Ranibizumab and Bevacizumab for Diabetic Macular Edema

Background:

* Diabetic macular edema is a common eye complication of diabetes. It causes the blood vessels in the retina at the back of the eye to leak, causing swelling. The macula is the center part of the retina that is important for seeing fine details and for tasks such as reading, driving, or sewing. Swelling of the macula leads to vision loss and possible blindness. Inflammation may play a role in diabetic macular edema. It is also possible that there is a problem with the blood vessels and the blood supply to cells of the retina.
* A chemical in the body called vascular endothelial growth factor (VEGF) is important in the formation of blood vessels in the body. Lowering VEGF levels may help treat diabetic macular edema by reducing abnormal leaking blood vessels in the eye. Drugs that can lower or block VEGF include ranibizumab and bevacizumab. Both drugs have been shown to help treat diabetic macular edema. Researchers want to see if one of the drugs works better than the other.

Objective: To compare the effectiveness of ranibizumab and bevacizumab injections for diabetic macular edema.

Eligibility: Individuals at least 18 years of age who have diabetic macular edema in at least one eye.

Design:

* Participants will be screened with a physical exam and medical history. A full eye exam will be performed. Blood and urine samples will be collected.
* One eye will be selected as the study eye to receive treatment. If both eyes are affected, both eyes may be enrolled in the study and receive different drug treatments.
* The main part of the study will last for 9 months. At each study visit, participants will have physical exams and eye exams. They will answer questions about their health and any side effects from the drugs.
* Participants will be assigned to one of four groups. Two groups will have two series of ranibizumab and one series of bevacizumab shots. The other two groups will have two series of bevacizumab and one series of ranibizumab shots. A series is three eye injections of the same drug every 4 weeks. The injections will be given at these study visits. The series order will vary for the different groups.
* After 9 months, participants will continue to have additional study visits. If the treatment seems to be successful, the study doctor may increase the time between visits. Study injections may be given as needed every 4 weeks for up to 3 years.
* Participants may have laser treatments in a study eye if needed. After being in the study for 1 year, they may also have steroid injections or other treatments as directed for the 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.

Eligibility Criteria:
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.