Minocycline to Treat Branch Retinal Vein Occlusion

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.

- INCLUSION CRITERIA:

To be eligible, the following inclusion criteria must be met, where applicable:

- Participant is 18 years of age or older.

- Participant must understand and sign the protocol s informed consent document.

- 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.

- 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.

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:

1. hormonal contraception (i.e., birth control pills*, injected hormones, dermal patch or
vaginal ring),

2. intrauterine device,

3. barrier methods (e.g., diaphragm) with spermicide, or

4. 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.

- 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.

- 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).

- 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.

- Participant has at least one eye that meets the study eye criteria listed in
Section 3.2.

EXCLUSION CRITERIA:

A participant is not eligible if any of the following exclusion criteria are present:

- Participant is in another investigational study and actively receiving
investigational product for BRVO.

- Participant is unable to comply with study procedures or follow-up visits.

- Participant has a known hypersensitivity to sodium fluorescein dye.

- 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).

- Participant has a history of chronic renal failure requiring dialysis or kidney
transplant.

- Participant has a history of chronic hepatitis or liver failure.

- Participant has an allergy or hypersensitivity to minocycline or any drug in the
tetracycline family.

- Participant is currently taking a tetracycline medication.

- Participant is taking any medication that could adversely interact with
minocycline such as methoxyflurane.

- Participant has a blood pressure of greater than 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.

- Participant is currently being treated with systemic anti-VEGF agents or systemic
steroids.

- Participant had a cerebral vascular event (CVA) or myocardial infarction (MI)
within three months prior to study entry.

- Participant has a history of thyroid cancer.

Study Eye Eligibility Criteria:

-The participant must have at least one eye meeting all inclusion criteria and none of
the exclusion criteria listed below:

- Study Eye Inclusion Criteria:

- The study eye has a best-corrected ETDRS visual acuity score between 78 and
34 letters (i.e., between 20/32 and 20/200).

- 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. Hemiretinal vein occlusion
(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.

- 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.

- 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.

- Study Eye Exclusion Criteria:

- The study eye has macular edema considered to be due to a cause other than
BRVO.

- 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.

- The study eye has a history of a recurrent RVO.

- The study eye has a history of RVO present for > 18 months.

- A brisk afferent pupillary defect (APD) is present in the study eye.

- 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).

- 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.).

- 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.

- The study eye has had panretinal or sectoral scatter photocoagulation
(PRP) within four months prior to study entry.

- The study eye has had pars plana vitrectomy within six months prior to
study entry.

- The study eye has undergone major ocular surgery (including cataract
extraction, scleral buckle, any intraocular surgery, etc.) within three
months prior to study entry.

- A yttrium aluminum garnet (YAG) capsulotomy has been performed on the
study eye within two months prior to study entry.

- The study eye has had treatment < 3 months prior to study entry of
intravitreal or periocular steroid injections.

- The study eye has had treatment < 28 days prior to study entry of
intravitreal anti-VEGF agents.

Study Eye Selection Criteria in Cases of Bilateral Disease:

If both eyes of a participant meet the criteria, the study eye will be determined at
the investigator's discretion.