Phase 2
N=129
Phase II Combination Steroid and Anti-VEGF for Persistent DME
Diabetic Macular Edema
Bottom Line
View on ClinicalTrials.gov: NCT01945866 ↗Enrolled (actual)
129
Serious AEs
12.9%
Results posted
Sep 2018
Primary outcome: Primary: Mean Change in Visual Acuity Letter Score — 2.7; 3.0 Letter Score
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- intravitreal ranibizumab 0.3 mg (Drug); dexamethasone intravitreal implant (Drug); Sham injection (Procedure)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Jaeb Center for Health Research
- Primary completion
- Jun 2017
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Mean Change in Visual Acuity Letter Score |
2.7; 3.0 | — |
| SECONDARY At 24 Weeks After Randomization, Number of Eyes With at Least 10 and at Least 15 Letter Gain (Increase) or Loss (Decrease) in E-ETDRS Letter Score Visual Acuity. |
7; 1; 14; 9; 8; 4 | — |
| SECONDARY Visual Acuity Area Under the Curve (AUC) Between Randomization and 24 Weeks |
1.9; 2.5 | — |
| SECONDARY Mean Change in OCT CSF Thickness, Adjusted for Thickness at Time of Randomization |
-110; -62 | — |
| SECONDARY Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness |
34; 22; 14; 8; 0; 1 | — |
| SECONDARY Eyes With OCT CSF Thickness < the Gender-specific Spectral Domain OCT Equivalent of 250 Microns on Zeiss Stratus |
32; 20 | — |
| SECONDARY OCT CSF Thickness Area Under the Curve Between Randomization and 24 Weeks |
-86.9; -33.5 | — |
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
- Age ≥ 18 years i) Individuals 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.
- 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.
- 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.
- 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.
- 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):
- 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.
- 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.).
- 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.).
- 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).
- History of intravitreal anti-VEGF drug within 21 days prior to enrollment.
- History of intravitreal or peribulbar corticosteroids within 3 months prior to enrollment.
- History of macular laser photocoagulation within 4 months prior to enrollment.
- 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.
- Any history of vitrectomy.
Data sourced from ClinicalTrials.gov (NCT01945866). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.