Phase II Combination Steroid and Anti-VEGF for Persistent DME
Condition: Diabetic Macular Edema
MeSH terms: Macular Edema; Edema
Intervention: intravitreal ranibizumab 0.3 mg; dexamethasone intravitreal implant; Sham injection
Intervention description: Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria; The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first.; No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.
Intervention MeSH terms: Dexamethasone; Ranibizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Enrollment: 129.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Diabetic Macular Edema; Anti-vascular endothelial growth factor; Dexamethasone Intravitreal implant; Ranibizumab intravitreal injection

Summary:

      Although anti-vascular endothelial growth factor (VEGF) therapy is generally effective as
      treatment for center-involved diabetic macular edema (DME), a substantial proportion of
      anti-VEGF-treated eyes with DME do not achieve vision of 20/20 or complete resolution of
      retinal thickening. Indeed, over 50% of ranibizumab-treated eyes did not achieve a 2 or more
      line improvement in visual acuity from baseline at 2 years in Protocol I, a previous DRCR.net
      (Diabetic Retinopathy Clinical Research Network) study. Furthermore, 27% of
      ranibizumab-treated eyes still had central subfield (CSF) thickness on time-domain optical
      coherence tomography (OCT) ≥ 300 at 1 year, and more than 40% of ranibizumab-treated eyes did
      not achieve complete resolution of retinal thickening (< 250 microns) by 2 years. Thus, there
      is a need for alternative or additional treatments that will improve vision by reducing
      retinal edema in eyes with persistent DME following previous anti-VEGF therapy. Intravitreal
      steroid is not as efficacious as ranibizumab in eyes with DME overall, but it has been shown
      to have a positive effect for DME in some eyes and might add benefit in eyes that are already
      receiving anti-VEGF.

      The main objective of this study is to assess the short-term effects of combination
      steroid+anti-VEGF therapy on visual acuity and retinal thickness on OCT in comparison with
      that of continued anti-VEGF therapy alone in eyes with persistent central-involved DME and
      visual acuity impairment despite previous anti-VEGF treatment. This study will provide
      important information for the design of a future confirmatory phase III clinical trial on the
      efficacy of combination steroid and anti-VEGF in eyes with persistent DME and vision
      impairment following previous anti-VEGF therapy. The primary outcome for efficacy will be the
      mean change in visual acuity at 24 weeks.

      Each study eye is required to complete a 12-week run-in phase. The run-in phase will identify
      study eyes that truly have persistent DME despite anti-VEGF therapy by requiring an
      additional 3 injections while also collecting standardized visual acuity and OCT
      measurements. At the enrollment, 4-week and 8-week visits of the run-in phase, enrolled eyes
      will receive an intravitreal injection of ranibizumab 3mg. Then at the 12-week run-in visit,
      if the eye still has persistent DME, it will be randomized to receive either intravitreal
      sham+intravitreal ranibizumab 0.3 or intravitreal dexamethasone+intravitreal ranibizumab 0.3
      injections. The randomized study duration is 24 week, during which a protocol visit takes
      place every month. The combination injections of sham+ranibizumab or dexamethasone
      +ranibizumab will be given at the randomization visit (baseline) and at the 12-week visit
      after randomization. In between, an intravitreal injection of ranibizumab only will be given
      to study eyes at the 4, 8, 16 and 20 week visits.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age ≥ 18 years i) Individuals <18 years old are not being included because DME is so
             rare in this age group that the diagnosis of DME may be questionable.

          2. Diagnosis of diabetes mellitus (type 1 or type 2)

          3. Any one of the following will be considered to be sufficient evidence that diabetes is
             present:

               1. Current regular use of insulin for the treatment of diabetes

               2. Current regular use of oral anti-hyperglycemia agents for the treatment of
                  diabetes

               3. Documented diabetes by ADA (American Diabetes Association) and/or WHO (World
                  Health Organization) criteria

          4. At least one eye meets the study eye criteria listed below.

          5. Fellow eye (if not a study eye) meets criteria.

          6. Able and willing to provide informed consent.

        Meets all of the following ocular criteria in at least the one eye:

          1. At least 3 injections of anti-VEGF drug (ranibizumab, bevacizumab, or aflibercept)
             within the prior 20 weeks.

          2. Visual acuity letter score in study eye ≤ 78 and ≥24 (approximate Snellen equivalent
             20/32 to 20/320).

          3. On clinical exam, definite retinal thickening due to DME involving the center of the
             macula.

          4. OCT CSF thickness, within 8 days of enrollment:

             i) On Zeiss Cirrus ≥ 290 microns in women; ≥ 305 in men ii) On Heidelberg Spectralis:
             ≥ 305 microns in women; ≥ 320 in men

          5. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate
             OCTs.

        Exclusion Criteria:

        An individual is not eligible if any of the following exclusion criteria are present:

          1. History of chronic renal failure requiring dialysis or kidney transplant.

          2. A condition that, in the opinion of the investigator, would preclude participation in
             the study (e.g., unstable medical status including blood pressure, cardiovascular
             disease, and glycemic control).

          3. Initiation of intensive insulin treatment (a pump or multiple daily injections) within
             4 months prior to randomization or plans to do so in the next 4 months.

          4. Participation in an investigational trial within 30 days of enrollment that involved
             treatment with any drug that has not received regulatory approval for the indication
             being studied. Note: study participants cannot receive another investigational drug
             while participating in the study.

          5. Known allergy to any component of the study drugs (including povidone iodine prep).

          6. Blood pressure > 180/110 (systolic above 180 OR diastolic above 110). If blood
             pressure is brought below 180/110 by anti-hypertensive treatment, the individual can
             become eligible.

          7. Myocardial infarction, other acute cardiac event requiring hospitalization, stroke,
             transient ischemic attack, or treatment for acute congestive heart failure within 1
             month prior to enrollment.

          8. Systemic steroid, anti-VEGF or pro-VEGF treatment within 4 months prior to enrollment
             or anticipated use during the study. These drugs cannot be used during the study.

          9. For women of child-bearing potential: pregnant or lactating or intending to become
             pregnant within the next 9 months. Women who are potential study participants should
             be questioned about the potential for pregnancy. Investigator judgment is used to
             determine when a pregnancy test is needed.

         10. Individual is expecting to move out of the area of the clinical center to an area not
             covered by another clinical center during the next 9 months.

        The following exclusions apply to the study eye only (i.e., they may be present for the
        non-study eye unless otherwise specified):

          1. Macular edema is considered to be due to a cause other than DME. An eye should not be
             considered eligible if: (1) the macular edema is considered to be related to ocular
             surgery such as cataract extraction or (2) clinical exam and/or OCT suggest that
             vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or epiretinal
             membrane) are the primary cause of the macular edema.

          2. An ocular condition is present such that, in the opinion of the investigator, visual
             acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy,
             pigment abnormalities, dense subfoveal hard exudates, non-retinal condition, etc.).

          3. An ocular condition is present (other than DME) 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, etc.).

          4. Substantial posterior capsule opacity that, in the opinion of the investigator, is
             likely to be decreasing visual acuity by 3 lines or more (i.e., opacity would be
             reducing acuity to 20/40 or worse if eye was otherwise normal).

          5. History of intravitreal anti-VEGF drug within 21 days prior to enrollment.

          6. History of intravitreal or peribulbar corticosteroids within 3 months prior to
             enrollment.

          7. History of macular laser photocoagulation within 4 months prior to enrollment.

          8. History of panretinal (scatter) photocoagulation (PRP) within 4 months prior to
             enrollment or anticipated need for PRP in the 6 months following enrollment into
             run-in phase.

          9. Any history of vitrectomy.