Minocycline to Treat Central Retinal Vein Occlusion

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 retinal vein occlusions found the presence of activated microglia. Microglia are capable
of migrating through the retina to sites of inflammation to associate closely with neurons
and the vasculature, and are key cellular players in the mediation of processes of chronic
inflammation. For these reasons, microglia represent a promising cellular target for forms of
therapy that limit the deleterious inflammatory changes found in vein occlusions.
Minocycline, a second-generation tetracycline, has been shown to exhibit anti-inflammatory
properties, including microglial inhibition. The objective of this study is to investigate
the safety and potential efficacy of minocycline as a microglia inhibitor in participants
with central retinal vein occlusion (CRVO).

Study Population:

A minimum of 10 and a maximum of 20 participants who meet the eligibility criteria may be
enrolled. Eligibility criteria include: foveal center-involved macular edema secondary to a
CRVO, retinal thickness in the central subfield >350 microns as measured by optical coherence
tomography (OCT); and visual acuity (VA) between 20/32 and 20/200 in the study eye.

Design:

In this pilot, double-masked, randomized multi-center study, participants will receive
monthly bevacizumab injections for the first three months, followed by PRN dosing. In
addition, participants will take an oral dose of 100 mg of minocycline or placebo twice daily
for 24 months. During each monthly visit, participants will have their visual acuity measured
and will undergo OCT testing to measure retinal thickness. At the Month 3 visit and
thereafter, participants will be evaluated for improvement and worsening and will be eligible
for additional bevacizumab treatment and/or investigational product (IP) depending on which
criteria they fulfill. Additionally, at Month 12, participants will also be evaluated for no
improvement.

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 greater than or equal to
1 logOCT scale step at 12 and 24 months compared to baseline, as well as and changes in fluid
leakage in the macula as demonstrated by fluorescein angiography at 12 and 24 months compared
to baseline. Safety outcomes include the number of participant withdrawals, number and
severity of systemic and ocular toxicities and the number of adverse events (AEs).

- INCLUSION CRITERIA:

To be eligible, the following participant-level 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:

- 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.

- Participants must agree to notify the study investigator or coordinator if any of
their doctors initiate a new medication during the course of this study.

- 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).

- 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 the Study
Eye Eligibility Criteria below.

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 CRVOs.

- 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 >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 study entry.

- Participant has a history of thyroid cancer.

STUDY ELE 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 definite retinal thickening due to a CRVO based on clinical
examination involving the center of the macula that is not refractory to further
therapy as based on the investigator s clinical judgment. CRVO is defined as an eye
that had retinal hemorrhage or other biomicroscopic evidence of RVO (e.g.,
telangiectatic capillary bed) and a dilated (or previously dilated) venous system in
at least three quadrants of the retina drained by the affected vein.

- 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:

- Macular edema is considered to be due to a cause other than CRVO.

--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 (other than RVO) is present such that, in the opinion of the
investigator, visual acuity would not improve from resolution of macular edema (e.g.,
foveal atrophy, pigmentary changes, dense subfoveal hard exudates, laser scar at
fovea, non-retinal condition).

- An ocular condition (other than RVO) is present that, in the opinion of the
investigator, might affect macular edema or alter visual acuity during the course of
the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease,
neovascular glaucoma, Irvine-Gass Syndrome, etc.).

- 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 described in Sections 3.2.1 and 3.2.2, the
study eye will be determined at the investigator s discretion.