Long-Term Efficacy & Safety of Aflibercept IVT for the Treatment of DME in Subjects Who Completed the VISTA-DME Trial

• Sponsor: Greater Houston Retina Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT02299336
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 60
• Locations: 3
• Arm: 1
• Actual Duration (Months): 25.5
• Patients Per Site: 20
• Patients Per Site Per Month: 0.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: Aflibercept; Procedure: Focal Laser	Phase 4

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Long-Term Efficacy and Safety of Intravitreal Aflibercept Injections for the Treatment of Diabetic Macular Edema in Subjects Who Completed the Three Year VISTA-DME Trial .
• Actual Study Start Date: Nov 24, 2014
• Actual Primary Completion Date: Jan 9, 2017
• Actual Study Completion Date: Jan 9, 2017

Arms and Interventions

Arm	Intervention/Treatment
Other: PRN (pro re nata) 2 mg intravitreal aflibercept (Eylea) PRN, focal laser administered based on pre-specified criteria, 104 weeks	Drug: Aflibercept; pro re nata (PRN); Other Names: Eylea ; Procedure: Focal Laser; Focal laser administered based on pre-specified criteria

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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

11. 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

12. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Retina Consultants of Houston/The Medical Center	Houston	Texas	United States	77030
2	Retina Consultants of Houston/Katy office	Katy	Texas	United States	77494
3	Retina Consultants of Houston	The Woodlands	Texas	United States	77384

Sponsors and Collaborators

• Greater Houston Retina Research
• Regeneron Pharmaceuticals

Investigators

• Principal Investigator: Charles C Wykoff, MD, Greater Houston Retina Research

Study Documents (Full-Text)

None provided.

More Information

Publications

• Arevalo JF, Sanchez JG, Wu L, Maia M, Alezzandrini AA, Brito M, Bonafonte S, Lujan S, Diaz-Llopis M, Restrepo N, Rodríguez FJ, Udaondo-Mirete P; Pan-American Collaborative Retina Study Group. Primary intravitreal bevacizumab for diffuse diabetic macular edema: the Pan-American Collaborative Retina Study Group at 24 months. Ophthalmology. 2009 Aug;116(8):1488-97, 1497.e1. doi: 10.1016/j.ophtha.2009.03.016. Epub 2009 Jul 9.
• Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: pathogenesis and treatment. Surv Ophthalmol. 2009 Jan-Feb;54(1):1-32. doi: 10.1016/j.survophthal.2008.10.001. Review.
• Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, Ferris FL 3rd, Friedman SM, Glassman AR, Miller KM, Scott IU, Stockdale CR, Sun JK. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010 Jun;117(6):1064-1077.e35. doi: 10.1016/j.ophtha.2010.02.031. Epub 2010 Apr 28.
• Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997 Feb;18(1):4-25. Review.
• Ferrara N. VEGF: an update on biological and therapeutic aspects. Curr Opin Biotechnol. 2000 Dec;11(6):617-24. Review.
• Grover D, Li TJ, Chong CC. Intravitreal steroids for macular edema in diabetes. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD005656. doi: 10.1002/14651858.CD005656.pub2. Review. Update in: Cochrane Database Syst Rev. 2020 Nov 17;11:CD005656.
• Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984 Dec;91(12):1464-74.
• Moss SE, Klein R, Klein BE. Ten-year incidence of visual loss in a diabetic population. Ophthalmology. 1994 Jun;101(6):1061-70.
• Moss SE, Klein R, Klein BE. The 14-year incidence of visual loss in a diabetic population. Ophthalmology. 1998 Jun;105(6):998-1003.
• Nguyen QD, Tatlipinar S, Shah SM, Haller JA, Quinlan E, Sung J, Zimmer-Galler I, Do DV, Campochiaro PA. Vascular endothelial growth factor is a critical stimulus for diabetic macular edema. Am J Ophthalmol. 2006 Dec;142(6):961-9. Epub 2006 Aug 2.
• Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985 Dec;103(12):1796-806.
• Saaddine JB, Honeycutt AA, Narayan KM, Zhang X, Klein R, Boyle JP. Projection of diabetic retinopathy and other major eye diseases among people with diabetes mellitus: United States, 2005-2050. Arch Ophthalmol. 2008 Dec;126(12):1740-7. doi: 10.1001/archopht.126.12.1740.
• Zhang X, Saaddine JB, Chou CF, Cotch MF, Cheng YJ, Geiss LS, Gregg EW, Albright AL, Klein BE, Klein R. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA. 2010 Aug 11;304(6):649-56. doi: 10.1001/jama.2010.1111.

• Responsible Party: Charles C Wykoff, PhD, MD, Principal Investigator, Greater Houston Retina Research
• ClinicalTrials.gov Identifier: NCT02299336
• Other Study ID Numbers: The Endurance 1 Trial
• First Posted: Nov 24, 2014
• Last Update Posted: Jun 4, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Macular Edema; Aflibercept

Study Results

Participant Flow

Arm/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Period Title: Overall Study
STARTED	60
COMPLETED	46
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Overall Participants	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.3 (9.2)
Sex: Female, Male (Count of Participants)
Female	29 48.3%
Male	31 51.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	5 8.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	9 15%
White	46 76.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	60 100%
Glycated Hemoglobin (Percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent]	7.5 (1.1)
Duration of Diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	18.6 (10.6)
Early Treatment Diabetic Retinopathy Study Best-Corrected Visual Acuity (letters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [letters]	69.6 (13.4)
Central Retinal Thickness (Microns) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Microns]	290 (88.8)

Outcome Measures

1. Primary Outcome

Title	Mean Number of Intravitreal Aflibercept Injections for Subjects Who Were Enrolled and Completed the 3-year VISTA DME (VGFT-OD-1009) Trial
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	46
Mean (Standard Error) [injections]	9.5 (6.7)

2. Secondary Outcome

Title	Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity From Baseline to Week 52 and Baseline to Week 104
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	60
52 Weeks	0.61 (1.28)
104 Weeks	0.83 (1.66)

3. Secondary Outcome

Title	Mean Number of Intravitreal Aflibercept Injections Before and After Receiving First Focal Laser Application.
Description	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

Outcome Measure Data

Analysis Population Description

Only participants who were eligible for focal laser treatment were analyzed.

Arm/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	27
Injections Before First Focal Laser	7.5 (3.7)
Injections After First Focal Laser	6.7 (4.2)

4. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	60
Week 52	35 58.3%
Week 104	30 50%

5. Secondary Outcome

Title	Mean Change in Central Retinal Thickness From Baseline to Week 52 and Baseline to Week 104.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	60
Week 52	-7 (8.6)
Week 104	1 (11.53)

6. Secondary Outcome

Title	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.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	60
Week 52	39 65%
Week 104	29 48.3%

7. Secondary Outcome

Title	Number of Subjects With Stable, Worsened, or Improved Diabetic Retinopathy
Description	Number of subjects with stable, worsened, or improved diabetic retinopathy through 104 weeks.
Time Frame	Week 52, Week 104

Outcome Measure Data

Analysis Population Description

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/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	60
Worsened Diabetic Retinopathy	5 8.3%
Stable Diabetic Retinopathy	46 76.7%
Improved Diabetic Retinopathy	3 5%
Worsened Diabetic Retinopathy	15 25%
Stable Diabetic Retinopathy	27 45%
Improved Diabetic Retinopathy	4 6.7%

8. Secondary Outcome

Title	Number of Subjects That Receive Focal Laser Treatment.
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	60
Week 52	25 41.7%
Week 104	27 45%

9. Secondary Outcome

Title	Mean Change in Early Treatment Diabetic Retinopathy Study Best-corrected Visual Acuity Before and After Focal Laser Therapy
Description	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

Outcome Measure Data

Analysis Population Description

All participants receiving laser were included in analysis.

Arm/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	27
Before First FLT	0.4 (6.2)
After First FLT	0.3 (11.9)

10. Secondary Outcome

Title	Mean Change in Central Retinal Thickness Before and After First Focal Laser Treatment
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	60
Before First FLT	-8.5 (52.6)
After First FLT	-6.8 (41.6)

11. Secondary Outcome

Title	Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Past and Future Anti-VEGF Treatment Burden
Description	Mean number of injections in 52 weeks and 104 weeks based on quantification of ischemic areas
Time Frame	Week 52, Week 104

Outcome Measure Data

Analysis Population Description

This analysis was never performed because we were logistically unable to collect the data.

Arm/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	0

12. Secondary Outcome

Title	Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Visual Outcomes
Description	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

Outcome Measure Data

Analysis Population Description

This analysis was never performed because we were logistically unable to collect the data.

Arm/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	0

13. Secondary Outcome

Title	Role of (Ultrawide-field, if Available) Fluorescein Angiography-determined Retinal Ischemia in Predicting Anatomic Outcomes
Description	Mean change in central retinal thickness from baseline to week 52 based on quantification of ischemic areas
Time Frame	Week 52, Week 104

Outcome Measure Data

Analysis Population Description

This analysis was never performed because we were logistically unable to collect the data.

Arm/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
Measure Participants	0

Adverse Events

Time Frame	104 weeks.
Adverse Event Reporting Description	Adverse events were assessed at every study visit during the 2-year study.
Arm/Group Title	PRN (Pro re Nata)
Arm/Group Description	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
All Cause Mortality
	PRN (Pro re Nata)
	Affected / at Risk (%)	# Events
Total	1/60 (1.7%)
Serious Adverse Events
	PRN (Pro re Nata)
	Affected / at Risk (%)	# Events
Total	19/60 (31.7%)
Cardiac disorders
Myocardial Infarction	2/60 (3.3%)
Worsening congestive heart failure	1/60 (1.7%)
Worsening arrhythmia	1/60 (1.7%)
Worsening coronary artery disease	1/60 (1.7%)
Eye disorders
Acute vision loss secondary to vitreous hemorrhage	2/60 (3.3%)
Acute vision loss due to worsening cataract	1/60 (1.7%)
Gastrointestinal disorders
Acute gastroenteritis	2/60 (3.3%)
Hepatobiliary disorders
Cholecystitis	1/60 (1.7%)
Infections and infestations
Worsening staph infection	1/60 (1.7%)
Pneumonia	1/60 (1.7%)
Flu	1/60 (1.7%)
Osteomyelitis	1/60 (1.7%)
Psychiatric disorders
Depression	1/60 (1.7%)
Renal and urinary disorders
Chronic kidney disease	1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/60 (1.7%)
Skin and subcutaneous tissue disorders
Cellulitis	1/60 (1.7%)
Vascular disorders
Deep vein thrombosis	1/60 (1.7%)
Stroke	2/60 (3.3%)
Hypotension	1/60 (1.7%)
Blocked fistula	1/60 (1.7%)
Blocked artery	1/60 (1.7%)
Accelerated hypertension	1/60 (1.7%)
Other (Not Including Serious) Adverse Events
	PRN (Pro re Nata)
	Affected / at Risk (%)	# Events
Total	26/60 (43.3%)
Eye disorders
Vitreous hemorrhage	9/60 (15%)
Neovascularization elsewhere	2/60 (3.3%)
Neovascularization of the disc	1/60 (1.7%)
Worsening cataract	8/60 (13.3%)
Corneal abrasion	1/60 (1.7%)
Subconjunctival hemorrhage	1/60 (1.7%)
Superficial punctate keratitis	1/60 (1.7%)
Eye swelling post-cataract extraction	1/60 (1.7%)
Posterior vitreous detachment	1/60 (1.7%)
Floaters	5/60 (8.3%)
Visual disturbance	1/60 (1.7%)
Epiphora	1/60 (1.7%)
Posterior capsule opafication	1/60 (1.7%)
Iritis	1/60 (1.7%)
Eye pain	1/60 (1.7%)
Vitreous debris	1/60 (1.7%)
Optic nerve pallor	1/60 (1.7%)
Decreased vision	4/60 (6.7%)
Ocular sensitivity	5/60 (8.3%)

Limitations/Caveats

Limitations of the ENDURANCE study include the small population and employment of aflibercept re-treatment criteria that allowed physicians to use their varying clinical judgement in determining anti-VEGF re-treatment instead of a strict protocol.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.