Efficacy & Safety Trial of Intravitreal Injections Combined With PRP for CSME Secondary to Diabetes Mellitus (DAVE)

Approximately 40 eyes will be randomized at 3 investigational centers in the United States.
This study consists of a screening period of up to 14 days (Days -14 to -1), and a 36-month
treatment period (Day 0 to Month 36). Subjects who provide consent will enter the screening
period to determine eligibility. As part of the screening process, the examining investigator
will evaluate the macular foveal avascular zone fluorescein images to determine subjects'
eligibility. Eligible subjects will be randomized in a 1:1 ratio so that approximately 20
eyes will receive 0.3 mg ranibizumab monotherapy, and approximately 20 eyes will receive 0.3
mg ranibizumab combined with Ultra wide 200° field angiogram guided targeted pan retinal
photocoagulation (PRP). Subjects must meet VA and retinal thickness eligibility requirements
during the screening period. The subject can have both eyes in the study. If both eyes are
eligible, one eye will be randomized, to cohort 1 while the other eye will be randomized to
the cohort 2. A subject with both eyes in the trial will have each eye in a separate cohort.

Inclusion Criteria:

- Willingness to provide signed informed consent and Health Insurance Portability and
Accountability Act (HIPAA) authorization.

- Age ≥ 18 years

- Diabetes Mellitus (Type 1 or 2). The following will be considered as sufficient
evidence that diabetes is present:

- Current regular use of insulin for the treatment of diabetes

- Current regular use of oral antihyperglycemic agents for the treatment of
diabetes

- Documented diabetes according to the American Diabetes Association and/or World
Health Organization criteria.

- BCVA score in the study eye of 20/32 to 20/320 approximate snellen equivalent using
the ETDRS protocol at an initial testing distance of 4 meters, confirmed by the
investigator.

- High Definition OCT (Spectralis) central retinal thickness measurement of ≥ 300 µm

- Decrease in visual acuity is determined to be primarily the result of DME and not to
other cause.

- Ability and willingness to return for all scheduled visits and assessments.

- Clear ocular media and adequate pupillary dilatation to permit good quality fundus
photography.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from this study:

General Exclusion Criteria

- Pregnancy (positive pregnancy test) or lactation

- Sexually active women of childbearing potential* who are unwilling to practice
adequate contraception or abstinence during the study. (*Although no birth control
method is 100% effective, the following are considered adequate means of
contraception: surgical sterilization, use of oral contraceptives, barrier
contraception using either a condom or diaphragm with spermicidal gel, intrauterine
devices, or contraceptive hormone implants or patches. A subject's primary care
physician, obstetrician, or gynecologist should be consulted regarding an appropriate
form of birth control)

- Any other condition that the investigator believes would pose a significant hazard to
the subject if the investigational therapy were initiated

- Participation in another simultaneous medical investigation or trial] Ocular Exclusion
Criteria

- Prior Ocular Treatment:

- History of vitrectomy surgery in the study eye

- Any pan-retinal photocoagulation in the study eye

- Prior treatment with intraocular or subconjunctival steroids in the study eye 4
months prior to screen

- Previous treatment with antiangiogenic drugs in either eye (pegaptanib sodium,
anecortave acetate, bevacizumab, ranibizumab, etc.) within 2 months of Day 0
visit

- Systemic corticosteroids 4 months prior to screen

Concurrent Ocular Conditions:

- Any concurrent ocular condition in the study eye (e.g., cataract or age-related
macular degeneration) that, in the opinion of the investigator could: require medical
or surgical intervention during the study period to prevent or treat visual loss that
might result from that condition; or, if allowed to progress untreated, could likely
contribute to a loss of at least 2 Snellen equivalent lines of BCVA over the study
period

- Active intraocular inflammation (grade trace or above) in the study eye

- Current vitreous hemorrhage in the study eye

- History of rhegmatogenous retinal detachment or macular hole (Stage 3 or 4) in the
study eye

- Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either
eye

- Aphakia or absence of the posterior capsule in the study eye

- Intraocular surgery (including cataract surgery) in the study eye within 2 months
preceding Day 0

- Uncontrolled glaucoma in the study eye (defined as IOP ≥ 30 mmHg despite treatment
with anti-glaucoma medication)

- History of glaucoma-filtering surgery in the study eye

- History of corneal transplant in the study eye

- High Risk PDR: New vessels within one disc diameter of the optic nerve head that are
larger than one-third disc area

- Vitreous or preretinal hemorrhage associated with less extensive NVD or with NVE
one-half disc area or more in size

- Extensive damage to the fovea vascular zone as determined by the principal
investigator or designated site personnel

- Spherical equivalent of the refractive error in the study eye of more that -8.00
diopter of myopia

- Vitreomacular traction (vitreomacular attachment ok) Concurrent Systemic Conditions

- Uncontrolled blood pressure (defined as systolic > 180 mmHg and/or diastolic > 110
mmHg while patient is seated. *If a subject's initial reading exceeds these values, a
second reading may be taken 30 or more minutes later. If the subject's blood pressure
needs to be controlled by antihypertensive medication, the subject can become eligible
if medication is taken continuously for at least 30 days prior to Day 0

- Atrial fibrillation not managed by subject's primary care physician or cardiologist
within 3 months of screening visit

- History of stroke within the last 3 months of screening visit

- History of other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that might affect the
interpretation of the results of the study or renders the patient at high risk for
treatment complications

- Current treatment for active systemic infection

- Active malignancy

- History of allergy to fluorescein, not amenable to treatment

- Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality
to be analyzed and graded.

- Previous participation in any studies of investigational drugs within 1 month
preceding Day 0 (excluding vitamins and minerals)