Diabetic Macular Edema
Conditions
Keywords
Non Proliferative Diabetic Retinopathy, Diabetic Retinopathy, Macular Edema, Background Diabetic Retinopathy, Pre Proliferative Diabetic Retinopathy
Brief summary
This study is a Phase I/II, multicenter, randomized, study of the efficacy and safety of ranibizumab injection monotherapy verses a duel therapy of 0.3mg ranibizumab combined with ultra wide, 200° field angiography guided pan retinal photocoagulation in patients with CSME-CI secondary to diabetes mellitus (Type 1 or 2).
Detailed description
Approximately 40 eyes will be randomized at 3 investigational centers in the United States. This study consists of a screening period of up to 14 days (Days -14 to -1), and a 36-month treatment period (Day 0 to Month 36). Subjects who provide consent will enter the screening period to determine eligibility. As part of the screening process, the examining investigator will evaluate the macular foveal avascular zone fluorescein images to determine subjects' eligibility. Eligible subjects will be randomized in a 1:1 ratio so that approximately 20 eyes will receive 0.3 mg ranibizumab monotherapy, and approximately 20 eyes will receive 0.3 mg ranibizumab combined with Ultra wide 200° field angiogram guided targeted pan retinal photocoagulation (PRP). Subjects must meet VA and retinal thickness eligibility requirements during the screening period. The subject can have both eyes in the study. If both eyes are eligible, one eye will be randomized, to cohort 1 while the other eye will be randomized to the cohort 2. A subject with both eyes in the trial will have each eye in a separate cohort.
Interventions
DRUG0.3 mg ranibizumab
Cohort 1: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.
Cohort 2: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan retinal photocoagulation (PRP) based on ultra wide 200º field angiography. After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.
Sponsors
Genentech, Inc.
David M. Brown, M.D.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willingness to provide signed informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization. * Age ≥ 18 years * Diabetes Mellitus (Type 1 or 2). The following will be considered as sufficient evidence that diabetes is present: * Current regular use of insulin for the treatment of diabetes * Current regular use of oral antihyperglycemic agents for the treatment of diabetes * Documented diabetes according to the American Diabetes Association and/or World Health Organization criteria. * BCVA score in the study eye of 20/32 to 20/320 approximate snellen equivalent using the ETDRS protocol at an initial testing distance of 4 meters, confirmed by the investigator. * High Definition OCT (Spectralis) central retinal thickness measurement of ≥ 300 µm * Decrease in visual acuity is determined to be primarily the result of DME and not to other cause. * Ability and willingness to return for all scheduled visits and assessments. * Clear ocular media and adequate pupillary dilatation to permit good quality fundus photography.
Exclusion criteria
Subjects who meet any of the following criteria will be excluded from this study: General
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Ranibizumab Injections in Each of the Two Cohorts in a 36 Month Period | 36 Months | Assess the number of ranibizumab injections in the ranibizumab and targeted panretinal photocoagulation (PRP) with ranibizumab cohorts through Month 36. |
| Mean Change Over Time in Early Treatment Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS BCVA) Through Month 36 | 36 Months | Evaluate the mean change over time in ETDRS BCVA in the ranibizumab and targeted PRP with ranibizumab cohorts through Month 36. |
| Incidence and Severity of Ocular and Non-ocular Adverse Events (AE's) Through Month 36. | 36 Months | Incidence and severity of ocular and non-ocular adverse events (AE's) in the monotherapy and combination cohorts through Month 36. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patients With Persistent Macular Edema Post-intravitreal Injection. | Month 36 | Percentage of patients with persistent macular edema post-intravitreal injection in the ranibizumab and targeted PRP with ranibizumab cohorts. |
| Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA. | Month 12, 24, and 36 | Percentage of patients in the ranibizumab and targeted PRP with ranibizumab cohorts who experience a loss of 15 or more letters from Baseline to Month 12, 24, and 36 in ETDRS BCVA. |
| Mean Change in Peripheral Visual Field as Measured by Goldmann Visual Field at Screen and Month and 36. | 36 Months | Mean change in peripheral visual field as measured by Goldmann visual field at screen and Month 36 in the ranibizumab and targeted PRP with ranibizumab cohorts. |
| Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA | Month 12, 24, and 36 | Determine percentage of patients who experience a gain of 15 or more letters from Baseline to Month 12, 24, and 36 in ETDRS BCVA in the ranibizumab and targeted PRP with ranibizumab cohorts. |
| Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's. | Month 12, 24, and 36 | Evaluate mean change in central retinal thickness in the ranibizumab and targeted PRP with ranibizumab cohorts over time through Month 12, 24, and 36 as assessed by high resolution OCT's. |
Countries
United States
Participant flow
Pre-assignment details
A total of 29 unique participants were enrolled in the study. 11 of these 29 had both eyes assigned to each intervention. Therefore, a total of 40 eyes were randomized in the trial.
Participants by arm
| Arm | Count |
|---|---|
| 0.3 mg Ranibizumab Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. | 20 |
| 0.3 mg Ranibizumab Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. | 20 |
| Targeted PRP With 0.3 mg Ranibizumab Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide 200º field angiography (see Appendix C). After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation. | 20 |
| Targeted PRP With 0.3 mg Ranibizumab Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide 200º field angiography (see Appendix C). After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation. | 20 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Relocation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | 0.3 mg Ranibizumab | Targeted PRP With 0.3 mg Ranibizumab | Total |
|---|---|---|---|
| Age, Customized Age | 55 years | 56 years | 55 years |
| Central Retinal Thickness | 571 microns | 488 microns | 530 microns |
| Diabetes Mellitus Diagnosis Year | 2002 year | 2001 year | 2001 year |
| Diabetic Macular Edema Diagnosis Year | 2012 year | 2012 year | 2012 year |
| Early Treatment Diabetic Retinopathy Study Best-Corrected Visual Acuity | 59.1 letters | 60.1 letters | 59.6 letters |
| Glycated Hemoglobin | 8.8 Percentage | 8.0 Percentage | 8.4 Percentage |
| Number of Right Eyes Enrolled | 7 Eyes | 11 Eyes | 18 Eyes |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex/Gender, Customized Gender : Female | 4 Eyes | 5 Eyes | 9 Eyes |
| Sex/Gender, Customized Gender : Male | 16 Eyes | 15 Eyes | 31 Eyes |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 12 / 20 | 13 / 20 |
| serious Total, serious adverse events | 9 / 20 | 10 / 20 |
Outcome results
Primary
Incidence and Severity of Ocular and Non-ocular Adverse Events (AE's) Through Month 36.
Incidence and severity of ocular and non-ocular adverse events (AE's) in the monotherapy and combination cohorts through Month 36.
Time frame: 36 Months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 0.3 mg Ranibizumab | Incidence and Severity of Ocular and Non-ocular Adverse Events (AE's) Through Month 36. | Participants Experiencing Serious Ocular AE | 2 Participants |
| 0.3 mg Ranibizumab | Incidence and Severity of Ocular and Non-ocular Adverse Events (AE's) Through Month 36. | Participants Experiencing Serious Systemic AE | 7 Participants |
| Targeted PRP With 0.3 mg Ranibizumab | Incidence and Severity of Ocular and Non-ocular Adverse Events (AE's) Through Month 36. | Participants Experiencing Serious Ocular AE | 1 Participants |
| Targeted PRP With 0.3 mg Ranibizumab | Incidence and Severity of Ocular and Non-ocular Adverse Events (AE's) Through Month 36. | Participants Experiencing Serious Systemic AE | 9 Participants |
Primary
Mean Change Over Time in Early Treatment Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS BCVA) Through Month 36
Evaluate the mean change over time in ETDRS BCVA in the ranibizumab and targeted PRP with ranibizumab cohorts through Month 36.
Time frame: 36 Months
Population: All participants were included in analysis. Among participants who failed to complete the study, the last observation was carried forward for analysis at Month 36.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 mg Ranibizumab | Mean Change Over Time in Early Treatment Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS BCVA) Through Month 36 | 13.9 letters | Standard Deviation 10.2 |
| Targeted PRP With 0.3 mg Ranibizumab | Mean Change Over Time in Early Treatment Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS BCVA) Through Month 36 | 8.2 letters | Standard Deviation 16.1 |
Primary
Total Number of Ranibizumab Injections in Each of the Two Cohorts in a 36 Month Period
Assess the number of ranibizumab injections in the ranibizumab and targeted panretinal photocoagulation (PRP) with ranibizumab cohorts through Month 36.
Time frame: 36 Months
Population: All participants were included in analysis. Among participants who failed to complete the study, the last observation was carried forward for analysis at Month 36.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| 0.3 mg Ranibizumab | Total Number of Ranibizumab Injections in Each of the Two Cohorts in a 36 Month Period | 24.4 injections |
| Targeted PRP With 0.3 mg Ranibizumab | Total Number of Ranibizumab Injections in Each of the Two Cohorts in a 36 Month Period | 27.1 injections |
Secondary
Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA
Determine percentage of patients who experience a gain of 15 or more letters from Baseline to Month 12, 24, and 36 in ETDRS BCVA in the ranibizumab and targeted PRP with ranibizumab cohorts.
Time frame: Month 12, 24, and 36
Population: All participants were included in analysis. Due to participant attrition and missed visits, the population analyzed at each time point is equal to or smaller than the population still enrolled at that time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 0.3 mg Ranibizumab | Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA | Month 12 | 10 Participants |
| 0.3 mg Ranibizumab | Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA | Month 24 | 10 Participants |
| 0.3 mg Ranibizumab | Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA | Month 36 | 9 Participants |
| Targeted PRP With 0.3 mg Ranibizumab | Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA | Month 12 | 5 Participants |
| Targeted PRP With 0.3 mg Ranibizumab | Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA | Month 24 | 6 Participants |
| Targeted PRP With 0.3 mg Ranibizumab | Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA | Month 36 | 5 Participants |
Secondary
Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's.
Evaluate mean change in central retinal thickness in the ranibizumab and targeted PRP with ranibizumab cohorts over time through Month 12, 24, and 36 as assessed by high resolution OCT's.
Time frame: Month 12, 24, and 36
Population: All participants were included in analysis. Due to participant attrition and missed visits, the population analyzed at each time point is equal to or smaller than the population still enrolled at that time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 0.3 mg Ranibizumab | Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's. | Month 12 | -301 microns | Standard Deviation 255 |
| 0.3 mg Ranibizumab | Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's. | Month 24 | -296 microns | Standard Deviation 238 |
| 0.3 mg Ranibizumab | Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's. | Month 36 | -302 microns | Standard Deviation 246 |
| Targeted PRP With 0.3 mg Ranibizumab | Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's. | Month 12 | -161 microns | Standard Deviation 188 |
| Targeted PRP With 0.3 mg Ranibizumab | Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's. | Month 24 | -169 microns | Standard Deviation 172 |
| Targeted PRP With 0.3 mg Ranibizumab | Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's. | Month 36 | -152 microns | Standard Deviation 149 |
Secondary
Mean Change in Peripheral Visual Field as Measured by Goldmann Visual Field at Screen and Month and 36.
Mean change in peripheral visual field as measured by Goldmann visual field at screen and Month 36 in the ranibizumab and targeted PRP with ranibizumab cohorts.
Time frame: 36 Months
Population: Participants that had poor fix (resulting in inaccurate results), missing baseline results, or missing Month 36 results were excluded.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 0.3 mg Ranibizumab | Mean Change in Peripheral Visual Field as Measured by Goldmann Visual Field at Screen and Month and 36. | -215 degrees squared | Standard Deviation 1957 |
| Targeted PRP With 0.3 mg Ranibizumab | Mean Change in Peripheral Visual Field as Measured by Goldmann Visual Field at Screen and Month and 36. | -1723 degrees squared | Standard Deviation 3532 |
Secondary
Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA.
Percentage of patients in the ranibizumab and targeted PRP with ranibizumab cohorts who experience a loss of 15 or more letters from Baseline to Month 12, 24, and 36 in ETDRS BCVA.
Time frame: Month 12, 24, and 36
Population: All participants were included in analysis. Due to participant attrition and missed visits, the population analyzed at each time point is equal to or smaller than the population still enrolled at that time point.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 0.3 mg Ranibizumab | Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA. | 12 Months | 0 Participants |
| 0.3 mg Ranibizumab | Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA. | 24 Months | 0 Participants |
| 0.3 mg Ranibizumab | Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA. | 36 Months | 0 Participants |
| Targeted PRP With 0.3 mg Ranibizumab | Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA. | 12 Months | 0 Participants |
| Targeted PRP With 0.3 mg Ranibizumab | Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA. | 24 Months | 1 Participants |
| Targeted PRP With 0.3 mg Ranibizumab | Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA. | 36 Months | 1 Participants |
Secondary
Patients With Persistent Macular Edema Post-intravitreal Injection.
Percentage of patients with persistent macular edema post-intravitreal injection in the ranibizumab and targeted PRP with ranibizumab cohorts.
Time frame: Month 36
Population: All participants were included in analysis. Due to participant attrition and missed visits, the population analyzed at each time point is equal to or smaller than the population still enrolled at that time point.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 0.3 mg Ranibizumab | Patients With Persistent Macular Edema Post-intravitreal Injection. | 9 Participants |
| Targeted PRP With 0.3 mg Ranibizumab | Patients With Persistent Macular Edema Post-intravitreal Injection. | 12 Participants |