A Study of Intravitreal Injections of 2.0mg Ranibizumab in Subjects With Chronic Fluid On OCT Post Multiple Injections With Ranibizumab (Super-dose Anti-VEgf SAVE Trial)

The purpose of this study is to determine whether 2.0mg Ranibizumab is effective in the treatment of recurrent fluid.

This is an open-label, Phase I/II study of intravitreally administered 2.0 mg ranibizumab in subjects with persistent fluid or recurrent fluid on OCT after having received at least nine ranibizumab injections in the past twelve months. Consented, enrolled subjects will receive have monthly ETDRS BCVA, ophthalmic examination and OCTs evaluation using Stratus, Cirrus and Spectralis machines. Fluorescein angiography and autofluorescence will be done at BSL, and Months 6 and 12. DNA samples for genetic analysis will be collected at baseline.

Subjects will receive open-label intravitreal injections of 2.0 mg ranibizumab administered every 28 days for 3 months: Following the three loading doses, all patients will receive a minimum "capped" PRN treatment (all patients will receive 2.0 mg intravitreal ranibizumab quarterly). Dosing should not occur earlier than 22 days after the previous treatment. Study visits should be scheduled to occur every 30 (±7) days relative to the date of the first injection (Day 0).

Subjects will be randomized into two re-treatment cohorts for additional re-treatment, if needed:

* Cohort A - Subjects can receive re-treatment every 4 weeks if there is persistent or recurrent intraretinal, subretinal ,or sub-RPE fluid on any OCT modality, or any evidence of hemorrhage on clinical evaluation.
* Cohort B - Subjects can receive re-treatment every 6 weeks if there is persistent or recurrent intraretinal, subretinal ,or sub-RPE fluid on any OCT modality, or any evidence of hemorrhage on clinical evaluation. Every 6 weeks regimen will test potential longer duration of action of 2.0 mg ranibizumab.

Eligibility Criteria:
Inclusion Criteria:

* Willingness to provide signed informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization
* Age ≥ 50 years
* For sexually active women of childbearing potential, agreement to the use of an appropriate form of contraception (or abstinence) for the duration of the study
* Although no birth control method is 100% effective, the following are considered effective means of contraception: surgical sterilization, use of oral contraceptives, barrier contraception using either a condom or diaphragm with spermicidal gel, an intrauterine device, or contraceptive hormone implant or patch. A patient's primary care physician, obstetrician, or gynecologist should be consulted regarding an appropriate form of birth control.
* Ability and willingness to return for all scheduled visits and assessments

Study eyes must meet the following criteria for entry into the SAVE trial:

* The last treatment with Ranibizumab is ≥ 28 days
* To have received at least 9 injections of Ranibizumab in the past 12 months
* Any CNVM lesion (Occult, Minimally Classic or Classic) (i.e., leakage on fluorescein angiography or subretinal, intraretinal, or sub-RPE fluid on Spectral Domain OCT) secondary to age-related macular degeneration.
* Best corrected visual acuity in the study eye, using e-ETDRS testing, between 20/25 and 20/320 (Snellen equivalent), inclusive.
* Only one eye will be enrolled in the Study. If both eyes are eligible study investigator will select the eye for entry.
* The total area of subretinal hemorrhage and fibrosis must comprise less than 50% of the total lesion.
* Clear ocular media and adequate pupillary dilation to permit good quality fundus imaging

Exclusion Criteria:

* Pregnancy (positive pregnancy test) or lactation Premenopausal women not using adequate contraception. The following are considered effective means of contraception: surgical sterilization or use of oral contraceptives, barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel, an IUD, or contraceptive hormone implant or patch.
* 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, submacular surgery, or other surgical intervention for AMD in the study eye
* Prior treatment with Visudyne®, external-beam radiation therapy, or transpupillary thermotherapy (TTT) in the study eye at a fluence equal to 100%, any fluence lower than 100% is permitted.
* Prior treatment with full or half fluence verteporfin PDT.
* Previous intravitreal drug delivery (e.g., intravitreal corticosteroid injection, anti-angiogenic drugs besides ranibizumab, or device implantation) in the study eye within the last 12 months.

CNV Lesion Exclusion Characteristics

* Subretinal hemorrhage in the study eye that involves the center of the fovea, if the size of the hemorrhage is either \> 50% of the total area of the lesion or \> 1 disc area (2.54 mm2) in size
* Subfoveal fibrosis or atrophy in the study eye
* CNV in either eye due to other causes, such as ocular histoplasmosis, trauma, or pathologic myopia Concurrent Ocular Conditions
* Retinal pigment epithelial tear involving the fovea in the study eye
* Any concurrent intraocular condition in the study eye (e.g., cataract or diabetic retinopathy) that, in the opinion of the investigator, could either:

Require medical or surgical intervention during the 24-month study period to prevent or treat visual loss that might result from that condition; or If allowed to progress untreated, could likely contribute to loss of at least 2 Snellen equivalent lines of BCVA over the 24-month 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

Concurrent Systemic Conditions (Exclusion)

* Uncontrolled blood pressure (defined as systolic \> 180 mmHg and/or diastolic \> 110 mmHg while patient is sitting) If a patient's initial reading exceeds these values, a second reading may be taken 30 or more minutes later. If the patient's blood pressure needs to be controlled by antihypertensive medication, the patient can become eligible if medication is taken continuously for at least 30 days prior to Day 0.
* Atrial fibrillation not managed by patient's primary care physician or cardiologist within 3 months of screening visit
* Women of childbearing potential not using adequate contraception (as defined in the inclusion criteria).

A woman is considered not to be of childbearing potential if she is postmenopausal, defined by amenorrhea for at least 1 year in a woman \> 45 years old; or has undergone hysterectomy and/or bilateral oophorectomy.

* 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 an investigational drug or that might affect 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 by the central reading center
* Inability to comply with study or follow-up procedures
* Previous participation in any studies of investigational drugs within 1 month preceding Day 0 (excluding vitamins and minerals)