Ranibizumab and Bevacizumab for Diabetic Macular Edema
Condition: Diabetic Macular Edema
MeSH terms: Macular Edema; Edema
Intervention: Ranibizumab; Bevacizumab
Intervention description: Series of three intravitreous injections of ranibizumab (0.3 mg)* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion.
*Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after FDA approval of the 0.3 mg dose for DME, the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).; Series of three intravitreous injections of ranibizumab (0.3 mg)* or bevacizumab (1.25 mg) administered every 4 weeks for three 12-week periods. Following this crossover phase, eyes received ranibizumab or bevacizumab to which they were originally assigned and treated on an as-needed basis until study completion.
*Eleven doses of ranibizumab 0.5 mg were given to participants at the start of the study; after FDA approval of the 0.3 mg dose for DME, the protocol was amended and 0.3 mg was used for the remainder of the study (98% of all injections).
Intervention MeSH terms: Bevacizumab; Ranibizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 56.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Diabetic Macular Edema; Ranibizumab; Bevacizumab

Summary:

      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.
    

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.