Diabetic Macular Edema
Conditions
Keywords
Diabetic Macular Edema, Anti-vascular endothelial growth factor, Dexamethasone Intravitreal implant, Ranibizumab intravitreal injection
Brief 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.
Interventions
DRUGintravitreal ranibizumab 0.3 mg
Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria
DRUGdexamethasone intravitreal implant
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.
PROCEDURESham injection
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.
Sponsors
Allergan
Genentech, Inc.
National Eye Institute (NEI)
Jaeb Center for Health Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Visual Acuity Letter Score | 24 weeks after randomization | At 24 weeks after randomization, mean change in visual acuity letter score, adjusted for visual acuity at time of randomization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Visual Acuity Area Under the Curve (AUC) Between Randomization and 24 Weeks | 24 weeks after randomization | Only included participants who completed the 24-week visit. Time points for which data were collected for this analysis include 0, 4 8,12, 16, 20, and 24 weeks post randomization. |
| Mean Change in OCT CSF Thickness, Adjusted for Thickness at Time of Randomization | 24 weeks after randomization | Change in optical coherence tomography (OCT) central subfield thickness (in microns) was truncated to 3 standard deviations from the mean \[-372, +201\] (calculated using observed changes at 24 weeks combining all treatment groups), to minimize the effect of outliers. Two values were truncated in the sham + ranibizumab group: one on the negative end, and one on the positive end. |
| 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. | 24 weeks weeks after randomization | ETDRS (Early Treatment Diabetic Retinopathy Study) |
| Eyes With OCT CSF Thickness < the Gender-specific Spectral Domain OCT Equivalent of 250 Microns on Zeiss Stratus | 24 weeks after randomization | Gender and OCT machine-specific values for OCT central subfield thickness (in microns) are defined as: \<290 in women and \<305 in men in Zeiss Cirrus; \<305 in women and \<320 in men in Heidelberg Spectralis |
| OCT CSF Thickness Area Under the Curve Between Randomization and 24 Weeks | 24 weeks after randomization | Including participants who completed the 24-week visit. Time points for which data were collected for this analysis include 0, 4 8,12, 16, 20, and 24 weeks post randomization. |
| Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness | 24 weeks after randomization | Change in optical coherence tomography (OCT) central subfield (CSF) thickness (in microns) was truncated to 3 standard deviations from the mean \[-372, +201\] (calculated using observed changes at 24 weeks combining all treatment groups), to minimize the effect of outliers. Two values were truncated in the sham + ranibizumab group: one on the negative end, and one on the positive end. |
Countries
United States
Participant flow
Recruitment details
Phase 2 multi center randomized trial conducted at 40 US sites; 129 eyes (116 adults) with diabetes between February 2014 and December 2016. Participants with 2 study eyes enrolled one eye in each arm. Therefore, each arm includes no more than 1 study eye per participant; thus the number of eyes is equal to the number of participants in each arm.
Pre-assignment details
A 12-week run-in phase was conducted to confirm that eyes with persistent diabetic macular edema (DME) still persisted after additional anti-vascular endothelial growth factor (VEGF) injections. At week 12 of the run-in phase, eyes that had received all run-in injections, and continued to meet specific criteria were eligible for randomization.
Participants by arm
| Arm | Count |
|---|---|
| Sham + Intravitreal Ranibizumab 0.3 mg Sham and ranibizumab, 0.3 mg, injections | 64 |
| Sham + Intravitreal Ranibizumab 0.3 mg Sham and ranibizumab, 0.3 mg, injections | 64 |
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg Combination of ranibizumab, 0.3 mg and intravitreous sustained dexamethasone drug-delivery system (Ozurdex; Allergan), 700 µg, injection | 65 |
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg Combination of ranibizumab, 0.3 mg and intravitreous sustained dexamethasone drug-delivery system (Ozurdex; Allergan), 700 µg, injection | 65 |
| Total | 258 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Eyes did not complete or were dropped | 2 | 0 |
Baseline characteristics
| Characteristic | Sham + Intravitreal Ranibizumab 0.3 mg | Total | Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg |
|---|---|---|---|
| Age, Customized Age | 66 years | 65 years | 64 years |
| Arterial Blood Pressure | 98 mmHg | 97 mmHg | 97 mmHg |
| Body Mass Index | 33 kg/m˄2 | 32 kg/m˄2 | 32 kg/m˄2 |
| Change in central subfield thickness from enrollment to randomization | -50 Microns STANDARD_DEVIATION 102 | -54 Microns STANDARD_DEVIATION 93 | -58 Microns STANDARD_DEVIATION 83 |
| Change in visual acuity letter score from enrollment to randomization | 3 units on a scale STANDARD_DEVIATION 7 | 3 units on a scale STANDARD_DEVIATION 7 | 3 units on a scale STANDARD_DEVIATION 6 |
| Diabetes Type Type 1 | 2 Eyes | 4 Eyes | 2 Eyes |
| Diabetes Type Type 2 | 61 Eyes | 123 Eyes | 62 Eyes |
| Diabetes Type Uncertain | 1 Eyes | 2 Eyes | 1 Eyes |
| Duration of Diabetes | 19 years | 17 years | 15 years |
| Hemoglobin A1c | 7.4 Percent Hemoglobin | 7.3 Percent Hemoglobin | 7.1 Percent Hemoglobin |
| Improvement in visual acuity(VA) and OCT CST thickness during run-in phase Neither VA nor OCT CST is improved | 12 Eyes | 27 Eyes | 15 Eyes |
| Improvement in visual acuity(VA) and OCT CST thickness during run-in phase VA and OCT CST are both improved | 22 Eyes | 44 Eyes | 22 Eyes |
| Improvement in visual acuity(VA) and OCT CST thickness during run-in phase VA is improved but OCT CST is not improved | 14 Eyes | 26 Eyes | 12 Eyes |
| Improvement in visual acuity(VA) and OCT CST thickness during run-in phase VA is not improved but OCT CST is improved | 16 Eyes | 32 Eyes | 16 Eyes |
| Insulin Used | 39 Participants | 79 Participants | 40 Participants |
| Participants with 2 study eyes | 13 participants | 26 participants | 13 participants |
| Prior Anti-VEGF for DME Aflibercept only | 8 Eyes | 15 Eyes | 7 Eyes |
| Prior Anti-VEGF for DME Bevacizumab only | 49 Eyes | 97 Eyes | 48 Eyes |
| Prior Anti-VEGF for DME Both aflibercept and bevacizumab | 0 Eyes | 4 Eyes | 4 Eyes |
| Prior Anti-VEGF for DME Both aflibercept and ranibizumab | 0 Eyes | 1 Eyes | 1 Eyes |
| Prior Anti-VEGF for DME Both bevacizumab and ranibizumab | 1 Eyes | 3 Eyes | 2 Eyes |
| Prior Anti-VEGF for DME Ranibizumab only | 6 Eyes | 9 Eyes | 3 Eyes |
| Prior macular laser treatment for DME | 31 Eyes | 62 Eyes | 31 Eyes |
| Race/Ethnicity, Customized Asian | 2 Eyes | 8 Eyes | 6 Eyes |
| Race/Ethnicity, Customized Black/African American | 9 Eyes | 15 Eyes | 6 Eyes |
| Race/Ethnicity, Customized Hispanic or Latino | 16 Eyes | 29 Eyes | 13 Eyes |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 1 Eyes | 1 Eyes | 0 Eyes |
| Race/Ethnicity, Customized Unknown/not reported | 1 Eyes | 2 Eyes | 1 Eyes |
| Race/Ethnicity, Customized White | 35 Eyes | 74 Eyes | 39 Eyes |
| Randomization central subfield thickness | 396 Microns STANDARD_DEVIATION 122 | 385 Microns STANDARD_DEVIATION 110 | 375 Microns STANDARD_DEVIATION 97 |
| Randomization diabetic retinopathy severity level on clinical examination Mild/moderate NPDR | 28 Eyes | 58 Eyes | 30 Eyes |
| Randomization diabetic retinopathy severity level on clinical examination PDR and/or prior scatter laser | 24 Eyes | 49 Eyes | 25 Eyes |
| Randomization diabetic retinopathy severity level on clinical examination Severe NPDR | 12 Eyes | 22 Eyes | 10 Eyes |
| Randomization retinal volume | 8.6 mm3 STANDARD_DEVIATION 2 | 8.5 mm3 STANDARD_DEVIATION 1.8 | 8.3 mm3 STANDARD_DEVIATION 1.6 |
| Randomization visual acuity letter score | 63 units on a scale STANDARD_DEVIATION 13 | 63 units on a scale STANDARD_DEVIATION 12 | 63 units on a scale STANDARD_DEVIATION 12 |
| Sex/Gender, Customized Male | 28 Eyes | 62 Eyes | 34 Eyes |
| Sex/Gender, Customized Women | 36 Eyes | 67 Eyes | 31 Eyes |
| Smoking status Current | 7 Eyes | 10 Eyes | 3 Eyes |
| Smoking status Never | 43 Eyes | 87 Eyes | 44 Eyes |
| Smoking status Prior | 14 Eyes | 32 Eyes | 18 Eyes |
| Total anti-VEGF injections for DME within the 20 weeks before run-in phase | 3 Injections | 3 Injections | 3 Injections |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 52 | 0 / 51 | 0 / 13 |
| other Total, other adverse events | 38 / 52 | 29 / 52 | 11 / 13 |
| serious Total, serious adverse events | 7 / 52 | 7 / 51 | 1 / 13 |
Outcome results
Primary
Mean Change in Visual Acuity Letter Score
At 24 weeks after randomization, mean change in visual acuity letter score, adjusted for visual acuity at time of randomization
Time frame: 24 weeks after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | Mean Change in Visual Acuity Letter Score | 2.7 Letter Score | Standard Deviation 9.8 |
| Sham + Intravitreal Ranibizumab 0.3 mg | Mean Change in Visual Acuity Letter Score | 3.0 Letter Score | Standard Deviation 7.1 |
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.
ETDRS (Early Treatment Diabetic Retinopathy Study)
Time frame: 24 weeks weeks after randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | 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. | >= 15 Letter Improvement | 7 Eyes |
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | 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. | >= 10 Letter Improvement | 14 Eyes |
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | 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. | >= 10 Letter Worsening | 8 Eyes |
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | 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. | >= 15 Letter Worsening | 4 Eyes |
| Sham + Intravitreal Ranibizumab 0.3 mg | 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. | >= 15 Letter Worsening | 3 Eyes |
| Sham + Intravitreal Ranibizumab 0.3 mg | 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. | >= 15 Letter Improvement | 1 Eyes |
| Sham + Intravitreal Ranibizumab 0.3 mg | 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. | >= 10 Letter Worsening | 4 Eyes |
| Sham + Intravitreal Ranibizumab 0.3 mg | 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. | >= 10 Letter Improvement | 9 Eyes |
Secondary
Eyes With OCT CSF Thickness < the Gender-specific Spectral Domain OCT Equivalent of 250 Microns on Zeiss Stratus
Gender and OCT machine-specific values for OCT central subfield thickness (in microns) are defined as: \<290 in women and \<305 in men in Zeiss Cirrus; \<305 in women and \<320 in men in Heidelberg Spectralis
Time frame: 24 weeks after randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | Eyes With OCT CSF Thickness < the Gender-specific Spectral Domain OCT Equivalent of 250 Microns on Zeiss Stratus | 32 Eyes |
| Sham + Intravitreal Ranibizumab 0.3 mg | Eyes With OCT CSF Thickness < the Gender-specific Spectral Domain OCT Equivalent of 250 Microns on Zeiss Stratus | 20 Eyes |
Secondary
Mean Change in OCT CSF Thickness, Adjusted for Thickness at Time of Randomization
Change in optical coherence tomography (OCT) central subfield thickness (in microns) was truncated to 3 standard deviations from the mean \[-372, +201\] (calculated using observed changes at 24 weeks combining all treatment groups), to minimize the effect of outliers. Two values were truncated in the sham + ranibizumab group: one on the negative end, and one on the positive end.
Time frame: 24 weeks after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | Mean Change in OCT CSF Thickness, Adjusted for Thickness at Time of Randomization | -110 microns | Standard Deviation 86 |
| Sham + Intravitreal Ranibizumab 0.3 mg | Mean Change in OCT CSF Thickness, Adjusted for Thickness at Time of Randomization | -62 microns | Standard Deviation 97 |
Secondary
Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness
Change in optical coherence tomography (OCT) central subfield (CSF) thickness (in microns) was truncated to 3 standard deviations from the mean \[-372, +201\] (calculated using observed changes at 24 weeks combining all treatment groups), to minimize the effect of outliers. Two values were truncated in the sham + ranibizumab group: one on the negative end, and one on the positive end.
Time frame: 24 weeks after randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness | >=1 LogOCT step improvement | 34 Eyes |
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness | >= 2 LogOCT step improvement | 14 Eyes |
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness | >=1 LogOCT step worsening | 0 Eyes |
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness | >=2 LogOCT step worsening | 0 Eyes |
| Sham + Intravitreal Ranibizumab 0.3 mg | Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness | >=2 LogOCT step worsening | 1 Eyes |
| Sham + Intravitreal Ranibizumab 0.3 mg | Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness | >=1 LogOCT step improvement | 22 Eyes |
| Sham + Intravitreal Ranibizumab 0.3 mg | Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness | >=1 LogOCT step worsening | 1 Eyes |
| Sham + Intravitreal Ranibizumab 0.3 mg | Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness | >= 2 LogOCT step improvement | 8 Eyes |
Secondary
OCT CSF Thickness Area Under the Curve Between Randomization and 24 Weeks
Including participants who completed the 24-week visit. Time points for which data were collected for this analysis include 0, 4 8,12, 16, 20, and 24 weeks post randomization.
Time frame: 24 weeks after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | OCT CSF Thickness Area Under the Curve Between Randomization and 24 Weeks | -86.9 microns | Standard Deviation 65.6 |
| Sham + Intravitreal Ranibizumab 0.3 mg | OCT CSF Thickness Area Under the Curve Between Randomization and 24 Weeks | -33.5 microns | Standard Deviation 56.8 |
Secondary
Visual Acuity Area Under the Curve (AUC) Between Randomization and 24 Weeks
Only included participants who completed the 24-week visit. Time points for which data were collected for this analysis include 0, 4 8,12, 16, 20, and 24 weeks post randomization.
Time frame: 24 weeks after randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravitreal Dexamethasone+Intravitreal Ranibizumab 0.3mg | Visual Acuity Area Under the Curve (AUC) Between Randomization and 24 Weeks | 1.9 Letter Score | Standard Deviation 6.3 |
| Sham + Intravitreal Ranibizumab 0.3 mg | Visual Acuity Area Under the Curve (AUC) Between Randomization and 24 Weeks | 2.5 Letter Score | Standard Deviation 4.4 |