations of the Minocycline and Placebo groups, respectively. 
 
The standard deviation of the difference between the means of the Minocycline and Placebo groups 
will be calculated as follows: 
𝜎𝑇1−𝑇2 = √𝜎1
2
𝑛1
+ 𝜎2
2
𝑛2
 
Where: 
𝜎1 and 𝜎2 are the standard deviations for the Minocycline and Placebo groups, respsectively. 
n1 and n2 are the number of observations of the Minocycline and Placebo groups, respectively. 
 
This analysis will be based on the primary outcome analysis population.  
Additional presentations stratified by site will be constructed as appropriate. 
Exploratory statistical analyses will be conducted as appropriate. 
Participants who were exposed to recent (< three months) systemic steroid or systemic anti-VEGF 
prior to enrolling will be analyzed separately as appropriate to assess for any possible confounding 
effects for treatment benefit.  
11.0 
SECONDARY OUTCOMES ANALYSIS 
These analyses will be based on the safety population who completed the respective visits.  
Additional presentation stratified by site will be constructed as appropriate. 
Exploratory statistical analyses will be conducted as appropriate. 
Participants who were exposed to recent (< three months) systemic steroid or systemic anti-VEGF 
prior to enrolling will be analyzed separately as appropriate to assess for any possible confounding 
effects for treatment benefit. 


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11.1 
Number of Bevacizumab Injections 
The number of bevacizumab injections from baseline to 12 months and from baseline to 24 months 
will be tabulated by participant (Table 8). Additionally, the average number of injections between 
baseline and Months 12 and 24 will be calculated for each treatment arm, and the difference in the 
number of injections between the two groups will be presented (Table 9). The difference in the 
number of injections between the two groups will be calculated as the number of injections in the 
Minocycline group minus the number of injections in the Placebo group. 
11.2 
Macular Sensitivity 
Mean change in macular sensitivity in the study eye, as measured by microperimetry, from 
baseline at Months 3, 6, 12, 18 and 24 will be summarized by treatment arm, and interval estimates 
will be constructed (Table 10). The difference in mean macular sensitivity between the two groups 
will also be presented. Interval estimates will be calculated using the method described in Section 
10.0. The mean difference in macular sensitivity between the two groups at a visit will be 
calculated as the mean change from baseline in the Minocycline group minus the mean change 
from baseline in the Placebo group.  
11.3 
Best-Corrected Visual Acuity (BCVA) 
The mean change in ETDRS BCVA of the study eye at 24 months compared to baseline will be 
analyzed similar to the primary outcome detailed in Section 10.0 (Table 11). Manifest refraction 
values for BCVA will be used when available. 
11.4 
Optical Coherence Tomography (OCT) 
The changes in retinal thickness in the study eye, as measured by aligned OCT, at 6, 12, 18 and 24 
months compared to baseline will be summarized by treatment arm, and interval estimates will be 
constructed (Table 12). The difference in retinal thickness between the two groups will also be 
presented. Interval estimates will be calculated using the method described in Section 10.0.  
The difference in retinal thickness between the two groups at a visit will be calculated as the mean 
change from baseline in the Minocycline group minus the mean change from baseline in the 
Placebo group.  


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11.5 
Improvement of ≥ 1 logOCT Scale Step 
The number of participants improving ≥ 1 logOCT scale step at 12 and 24 months compared to 
baseline in the study eye will be presented by treatment arm (Table 13). The difference in the 
number of participants improving ≥ 1 logOCT scale step from baseline will be calculated as the 
number of participants improving in the Minocycline group minus the number of participants 
improving in Placebo group and will use aligned OCT.  
Improvement of ≥ 1 logOCT scale step is defined as a decrease of ≥ 1-step on the logOCT scale, 
where: 
𝐿𝑜𝑔𝑆𝑐𝑜𝑟𝑒= 10 ∗log10(𝑡ℎ𝑖𝑐𝑘𝑛𝑒𝑠𝑠/300)   
𝑆𝑡𝑒𝑝 𝑐ℎ𝑎𝑛𝑔𝑒 𝑜𝑛 𝑙𝑜𝑔𝑂𝐶𝑇 𝑠𝑐𝑎𝑙𝑒= 𝐿𝑜𝑔𝑆𝑐𝑜𝑟𝑒𝐹𝑜𝑙𝑙𝑜𝑤 𝑢𝑝−𝐿𝑜𝑔𝑆𝑐𝑜𝑟𝑒𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒   
A decrease in one-step is considered clinically significant (7). 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). The table below 
presents examples of OCT measurements with their corresponding LogScore. 
  
OCT and Corresponding LogScores (7) 
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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11.1 
Changes in Fluid Leakage 
Changes in the fluid leakage in the macula of the study eye, as demonstrated by fluorescein 
angiography, at 12 and 24 months compared to baseline will be summarized by treatment arm 
(Table 14). The difference in changes in fluid leakage between the two groups will also be 
presented as the change in fluid leakage in the Minocycline group minus the change in fluid 
leakage in Placebo group.  
12.0 
SAFETY ANALYSIS 
These analyses will be based on the safety population, unless otherwise specified. All relevant 
information will be listed; data for all enrolled participants will be included in the listings. Relevant 
data may be plotted against time.  
Additional presentations stratified by site will be constructed as appropriate. 
12.1 
Adverse Events (AEs) 
All AEs reported will be summarized by treatment arm and overall. Total number and percentage 
of particpants with AEs will be presented by severity, ocular specification, outcome, and relation 
to IP (Table 15). AEs will also be summarized by system organ class (SOC) and preferred term 
(PT) (Table 16). If sufficient data is present, summaries similar to Table 15 and Table 16 will be 
generated for all serious adverse events (SAEs), and summaries similar to Table 16 will be 
presented for natural progression of the disease.  
All AEs and events corresponding to natural progressions of the disease will be listed.  
12.2 
Withdrawal from IP Due to Vision Loss and Adverse Events and Participants with 
Worsening Disease 
Participants who discontinue IP due to vision loss and adverse events will be summarized in Table 
1. Participants who are deemed to have worsening disease in the study or fellow eye at any point 
during follow-up will also be presented in Table 1. Worsening disease is defined as a loss of 15 or 
more ETDRS letters of vision compared to baseline OR a 1-step increase in the logOCT scale.  


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12.3 
Best-Corrected Visual Acuity (BCVA) 
Visual acuity will be collected at baseline and all follow-up visits for both eyes. Total letters read 
at each visit and change from baseline at each follow-up visit will be presented overall and by 
treatment arm for both the study and fellow eyes in Table 17. The number and percentage of 
participants with ≥ 10 letter change at each visit will also be included. Manifest refraction values 
for BCVA will be used when available. 
Mean BCVA will be plotted over time for the minocycline and placebo treatment arms for both 
the study and fellow eyes (Figure 2). Individual BCVA will also be plotted over time for both eyes 
(Figure 3).  
12.4 
Optical Coherence Tomography (OCT) 
Central retinal thickness, as measured by OCT, is assessed at all visits for both eyes. Central retinal 
thickness and change from baseline at each follow-up visit will be presented overall and by 
treatment arm for the study and fellow eyes in Table 18.  
Mean central retinal thickness will be plotted over time for the minocycline and placebo treatment 
arms for both the study and fellow eyes (Figure 4). Individual central retinal thickness will also be 
plotted over time for both eyes (Figure 5).  
12.5 
Intraocular Pressure (IOP) 
Intraocular pressure (IOP) is assessed at all visits for both eyes. IOP measurements at each visit 
and change from baseline at each follow-up visit will be summarized using descriptive statistics 
and will be presented overall and by treatment arm for both the study and fellow eyes (Table 19).  
12.6 
Thyroid Palpation Assessment and Review of Systems 
A thyroid palpation assessment and a review of systems is completed at every visit. The number 
and percentage of participants with clinically significant thyroid palpation findings will be 
summarized overall and by treatment arm (Table 20). The number of percentage of participants 
who experienced dizziness, sun sensitivity, or diarrhea between visits will also be summarized in 
Table 20. 


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12.7 
Laboratory Assessments 
An acute care panel, hepatic panel and thyroid function testing will be 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. Frequency and percentage of participants reporting laboratory abnormalities at 
baseline will be summarized with shift from baseline to each follow-up visit (Table 21).  
12.8 
Other Safety Outcomes 
Exploratory analyses and/or descriptive summary statistics of color fundus photography (CFP), 
fluorescein angiogram (FA), microperimetry and other assessments will be performed as 
appropriate. 
13.0 
QUALITY ASSURANCE PLANS 
To ensure accurate, reliable study results, two statisticians will separately analyze and compare the 
primary study outcome. All SAS or R code used to generate primary and secondary outcomes  
will undergo a code validation by an independent statistician or SAS programmer.  
Documentation related to code validation audits will be maintained on file at the Coordinating 
Center. 
 
 


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14.0 
REFERENCES 
1. Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in 
Australia. The Blue Mountains Eye Study. Archives of ophthalmology 1996; 114(10): 1243- 
1247  
2. Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein occlusion: the 
Beaver Dam Eye Study. Transactions of the American Ophthalmological Society 2000; 98: 
133-141; discussion 141-133. 
3. Zemke D, Majid A. The potential of minocycline for neuroprotection in human neurologic 
disease. Clin Neuropharmacol 2004; 27(6): 293-298.  
4. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline 
derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation 
of microglia. J Neurosci 2001; 21(8): 2580-2588.  
5. Bosco A, Inman DM, Steele MR et al. Reduced retina microglial activation and improved 
optic nerve integrity with minocycline treatment in the DBA/2J mouse model of glaucoma. 
Investigative ophthalmology & visual science 2008; 49(4): 1437-1446.  
6. Yang LP, Zhu XA, Tso MO. A possible mechanism of microglia-photoreceptor crosstalk. 
Molecular vision 2007; 13: 2048-2057.  
7. Ferris FL 3rd, Miller KM, Glassman AR, Beck RW; Diabetic Retinopathy Clinical Research 
Network. A proposed method of logarithmic transformation of optical coherence tomography 
data for use in clinical research. Ophthalmology. 2010 Aug;117(8): 1512-6. 
 
 
 
 


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15.0 
MOCK SHELLS 
TABLES 
Table 1: Participant Disposition 
 
BEH 
NEI 
Total 
Disposition 
Minocycline 
(N=X)1 
Placebo 
(N=X)1 
Total 
(N=X)1 
Minocycline 
(N=X)1 
Placebo 
(N=X)1 
Total 
(N=X)1 
Minocycline 
(N=X)1 
Placebo 
(N=X)1 
Total 
(N=X)1 
Enrolled 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
Completed Follow-up Through Month 12 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
 
 
 
 
 
 
 
 
 
Completed Study 
     Completed Follow-up 
     Terminated per protocol 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
Discontinued IP Early 
     Prior to Month 12 
     After Month 12 
     Reason 
          Participant non-compliance 
          Safety Withdrawal 
               Vision loss2 
               AEs3 
          Other 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
Discontinued Study Early 
     Prior to Month 12 
     After Month 12 
     Reason 
          AE/intercurrent illness 
          Death 
          Requested termination 
          Other 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
Deemed to Have Worsening Disease4,5 
     Prior to Month 125 
          Study Eye 
          Fellow Eye 
     After Month 125 
          Study Eye 
          Fellow Eye 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
1 Column header counts and denominators are the number of participants in the enrolled population in each treatment arm and overall. Percentages are rounded to the nearest whole number. 
2 Manually identified based on investigator’s comments for those participants with reason for withdrawal from IP as “safety withdrawal”. 
3 Participants with reason for withdrawal from IP indicated as “safety withdrawal” for the occurrence of AEs assessed as being related to the study IP that preclude further administration of IP.  
4 Worsening disease is defined as a loss of 15 or more ETDRS letters of vision compared to baseline OR a 1-step increase in the logOCT scale.  
5 If a participant experienced worsening disease in both the study and fellow eyes, the participant will only be counted once. 


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Table 2: Demographic Information by Site and Treatment Arm 
 
 
BEH 
NEI 
Total 
Demographic Characteristics 
Minocycline 
(N=X)1 
Placebo 
(N=X)1 
Total 
(N=X)1 
Minocycline 
(N=X)1 
Placebo 
(N=X)1 
Total 
(N=X)1 
Minocycline 
(N=X)1 
Placebo 
(N=X)1 
Total 
(N=X)1 
Gender N (%) 
     Female 
     Male 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
Age Category (years) at Baseline N (%) 
     56-60 
     61-65 
     66-70 
     71-75 
     76-80 
     81-85 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
Age (years) at Baseline 
     N 
     Mean (SD) 
     Median 
     Range (Min, Max) 
 
x 
x.x (x.x) 
x 
(x, x) 
 
x 
x.x (x.x) 
x 
(x, x) 
 
x 
x.x (x.x) 
x 
(x, x) 
 
x 
x.x (x.x) 
x 
(x, x) 
 
x 
x.x (x.x) 
x 
(x, x) 
 
x 
x.x (x.x) 
x 
(x, x) 
 
x 
x.x (x.x) 
x 
(x, x) 
 
x 
x.x (x.x) 
x 
(x, x) 
 
x 
x.x (x.x) 
x 
(x, x) 
Ethnicity N (%) 
     Hispanic or Latino 
     Not Hispanic or Latino 
     Unknown 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
Race N (%) 
     American Indian or Alaskan Native 
     Asian 
     Black 
     Hawaiian or Pacific Islander 
     White 
     Multiple Race 
     Unknown 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
1 Column header counts and denominators are the number of participants in the enrolled population in each treatment arm and overall. Percentages are rounded to the nearest whole number. 
 


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Table 3: Medical and Ocular History 
 
 
Minocycline 
Placebo 
Total 
Conditions/Procedures 
Study Eye 
(N=X)1 
Fellow Eye 
(N=X)1 
Total 
(N=X)1,2 
Study Eye 
(N=X)1 
Fellow Eye 
(N=X)1 
Total 
(N=X)1,2 
Study Eye 
(N=X)1 
Fellow Eye 
(N=X)1 
Total 
(N=X)1,2 
Any Medical Condition 
     Renal disease 
          Yes 
          No 
     Hepatitis 
          Yes 
          No 
     … 
 
 
 
 
 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
 
 
 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
 
 
 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
Any Medication History 
     Systemic anti-VEGF 
          Yes 
          No 
     Systemic steroid 
          Yes 
          No 
 
 
 
 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
 
 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
 
 
 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
Any Ocular Condition 
     Recurrent RVO 
          Yes 
          No 
     RVO present > 18 months 
          Yes 
          No 
 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
Any Ocular Procedure 
     Intravitreal steroid injection 
          Yes 
          No 
     Cataract surgery 
          Yes 
          No 
     … 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
1 Column header counts and denominators are the number of participants in the enrolled population in each treatment arm and overall. Percentages are rounded to the nearest whole number. 
2 If a participant reported an ocular condition or procedure in both eyes, the participant will only be counted only once. 


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Table 4: Protocol Deviations and Unanticipated Problems 
 
 
Participant-Specific 
Non-Participant Specific 
Total 
 
Number of 
Events 
Number of Participants 
with Events 
(N=X)1 
Number of  
Events 
Number of 
Events 
All Events 
     Protocol Deviations 
     Unanticipated Problems 
 
x 
x 
x 
x (x%) 
x (x%) 
x (x%) 
x 
x 
x 
x 
x 
x 
Number of Events per Participant 
     Mean (SD) 
     Median 
     Range (Min, Max) 
 
 
x.x (x.x) 
x 
x, x 
 
 
 
Type 
     Serious 
     Not serious 
 
 
x 
x 
 
x (x%) 
x (x%) 
 
x 
x 
 
x 
x 
Outcome 
     Participant follow-up continues 
     Participant follow-up terminated 
     … 
 
x 
x 
x 
 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
 
x 
x 
x 
1 Column header count and denominators are the number of participants in the enrolled population. Percentages are rounded to the nearest whole 
number. 
 
 
Table 5: Missed Study Procedures 
 
Category 
Site 
Participant ID/ 
Procedure 
Number of 
Expected 
Procedures 
Number of 
Missed 
Procedures 
Percentage of 
Missed 
Procedures 
Participant 
xxx 
001 
xx 
xx 
x.x 
 
xxx 
002 
xx 
xx 
x.x 
 
xxx 
003 
xx 
xx 
x.x 
 
 
… 
xx 
xx 
x.x 
 
 
… 
xx 
xx 
x.x 
 
 
 
 
 
 
Procedure 
 
Acute Care Panel 
xx 
xx 
x.x 
 
 
Adverse Event 
Assessment 
xx 
xx 
x.x 
 
 
BCVA (ETDRS) 
xx 
xx 
x.x 
 
 
… 
xx 
xx 
x.x 
 
 
… 
xx 
xx 
x.x 
 
 
 
 
 
 
Total 
 
 
xx 
xx 
x.x 
 
 
 
 


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Table 6: Missed and Out of Window Study Visits 
 
Site 
Participant 
ID 
Number of 
Expected Visits 
Number of 
Missed Visits 
Percentage of 
Missed Visits 
Number of Out 
of Window 
Visits 
Percentage of 
Out of Window 
Visits 
Visits Missed or 
Out of Window 
xxx 
001 
xx 
xx 
x.x 
xx 
x.x 
xxx 
xxx 
002 
xx 
xx 
x.x 
xx 
x.x 
 
… 
… 
xx 
xx 
x.x 
xx 
x.x 
 
Total 
 
xx 
xx 
x.x 
xx 
x.x 
 
 
 
 
Table 7: Analysis of Primary Outcome of Change in BCVA of the Study Eye from Baseline at Month 12 
 
 
Minocycline 
Placebo 
Difference1 
Visit 
BCVA 
(letters read) 
Δ 
(letters read) 
BCVA 
(letters read) 
Δ 
(letters read) 
BCVA 
(letters read) 
Δ 
(letters read) 
Baseline 
     N 
     Mean (SD) 
     95% Confidence Interval 
 
x 
x (x) 
(x, x) 
 
 
x 
x (x) 
(x, x) 
 
 
 
x (x) 
(x, x) 
 
 
 
 
 
 
 
 
Month 12 
     N 
     Mean (SD) 
     95% Confidence Interval 
 
x 
x (x) 
(x, x) 
 
x 
x (x) 
(x, x) 
 
x 
x (x) 
(x, x) 
 
x 
x (x) 
(x, x) 
 
 
x (x) 
(x, x) 
 
 
x (x) 
(x.x, x.x) 
Δ indicates change from baseline. 
1 Difference is defined as the Minocycline – Placebo treatment arms. Negative values indicate that participants in the Placebo group experienced a higher visual acuity or a 
more positive change from baseline at Month 12.   
 


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Table 8: Analysis of Secondary Outcome of Number of Bevacizumab Injections by Participant from Baseline to Month 12 and 
from Baseline to Month 24 
 
Site 
Participant ID 
Treatment Arm 
Visit Period 
Number of Bevacizumab Injections 
xxx 
001 
Minocycline/Placebo 
Baseline to Month 12 
xx 
 
 
 
Baseline to Month 24 
xx 
 
 
 
 
 
xxx 
002 
Minocycline/Placebo 
Baseline to Month 12 
xx 
 
 
 
Baseline to Month 24 
xx 
… 
… 
… 
… 
… 
 
 
 
Table 9: Analysis of Secondary Outcome of Summary of Bevacizumab Injections by Treatment Arm from Baseline to Month 
12 and from Baseline to Month 24 
 
Visit Period 
Minocycline 
(N=X)1 
Placebo 
(N=X)1 
Difference2 
Baseline to Month 12 
     Number of Injections 
     Mean 
 
 
xx 
x.x 
 
xx 
x.x 
 
xx 
x.x 
 
 
 
 
Baseline to Month 24 
     Number of Injections 
     Mean 
 
xx 
x.x 
 
xx 
x.x 
 
xx 
x.x 
1 Column header counts are the number of participants in the safety population in each treatment arm and overall. 
2 Difference is defined as the Minocycline – Placebo treatment arms. Negative values indicate that participants in the Placebo group received more injections during the 
respective visit period. 
 
 


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Table 10: Analysis of Secondary Outcome of Change in Macular Sensitivity as Measured 
by Microperimetry from Baseline at Months 3, 6, 12, 18 and 24 
This table will be similar to Table 7.  
 
Table 11: Analysis of Secondary Outcome of Change in BCVA of the Study Eye from 
Baseline at Month 24 
This table will be similar to Table 7. 
 
Table 12: Analysis of Secondary Outcome of Change in Central Retinal Thickness of the 
Study Eye from Baseline at Months 6, 12, 18 and 24 
This table will be similar to Table 7.  
 
Table 13: Analysis of Secondary Outcome of Number of Participants Improving ≥ 1 
logOCT Scale Step in the Study Eye at 12 and 24 Months Compared to Baseline 
 
Visit 
Minocycline 
N (%)1 
Placebo 
N (%)1 
Difference2 
Month 12 
x (x%) 
x (x%) 
x 
Month 24 
x (x%) 
x (x%) 
x 
1 Denominators are the number of participants in the safety population in each treatment arm and overall with data at the given 
visit. Percentages are rounded to the nearest whole number. 
2 Difference is defined as Minocycline – Placebo treatment arms. Negative values indicate that more participants in the 
Placebo group improved by ≥ 1 logOCT scale step at the respective visit compared to baseline. 
 
Table 14: Analysis of Secondary Outcome of Change in Fluid Leakage in the Macula in the 
Study Eye at 12 and 24 Months Compared to Baseline 
 
Visit 
Minocycline 
N (%)1 
Placebo 
N (%)1 
Difference2 
Month 12 
     Increase 
     Decrease 
     No Change 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
 
 
 
 
Month 24 
     Increase 
     Decrease 
     No Change 
 
x (x%) 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
1 Denominators are the number of participants in the safety population in each treatment arm and overall with data at the given 
visit. Percentages are rounded to the nearest whole number. 
2 Difference is defined as Minocycline – Placebo treatment arms. Negative values indicate that more participants in the 
Placebo group experienced a certain change in fluid leakage at the respective visit compared to baseline.  
 


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Table 15: Summary of Adverse Events 
 
 
Minocycline 
Placebo 
Total 
 
Participants 
with Events 
N (%)1 
Number of 
Events 
N 
Participants 
with Events 
N (%)1 
Number of 
Events 
N 
Participants 
with Events 
N (%)1 
Number of 
Events 
N 
All AEs 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
Serious Adverse Events 
x (x%) 
x 
x (x%) 
x 
x (x%) 
x 
Severity 
     Mild 
     Moderate 
     Severe 
     Life-threatening 
     Death 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
x 
x 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
x 
x 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
x 
x 
Eye 
     Non-ocular 
     Study eye 
     Fellow eye 
 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
Outcome 
     Resolved 
     Resolved with sequalae 
     Death 
     Resolved by convention 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
x 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
x 
 
x (x%) 
x (x%) 
x (x%) 
x (x%) 
 
x 
x 
x 
x 
Relation to IP 
     Yes 
     No 
 
x (x%) 
x (x%) 
 
x 
x 
 
x (x%) 
x (x%) 
 
x 
x 
 
x (x%) 
x (x%) 
 
x 
x 
1 Denominators are the number of participants in the safety population in each treatment arm and overall. Percentages are rounded to the nearest whole number. 
 
 


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Table 16: Summary of Adverse Events by System Organ Class (SOC) and Preferred Term (PT) 
 
 
Minocycline 
Placebo 
Total 
System Organ Class/ 
Preferred Term 
Participants 
with Events 
N (%)1 
Number of 
Events 
N 
Participants 
with Events 
N (%)1 
Number of 
Events 
N 
Participants 
with Events 
N (%)1 
Number of 
Events 
N 
SOC1 
     PT1 
     PT2 
x (x%) 
x (x%) 
x (x%) 
x 
x 
x 
x (x%) 
x (x%) 
x (x%) 
x 
x 
x 
x (x%) 
x (x%) 
x (x%) 
x 
x 
x 
SOC2 
     PT1 
     PT2 
x (x%) 
x (x%) 
x (x%) 
x 
x 
x 
x (x%) 
x (x%) 
x (x%) 
x 
x 
x 
x (x%) 
x (x%) 
x (x%) 
x 
x 
x 
… 
 
 
 
 
 
 
… 
 
 
 
 
 
 
1 Denominators are the number of participants in the safety population in each treatment arm and overall. Percentages are rounded to the nearest whole number. 
 
 
 


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Table 17: Summary of Visual Acuity Over Time 
 
 
Minocycline 
Placebo 
Total 
 
BCVA 
(letters read) 
Δ 
(letters read) 
BCVA 
(letters read) 
Δ 
(letters read) 
BCVA 
(letters read) 
Δ 
(letters read) 
Visit 
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
Study 
Eye 
Fellow 
Eye 
Baseline 
     N 
     Median 
     Mean (SD) 
     (Min, Max) 
 
x 
x.x 
x (x) 
(x, x) 
 
x 
x.x 
x (x) 
(x, x) 
 
 
 
x 
x.x 
x (x) 
(x, x) 
 
x 
x.x 
x (x) 
(x, x) 
 
 
 
x 
x.x 
x (x) 
(x, x) 
 
x 
x.x 
x (x) 
(x, x) 
 
 
Month 1 
     N 
     Median 
     Mean (SD) 
     (Min, Max) 
     Change of ≥ 10 letters, N(%)1     
 
x 
x.x 
x (x) 
(x, x) 
 
x 
x.x 
x (x) 
(x, x) 
x (x%) 
 
x 
x.x 
x (x) 
(x, x) 
 
x 
x.x 
x (x) 
(x, x) 
x (x%) 
 
x 
x.x 
x (x) 
(x, x) 
 
x 
x.x 
x (x) 
(x, x) 
x (x%) 
 
x 
x.x 
x (x) 
(x, x) 
 
x 
x.x 
x (x) 
(x, x) 
x (x%) 
 
x 
x.x 
x (x) 
(x, x) 
 
x 
x.x 
x (x) 
(x, x) 
x (x%) 
 
x 
x.x 
x (x) 
(x, x) 
 
x 
x.x 
x (x) 
(x, x) 
x (x%) 
Month 2 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Month 24 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Δ indicates change from baseline. 
1 Denominators are the number of participants in the safety population in each treatment arm and overall with data at the given visit. Percentages are rounded to the nearest whole number. 
 
 
 
 
 
 
 
 
 
 


MiBRVO SAP 
February 18, 2021 
Version 1.0 
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Page 39 
Table 18: Summary of Central Retinal Thickness Over Time 
This table will be similar to Table 17. The row corresponding to Change of ≥ 10 letters will be excluded. 
 
Table 19: Summary of IOP Over Time 
This table will be similar to Table 17. The row corresponding to Change of ≥ 10 letters will be excluded. 
 
 
Table 20: Results of Thyroid Palpation Assessment and Review of Systems Over Time 
 
 
Minocycline 
Placebo 
Total 
 
Significant 
Findings 
Review of Systems 
Significant 
Findings 
Review of Systems 
Significant 
Findings 
Review of Systems 
Visit 
Thyroid 
Palpation 
Dizziness 
Sun 
Sensitivity Diarrhea 
Thyroid 
Palpation 
Dizziness 
Sun 
Sensitivity Diarrhea 
Thyroid 
Palpation 
Dizziness 
Sun 
Sensitivity Diarrhea 
Baseline 
     Yes 
     No 
 
x (x%) 
x (x%) 
 
 
 
 
x (x%) 
x (x%) 
 
 
 
 
x (x%) 
x (x%) 
 
 
 
Month 1 
     Yes 
     No 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
Month 2 
     Yes 
     No 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
… 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Month 24 
     Yes 
     No 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
 
x (x%) 
x (x%) 
Denominators are the number of participants in the safety population in each treatment arm and overall with data at the given visit. Percentages are rounded to the nearest whole number. 
 
 


MiBRVO SAP 
February 18, 2021 
Version 1.0 
Confidential 
Page 40 
Table 21: Summary of Laboratory Assessments Over Time 
 
 
Minocycline 
Placebo 
Total 
Visit 
Participants 
with Lab 
Assessments  
N1 
Abnormal 
Lab 
Assessments 
N (%)2 
Any Δ 
N (%)2 
Clinically 
Significant 
Δ 
N (%)2 
Participants 
with Lab 
Assessments  
N1 
Abnormal 
Lab 
Assessments 
N (%)2 
Any Δ 
N (%)2 
Clinically 
Significant 
Δ 
N (%)2 
Participants 
with Lab 
Assessments  
N1 
Abnormal 
Lab 
Assessments 
N (%)2 
Any Δ 
N (%)2 
Clinically 
Significant 
Δ 
N (%)2 
Baseline 
x 
x (%) 
 
 
x 
x (%) 
 
 
x 
x (%) 
 
 
Month 2 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
Month 6 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
Month 10 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
… 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
… 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
Month 22 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
Month 24 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
x 
 
x (%) 
x (%) 
Δ indicates changes from baseline 
1 Participants in the safety population in each treatment arm and overall with laboratory assessment data at the given visit. 
2 Denominators are the number of participants in the safety population in each treatment arm and overall with laboratory assessment data at the given visit.  
 
 


MiBRVO SAP 
February 18, 2021 
Version 1.0 
Confidential 
Page 41 
FIGURES 
Figure 1: Consort Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomized 
NEI: N = X 
BEH: N = X 
Allocated to Minocycline 
NEI: N = X 
BEH: N = X 
Allocated to Placebo 
NEI: N = X 
BEH: N = X 
Prior to Month 12 
Discontinued intervention: 
NEI: N = X 
BEH: N = X 
 
Lost to follow-up: 
NEI: N = X 
BEH: N = X 
Prior to Month 12 
Discontinued intervention: 
NEI: N = X 
BEH: N = X 
 
Lost to follow-up: 
NEI: N = X 
BEH: N = X 
Analyzed (Primary – Month 12) 
NEI: N = X 
BEH: N = X 
Between Month 12 and Month 24 
Discontinued intervention: 
NEI: N = X 
BEH: N = X 
 
Lost to follow-up: 
NEI: N = X 
BEH: N = X 
Analyzed (Secondary – Month 24) 
NEI: N = X 
BEH: N = X 
Analyzed (Primary – Month 12) 
NEI: N = X 
BEH: N = X 
Between Month 12 and Month 24 
Discontinued intervention: 
NEI: N = X 
BEH: N = X 
 
Lost to follow-up: 
NEI: N = X 
BEH: N = X 
Analyzed (Secondary – Month 24) 
NEI: N = X 
BEH: N = X 


MiBRVO SAP 
February 18, 2021 
Version 1.0 
Confidential 
Page 42 
Figure 2: Mean Best-Corrected Visual Acuity Over Time by Treatment Arm 
 
 
 
 
 
 
 
 
 
Study Eye
Fellow Eye
eye
Mean BCVA (letters read)
Placebo
Minocycline
0
5
10
15
20
25
Time from Baseline (Months)
60
65
70
75
80
60
70
80


MiBRVO SAP 
February 18, 2021 
Version 1.0 
Confidential 
Page 43 
Figure 3: Best-Corrected Visual Acuity Over Time by Participant 
 
 
 
 
Figure 4: Mean Central Retinal Thickness Over Time by Treatment Arm 
This figure will be similar to Figure 2. 
Figure 5: Central Retinal Thickness Over Time by Participant 
This figure will be similar to Figure 3.  
 
10
9
8
7
6
5
4
3
2
1
id
BCVA (letters read)
Study Eye
Fellow Eye
0
5
10
15
20
25
Time from Baseline (Months)
50
60
70
80
70
75
80
85
90


MiBRVO SAP 
February 18, 2021 
Version 1.0 
Confidential 
Page 44 
LISTINGS 
Listing 1: Demographic Information by Participant 
 
Site 
Participant 
ID 
Treatment  
Arm 
Registration 
Date 
Study 
Eye 
Age 
Gender 
Race 
Ethnicity 
xxx 
001 
xx 
mm/dd/yy 
xx 
xx 
xxx 
xxx 
xxx 
xxx 
002 
xx 
mm/dd/yy 
xx 
xx 
xxx 
xxx 
xxx 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 
Listing 2: IP Compliance 
 
Site 
Participant 
ID 
Treatment 
Arm 
Number of 
Doses Taken 
Number of 
Doses Missed 
Expected Number 
of Doses Taken 
Compliance 
Rate (%) 
xxx 
001 
xx 
xx 
xx 
xx 
x.x 
xxx 
002 
xx 
xx 
xx 
xx 
x.x 
… 
… 
… 
… 
… 
… 
… 
 
 


MiBRVO SAP 
February 18, 2021 
Version 1.0 
Confidential 
Page 45 
Appendix: Assessment of COVID-19 Impacts  
Listing A1. Visit Schedule Deviations Due to COVID-19 
 
Participant ID Visit Number  
Type of Deviation 
001 
Month X 
Missed / Out-of-Window 
 
Month X 
Missed/Out-of-Window 
002 
Month X  
Missed/Out-of-Window 
… 
Month X  
Missed/Out-of-Window 
… 
Month X  
Missed/Out-of-Window