Ranibizumab and Bevacizumab for Diabetic Macular Edema

Objective: Diabetic retinopathy (DR) remains a leading cause of visual impairment. A
frequent manifestation of DR is diabetic macular edema (DME) for which laser
photocoagulation has been the only proven treatment for the last several decades. Studies
have shown that anti-vascular endothelial growth factor (VEGF) injections such as
bevacizumab or ranibizumab have been efficacious in treating patients with DME. However,
there has been no direct comparison of these agents to determine whether one treatment is
more effective than the other. The objective of this study is to compare the treatment
efficacy of ranibizumab versus bevacizumab in eyes with DME.

Study Population: Sixty (60) participants with macular edema secondary to diabetes and any
stage of DR (other than those requiring scatter laser photocoagulation for proliferative DR)
in one or both eyes will be enrolled in this randomized study.

Design: In this Phase II, multi-center, comparative, double-masked study, eyes will be
randomly assigned to receive ranibizumab or bevacizumab. During the initial phase of the
study participants will participate in a three-period, 36-week, crossover study in which
study eyes will be assigned to one of four treatment groups (i.e., treatment sequences). The
two drugs and three periods form a RRB/RBB/BBR/BRR pattern as follows:

- Group 1 (RRB pattern) eyes will receive a series of intravitreal injections of
ranibizumab at baseline and Weeks 4, 8, 12, 16 and 20, then crossover to receive a
series of intravitreal injections of bevacizumab at Weeks 24, 28 and 32.

- Group 2 (RBB pattern) eyes will receive a series of intravitreal injections of
ranibizumab at baseline and Weeks 4 and 8, then crossover to receive a series of
intravitreal injections of bevacizumab at Weeks 12, 16, 20, 24, 28 and 32.

- Group 3 (BBR pattern) eyes will receive a series of intravitreal injections of
bevacizumab at baseline and Weeks 4, 8, 12, 16 and 20, then crossover to receive a
series of intravitreal injections of ranibizumab at Weeks 24, 28 and 32.

- Group 4 (BRR pattern) eyes will receive a series of intravitreal injections of
bevacizumab at baseline and Weeks 4 and 8, then crossover to receive a series of
intravitreal injections of ranibizumab at Weeks 12, 16, 20, 24, 28 and 32.

Participants for whom one eye is enrolled in the study will have this eye randomly assigned
to one of the four groups above. Participants for whom both eyes are enrolled in the study
will have the right eye randomly assigned to one of the four groups above; the left eye will
be assigned to the group with the schedule inverse to that for the right eye. For example,
if the right eye is randomly assigned to Group 1 (RRB pattern), the left eye will be
automatically assigned to Group 3 (BBR pattern). Thus, at each treatment, the right eye for
a participant enrolling both eyes in the study will always receive a different
investigational product than the left eye. Following this crossover phase, eyes will be
returned to the treatment (ranibizumab or bevacizumab) to which they were originally
assigned and treated on an as-needed basis through a common termination date one year from
enrollment of the last-enrolled participant at the National Eye Institute (NEI) and through
Year 1 at the Bristol Eye Hospital (BEH). Both the treating investigators and participants
will be masked to the group assignments. The primary outcome will be assessed at Weeks 12,
24, 36 and Year 1.

Outcome Measures: The primary outcome measure is the mean change in Early Treatment Diabetic
Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA). Changes in BCVA from baseline
to four weeks following the end of each of the three periods (i.e., Weeks 12, 24 and 36) and
at Year 1 will be used for the primary analysis.

Secondary outcomes (assessed between the baseline and Week 12 visits, Weeks 12 and 24 visits
and Weeks 24 and 36 visits and at Year 1) will include the mean changes in central macular
thickness and central retinal volume by treatment group as measured by optical coherence
tomography (OCT); the slope of the changes in BCVA, central macular thickness and retinal
volume; the proportion of eyes with visual improvement ≥ 10 letters; the proportion of eyes
with visual improvement ≥ 15 letters; the proportion of eyes with ≥ 0.1 log unit loss or
gain in logOCT; the proportion of eyes with ≥ 0.05 log unit loss or gain in logOCT; changes
in fluid leakage in the macula as demonstrated by fluorescein angiography; and changes in
macular structural improvement (i.e., resolution of cystic changes) as measured by OCT. The
digital OCT images collected between the Baseline and Week 36 visits will be graded by a
masked, external Reading Center.

Other secondary outcomes will include the proportion of eyes meeting criteria for
significant worsening, treatment success, or treatment failure, the frequency of
re-injection among eyes in the treatment-as-needed phase of the study, and the proportion of
eyes receiving focal/grid laser photocoagulation or other adjuvant treatment during the
course of the study.

Safety outcomes include the number and severity of adverse events. The number of eyes
withdrawn from the investigational product due to vision loss or adverse events and the
number of eyes deemed to have worsening disease will also contribute to the assessment of
safety.

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 has a diagnosis of diabetic mellitus (type 1 or type 2). Any one of the
following will be considered to be sufficient evidence that diabetes is present:

- Current regular use of insulin for the treatment of diabetes;

- Current regular use of oral anti-hyperglycemia agents for the treatment of
diabetes;

- Documented diabetes by American Diabetes Association (ADA) and/or World Health
Organization (WHO) criteria.

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

4. Female participants of childbearing potential must not be pregnant or breast-feeding
and must have a negative pregnancy test at screening and must agree to pregnancy
testing throughout the study.

5. 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 four weeks after
their last injection. Acceptable methods of contraception include:

- Hormonal contraception (i.e., birth control pills, injected hormones, dermal
patch or vaginal ring),

- Intrauterine device,

- Barrier methods (i.e., diaphragm, condom) with spermicide, or

- Tubal ligation.

6. Participant has at least one eye that meets the study eye eligibility criteria.

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
investigational product for DME.

2. Participant has a known hypersensitivity to sodium fluorescein dye.

3. 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).

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

5. Participant has a history of liver failure.

6. Participant has a known hypersensitivity to bevacizumab, ranibizumab or any of their
components.

7. 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, a
patient can become eligible.

8. Participant has a history of treatment with oral steroids (greater than or equal to
10 mg of prednisone daily or equivalent) within three months prior to enrollment.
Non-ocular depot and inhaled steroid treatments will not exclude a participant.

9. Participant has a history of treatment with systemic anti-VEGF agents within four
weeks prior to enrollment.

STUDY EYE ELIGIBILITY CRITERIA:

The participant must have at least one eye meeting all inclusion criteria and none of the
exclusion criteria listed below. Participants for whom both eyes meet all of the inclusion
criteria and none of the exclusion criteria listed below may have both eyes enrolled in
the study if they and the investigator so choose. If both eyes meet all of the inclusion
criteria and none of the exclusion criteria listed below, and if the participant and the
investigator decide that only one eye should be enrolled in the study, the study eye will
be selected by the investigator in consultation with the participant.

STUDY EYE INCLUSION CRITERIA:

1. Eye has a BCVA ETDRS score between 20/32 and 20/400.

2. Eye has definite retinal thickening or cystic changes due to DME based on clinical
exam involving the center of the macula that is not refractory to further therapy as
based on the investigator's clinical judgment.

3. Eye has retinal thickness in the central subfield on baseline OCT measurement greater
than or equal to 330 microns, as measured by Cirrus OCT.

4. Eye has clear ocular media and adequate pupillary dilation sufficient for adequate
fundus photographs.

STUDY EYE EXCLUSION CRITERIA:

1. Eye has macular edema considered to be due to a cause other than diabetes.

An eye is not 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.

2. Eye has an ocular condition 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, non-retinal condition).

3. Eye has an ocular condition present (other than DR) 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.).

4. Eye has a history of panretinal scatter photocoagulation (PRP) within three months
prior to enrollment.

5. Eye has a history of prior pars plana vitrectomy prior to enrollment.

6. Eye has a history of major ocular surgery (including cataract extraction, scleral
buckle, any intraocular surgery, etc.) within three months prior to enrollment.

7. Eye has a history of Yttrium-Aluminum-Garnet (YAG) capsulotomy performed within two
months prior to enrollment.

8. Eye had laser photocoagulation treatment, or received intravitreal or periocular
steroids within three months prior to enrollment.

9. Eye has a history of intravitreal anti-VEGF agents within eight weeks prior to
enrollment.

10. Eye has had greater than four intravitreal anti-VEGF injections within one year prior
to enrollment.

11. Eye has high-risk proliferative DR requiring laser photocoagulation treatment.