Diabetic Macular Edema
Conditions
Brief summary
The Endurance Trial is a phase IV open label clinical study to assess the need for ongoing intravitreal aflibercept injections after the 3-year VISTA DME (VGFT-OD-1009; NCT01363440) end-point. Subjects will be treated with intravitreal aflibercept injections pro re nata (PRN) based on the presence of CR-DME (Clinically Relevant-DME). In addition, subjects who meet re-treatment criteria will be eligible for focal laser treatment every 90 days.
Detailed description
The investigational product is aflibercept, which will be supplied by Regeneron Pharmaceuticals, Inc. in sterile vials for intravitreal (IVT) injection. Vials must be used (defined as entered with needle) only once. All drug supplies are to be kept under recommended storage conditions. The injection volume will be 50μL (0.05 mL) and will be administered to the subjects by IVT injection. Throughout the trial, subjects will be treated with intravitreal aflibercept injections PRN in the presence of CR-DME; this is defined as DME that the treating investigator believes is limiting visual function. All subjects will initially be evaluated every 4 weeks (28 days) for CR-DME and treated PRN. If CR-DME is present the subject will receive IVT aflibercept injection. If CR-DME is not present the subject will not receive an IVT aflibercept injection and will be observed. At any point throughout the study, once a subject has been evaluated and observed (with no IVT aflibercept) for a total of 8 weeks (3 consecutive monthly visits), the interval between visits will be increased to 8 weeks. After an additional 24 weeks (3 consecutive visits, every 8 weeks) without an IVT aflibercept injection, the interval between visits will be increased to 12 weeks. If a subject has recurrent CR-DME they will receive an IVT aflibercept injection and the interval between visits will reduce back to 4 weeks. Subjects can again extend the interval between visits to 8 weeks once they have not received an IVT aflibercept injection for a total of 8 weeks (3 consecutive visits) as described above. Extension to 12 weeks is then performed as above. Starting at week 52, once a subject has extended to a 12 week interval, if CR-DME is not present the subject will not receive an IVT aflibercept injection and will be extended to a 16 week interval. Once at a 16 week interval, if CR-DME is not present the subject will not receive an IVT aflibercept injection and will be extended to a 20 week interval. At any point past a 12 week interval extension, if a subject has recurrent CR-DME they will receive an IVT aflibercept injection and the interval for the next visit will be reduced at investigator discretion to be either 12 or 16 weeks. If the interval is needed to be reduced to below 12 weeks, the subject will return to a 4 or 8 week interval, at investigator discretion and return to the protocol above. All subjects receiving PRN IVT aflibercept injections will be evaluated for focal laser treatment beginning at week 12 through the end of the study. If the subject meets any of the criteria for focal laser treatment (FLT), fluorescein angiography (FA) will be performed to guide the focal laser treatment. Focal laser treatment and focal laser re-treatment will be administered no more than once every 90 days. When a subject receives ≥ 2 IVT aflibercept injections in ≤ 24 weeks FLT will be applied. Once the initial session of FLT is applied subjects are eligible for FLT re-treatment after 90 days, when they have received ≥ 2 IVT aflibercept injections within the prior 90 day period. FLT will be applied to: 1. All leaking microaneurysms. 2. Grid to all areas of diffuse leakage. 3. Grid to all areas of retinal ischemia outside of the FAZ (once ischemic areas are treated once with grid FLT, these same areas should not be treated again). 4. Laser will not be applied within the capillaries of the FAZ. FLT will not be applied if any of the following apply and are identified: 1. Significant macular ischemia involving the foveal avascular zone (once this has been determine additional fluorescein angiography for FLT planning should not be performed and subjects will not longer be eligible for rescue FLT). 2. Treatment would be too close to the foveal avascular zone. 3. Macular edema is not related to DME (eg: postoperative CME, etc).
Interventions
DRUGAflibercept
pro re nata (PRN)
PROCEDUREFocal Laser
Focal laser administered based on pre-specified criteria
Sponsors
Regeneron Pharmaceuticals
Greater Houston Retina Research
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A subject must meet the following criteria to be eligible for inclusion in the study: 1. Enrolled and Completed VISTA DME (VGFT-OD-1009) clinical trial 2. Willing and able to comply with clinic visits and study-related procedures 3. Provide signed informed consent 4. Enrollment in the trial within 12 weeks of trial activation.
Exclusion criteria
* A subject who meets any of the following criteria will be excluded from the study: 1. Prior treatment with anti-VEGF therapy in the study eye within 28 days of baseline 2. Pregnant or breast-feeding women 3. Sexually active men\* or women of childbearing potential\*\* who are unwilling to practice adequate contraception during the study (adequate contraceptive measures include stable use of oral contraceptives or other prescription pharmaceutical contraceptives for 2 or more menstrual cycles prior to screening; intrauterine device \[IUD\]; bilateral tubal ligation; vasectomy; condom plus contraceptive sponge, foam, or jelly, or diaphragm plus contraceptive sponge, foam, or jelly). * Contraception is not required for men with documented vasectomy. \*\*Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of child bearing potential. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Intravitreal Aflibercept Injections for Subjects Who Were Enrolled and Completed the 3-year VISTA DME (VGFT-OD-1009) Trial | Week 104 | Measured by evaluating mean number of injections required for subjects who were enrolled and completed the 3-year VISTA DME (VGFT-OD-1009) trial |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Number of Intravitreal Aflibercept Injections Before and After Receiving First Focal Laser Application. | Before First Focal Laser Treatment (FLT) at Week 12 or later; After First FLT at up to 104 weeks | Measure the role of focal laser treatment (fluorescein angiography-guided, if applicable) in decreasing the treatment burden among subjects who require ongoing aflibercept treatment in the management of diabetic macular edema. |
| Percentage of Subjects With Gain or Loss of 0 to 5 Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity Letters From Baseline to Week 52 and Baseline to Week 104 | Week 52, Week 104 | Evaluate the percentage of subjects with a gain or loss in Early Treatment Diabetic Retinopathy Study best-corrected visual acuity letters in patients treated with aflibercept from baseline to week 52 and baseline to week 104 |
| Mean Change in Central Retinal Thickness From Baseline to Week 52 and Baseline to Week 104. | Week 52, Week 104 | Evaluate the mean change in central retinal thickness from baseline to week 52 and baseline to week 104 in patients treated with aflibercept. |
| Number of Subjects With no Clinically-relevant Diabetic Macular Edema (as Defined in the Protocol) on Spectral Domain Optical Coherence Tomography From Baseline to Week 52 and Baseline to Week 104. | Week 52, Week 104 | Evaluate the number of subjects with no clinically-relevant diabetic macular edema (as defined in the protocol) on spectral domain optical coherence tomography from baseline to week 52 and baseline to week 104 in patients treated with aflibercept. |
| Number of Subjects With Stable, Worsened, or Improved Diabetic Retinopathy | Week 52, Week 104 | Number of subjects with stable, worsened, or improved diabetic retinopathy through 104 weeks. |
| Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity From Baseline to Week 52 and Baseline to Week 104 | Week 52, Week 104 | Evaluate the mean change over time in Early Treatment Diabetic Retinopathy Study best-corrected visual acuity at week 52 from baseline and at week 104 from baseline. Participants were challenged with reading letters on lines of an eye chart (5 letters per line) in standardized lighting conditions. Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until they reached a row where a minimum of three letters on a line could be read, and were scored by how many letters could be correctly identified. |
| Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity Before and After Focal Laser Therapy | 104 weeks | Evaluation of the effect of laser on Early Treatment Diabetic Retinopathy Study best-corrected visual acuity outcomes. Participants were challenged with reading letters on lines of an eye chart (5 letters per line) in standardized lighting conditions. Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until they reached a row where a minimum of three letters on a line could be read, and were scored by how many letters could be correctly identified. |
| Mean Change in Central Retinal Thickness Before and After First Focal Laser Treatment | 104 weeks | Evaluate the mean change in central retinal thickness before and after first focal laser treatment in patients treated with pro re nata aflibercept. |
| Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Past and Future Anti-VEGF Treatment Burden | Week 52, Week 104 | Mean number of injections in 52 weeks and 104 weeks based on quantification of ischemic areas |
| Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Visual Outcomes | Week 52, Week 104 | Mean change in visual acuity from baseline to week 52 and baseline to week 104 based on quantification of ischemic areas |
| Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Anatomic Outcomes | Week 52, Week 104 | Mean change in central retinal thickness from baseline to week 52 based on quantification of ischemic areas |
| Number of Subjects That Receive Focal Laser Treatment. | Week 52, Week 104 | Number of subjects that receive focal laser treatment from baseline to week 52 and from baseline to week 104. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PRN (Pro re Nata) 2 mg intravitreal aflibercept (Eylea) PRN, focal laser administered based on pre-specified criteria, 104 weeks
Aflibercept: pro re nata (PRN)
Focal Laser: Focal laser administered based on pre-specified criteria | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Withdrawal by Subject | 11 |
Baseline characteristics
| Characteristic | PRN (Pro re Nata) |
|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 9.2 |
| Central Retinal Thickness | 290 Microns STANDARD_DEVIATION 88.8 |
| Duration of Diabetes | 18.6 years STANDARD_DEVIATION 10.6 |
| Early Treatment Diabetic Retinopathy Study Best-Corrected Visual Acuity | 69.6 letters STANDARD_DEVIATION 13.4 |
| Glycated Hemoglobin | 7.5 Percent STANDARD_DEVIATION 1.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 46 Participants |
| Region of Enrollment United States | 60 participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 60 |
| other Total, other adverse events | 26 / 60 |
| serious Total, serious adverse events | 19 / 60 |
Outcome results
Primary
Mean Number of Intravitreal Aflibercept Injections for Subjects Who Were Enrolled and Completed the 3-year VISTA DME (VGFT-OD-1009) Trial
Measured by evaluating mean number of injections required for subjects who were enrolled and completed the 3-year VISTA DME (VGFT-OD-1009) trial
Time frame: Week 104
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PRN (Pro re Nata) | Mean Number of Intravitreal Aflibercept Injections for Subjects Who Were Enrolled and Completed the 3-year VISTA DME (VGFT-OD-1009) Trial | 9.5 injections | Standard Error 6.7 |
Secondary
Mean Change in Central Retinal Thickness Before and After First Focal Laser Treatment
Evaluate the mean change in central retinal thickness before and after first focal laser treatment in patients treated with pro re nata aflibercept.
Time frame: 104 weeks
Population: All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals, 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 |
|---|---|---|---|---|
| PRN (Pro re Nata) | Mean Change in Central Retinal Thickness Before and After First Focal Laser Treatment | Before First FLT | -8.5 microns | Standard Error 52.6 |
| PRN (Pro re Nata) | Mean Change in Central Retinal Thickness Before and After First Focal Laser Treatment | After First FLT | -6.8 microns | Standard Error 41.6 |
Secondary
Mean Change in Central Retinal Thickness From Baseline to Week 52 and Baseline to Week 104.
Evaluate the mean change in central retinal thickness from baseline to week 52 and baseline to week 104 in patients treated with aflibercept.
Time frame: Week 52, Week 104
Population: All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals, 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 |
|---|---|---|---|---|
| PRN (Pro re Nata) | Mean Change in Central Retinal Thickness From Baseline to Week 52 and Baseline to Week 104. | Week 52 | -7 Microns | Standard Error 8.6 |
| PRN (Pro re Nata) | Mean Change in Central Retinal Thickness From Baseline to Week 52 and Baseline to Week 104. | Week 104 | 1 Microns | Standard Error 11.53 |
Secondary
Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity Before and After Focal Laser Therapy
Evaluation of the effect of laser on Early Treatment Diabetic Retinopathy Study best-corrected visual acuity outcomes. Participants were challenged with reading letters on lines of an eye chart (5 letters per line) in standardized lighting conditions. Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until they reached a row where a minimum of three letters on a line could be read, and were scored by how many letters could be correctly identified.
Time frame: 104 weeks
Population: All participants receiving laser were included in analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PRN (Pro re Nata) | Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity Before and After Focal Laser Therapy | Before First FLT | 0.4 letters | Standard Deviation 6.2 |
| PRN (Pro re Nata) | Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity Before and After Focal Laser Therapy | After First FLT | 0.3 letters | Standard Deviation 11.9 |
Secondary
Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity From Baseline to Week 52 and Baseline to Week 104
Evaluate the mean change over time in Early Treatment Diabetic Retinopathy Study best-corrected visual acuity at week 52 from baseline and at week 104 from baseline. Participants were challenged with reading letters on lines of an eye chart (5 letters per line) in standardized lighting conditions. Lines became smaller as participants progressed from the top to the bottom of the chart. Participants read down the chart until they reached a row where a minimum of three letters on a line could be read, and were scored by how many letters could be correctly identified.
Time frame: Week 52, Week 104
Population: All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals, 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 |
|---|---|---|---|---|
| PRN (Pro re Nata) | Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity From Baseline to Week 52 and Baseline to Week 104 | 52 Weeks | 0.61 letters | Standard Error 1.28 |
| PRN (Pro re Nata) | Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity From Baseline to Week 52 and Baseline to Week 104 | 104 Weeks | 0.83 letters | Standard Error 1.66 |
Secondary
Mean Number of Intravitreal Aflibercept Injections Before and After Receiving First Focal Laser Application.
Measure the role of focal laser treatment (fluorescein angiography-guided, if applicable) in decreasing the treatment burden among subjects who require ongoing aflibercept treatment in the management of diabetic macular edema.
Time frame: Before First Focal Laser Treatment (FLT) at Week 12 or later; After First FLT at up to 104 weeks
Population: Only participants who were eligible for focal laser treatment were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PRN (Pro re Nata) | Mean Number of Intravitreal Aflibercept Injections Before and After Receiving First Focal Laser Application. | Injections Before First Focal Laser | 7.5 Injections | Standard Deviation 3.7 |
| PRN (Pro re Nata) | Mean Number of Intravitreal Aflibercept Injections Before and After Receiving First Focal Laser Application. | Injections After First Focal Laser | 6.7 Injections | Standard Deviation 4.2 |
Secondary
Number of Subjects That Receive Focal Laser Treatment.
Number of subjects that receive focal laser treatment from baseline to week 52 and from baseline to week 104.
Time frame: Week 52, Week 104
Population: All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals, 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) |
|---|---|---|---|
| PRN (Pro re Nata) | Number of Subjects That Receive Focal Laser Treatment. | Week 104 | 27 Participants |
| PRN (Pro re Nata) | Number of Subjects That Receive Focal Laser Treatment. | Week 52 | 25 Participants |
Secondary
Number of Subjects With no Clinically-relevant Diabetic Macular Edema (as Defined in the Protocol) on Spectral Domain Optical Coherence Tomography From Baseline to Week 52 and Baseline to Week 104.
Evaluate the number of subjects with no clinically-relevant diabetic macular edema (as defined in the protocol) on spectral domain optical coherence tomography from baseline to week 52 and baseline to week 104 in patients treated with aflibercept.
Time frame: Week 52, Week 104
Population: All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals, 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) |
|---|---|---|---|
| PRN (Pro re Nata) | Number of Subjects With no Clinically-relevant Diabetic Macular Edema (as Defined in the Protocol) on Spectral Domain Optical Coherence Tomography From Baseline to Week 52 and Baseline to Week 104. | Week 52 | 39 Participants |
| PRN (Pro re Nata) | Number of Subjects With no Clinically-relevant Diabetic Macular Edema (as Defined in the Protocol) on Spectral Domain Optical Coherence Tomography From Baseline to Week 52 and Baseline to Week 104. | Week 104 | 29 Participants |
Secondary
Number of Subjects With Stable, Worsened, or Improved Diabetic Retinopathy
Number of subjects with stable, worsened, or improved diabetic retinopathy through 104 weeks.
Time frame: Week 52, Week 104
Population: All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals, the population analyzed at each time point is equal to or smaller than the population still enrolled at that time point.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| PRN (Pro re Nata) | Number of Subjects With Stable, Worsened, or Improved Diabetic Retinopathy | Week 52 | Worsened Diabetic Retinopathy | 5 Participants |
| PRN (Pro re Nata) | Number of Subjects With Stable, Worsened, or Improved Diabetic Retinopathy | Week 52 | Stable Diabetic Retinopathy | 46 Participants |
| PRN (Pro re Nata) | Number of Subjects With Stable, Worsened, or Improved Diabetic Retinopathy | Week 52 | Improved Diabetic Retinopathy | 3 Participants |
| PRN (Pro re Nata) | Number of Subjects With Stable, Worsened, or Improved Diabetic Retinopathy | Week 104 | Worsened Diabetic Retinopathy | 15 Participants |
| PRN (Pro re Nata) | Number of Subjects With Stable, Worsened, or Improved Diabetic Retinopathy | Week 104 | Stable Diabetic Retinopathy | 27 Participants |
| PRN (Pro re Nata) | Number of Subjects With Stable, Worsened, or Improved Diabetic Retinopathy | Week 104 | Improved Diabetic Retinopathy | 4 Participants |
Secondary
Percentage of Subjects With Gain or Loss of 0 to 5 Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity Letters From Baseline to Week 52 and Baseline to Week 104
Evaluate the percentage of subjects with a gain or loss in Early Treatment Diabetic Retinopathy Study best-corrected visual acuity letters in patients treated with aflibercept from baseline to week 52 and baseline to week 104
Time frame: Week 52, Week 104
Population: All participants were included in analysis. Due to participant attrition, missed visits, and variable follow-up intervals, 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) |
|---|---|---|---|
| PRN (Pro re Nata) | Percentage of Subjects With Gain or Loss of 0 to 5 Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity Letters From Baseline to Week 52 and Baseline to Week 104 | Week 52 | 35 Participants |
| PRN (Pro re Nata) | Percentage of Subjects With Gain or Loss of 0 to 5 Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity Letters From Baseline to Week 52 and Baseline to Week 104 | Week 104 | 30 Participants |
Secondary
Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Anatomic Outcomes
Mean change in central retinal thickness from baseline to week 52 based on quantification of ischemic areas
Time frame: Week 52, Week 104
Population: This analysis was never performed because we were logistically unable to collect the data.
Secondary
Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Past and Future Anti-VEGF Treatment Burden
Mean number of injections in 52 weeks and 104 weeks based on quantification of ischemic areas
Time frame: Week 52, Week 104
Population: This analysis was never performed because we were logistically unable to collect the data.
Secondary
Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Visual Outcomes
Mean change in visual acuity from baseline to week 52 and baseline to week 104 based on quantification of ischemic areas
Time frame: Week 52, Week 104
Population: This analysis was never performed because we were logistically unable to collect the data.