Treatment for CI-DME in Eyes With Very Good VA Study

Diabetic Macular Edema Clinical Trial

— Protocol V  

Official title:

Treatment for Central-Involved Diabetic Macular Edema in Eyes With Very Good Visual Acuity

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01909791
• Other study ID #: DRCR.net Protocol V
• Secondary ID: EY14231EY23207EY
• Status: Completed
• Phase: Phase 3
• Start date: October 2013
• Est. completion date: September 11, 2018

Study information

• Verified date: July 2020
• Source: Jaeb Center for Health Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Although multiple studies have clearly demonstrated that ranibizumab therapy is more effective than laser alone for vision gain and avoiding vision loss in patients with central-involved Diabetic Macular Edema (DME), only eyes with poor visual acuity, such as a visual acuity letter score of 78 or worse (approximate Snellen equivalent of 20/32 or worse) were eligible. Eyes that have central-involved DME with "good" visual acuity (20/25 or better) have not been addressed systematically by recent studies for treatment of DME. Baseline cohort characteristics from the Early Treatment Diabetic Retinopathy Study (ETDRS) suggest that a substantial percentage of eyes with central-involved DME may retain good vision. The investigators do not know definitively whether eyes with central-involved DME and good vision do better with anti-VEGF (vascular endothelial growth factor) (e.g. aflibercept) therapy initially, or focal/grid laser treatment or observation initially followed by anti-VEGF only if vision worsens.

The primary objective of the protocol is to compare the % of eyes that have lost at least 5 letters of visual acuity at 2 years compared with baseline mean visual acuity in eyes with central-involved DME and good visual acuity defined as a Snellen equivalent of 20/25 or better (electronic-ETDRS letter score of 79 or better) that receive (1) prompt focal/grid photocoagulation + deferred anti-VEGF, (2) observation + deferred anti-VEGF, or (3) prompt anti-VEGF.

Secondary objectives include:

• Comparing other visual acuity outcomes between treatment groups, such as the percent of eyes with at least 5, 10 and 15 letter losses in visual acuity from baseline mean visual acuity, percent of eyes with at least 5 letter gain in visual acuity from baseline, mean visual acuity, mean change in visual acuity, adjusted for baseline mean visual acuity

• For eyes randomized to deferred anti-VEGF, the percentage of eyes needing anti-VEGF treatment

• Comparing optical coherence tomography (OCT) outcomes, such as the mean change in OCT central subfield (CSF) thickness, adjusted for baseline mean thickness

• Comparing the number of eyes with PDR at randomization, proportion of eyes avoiding vitreous hemorrhage or panretinal photocoagulation (PRP) or vitrectomy for PDR between treatment groups

• Comparing safety outcomes between treatment groups

• Comparing associated treatment and follow-up exam costs between treatment groups

Recruitment information / eligibility

• Status: Completed
• Enrollment: 702
• Est. completion date: September 11, 2018
• Est. primary completion date: September 11, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Age >= 18 years

2. Diagnosis of diabetes mellitus (type 1 or type 2)

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 American Diabetes Association (ADA) and/or World Health Organization (WHO) criteria.

3. Able and willing to provide informed consent.

Meets all of the following ocular criteria in at least the one eye:

1. Best corrected E-ETDRS visual acuity letter score = 79 (approximate Snellen equivalent 20/25 or better) at two consecutive visits within 1 to 28 days.

2. On clinical exam, definite retinal thickening due to DME involving the center of the macula.

3. Diabetic macular edema confirmed on OCT (equivalent to CSF thickness on OCT =250 microns on Zeiss Stratus or gender-specific spectral domain OCT equivalent) at two consecutive visits within 1 to 28 days.

(a) Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality.

4. The investigator is comfortable with the eye being randomized to any of the three treatment groups (observation, laser, or anti-VEGF initially).

(a) If focal/grid photocoagulation is contraindicated because all leaking microaneurysms are too close to the fovea or the investigator believes the DME that is present will not benefit from focal/grid photocoagulation, the eye should not be enrolled.

5. Media clarity, pupillary dilation, and individual cooperation sufficient for adequate OCT and fundus photographs.

Exclusion Criteria:

1. History of chronic renal failure requiring dialysis or kidney transplant.

2. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control).

3. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months.

4. Participation in an investigational trial within 30 days of randomization that involved treatment with any drug that has not received regulatory approval for the indication being studied.

(a) Note: study participants cannot receive another investigational drug while participating in the study.

5. Known allergy to any component of the study drug.

6. Blood pressure >180/110 (systolic above 180 OR diastolic above 110). If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual can become eligible.

7. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.

These drugs should not be used during the study.

8. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 24 months.

(a) Women who are potential study participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed.

9. Individual is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the 24 months of the study.

Individual has any of the following ocular characteristics:

1. Macular edema is considered to be due to a cause other than DME.

a) An eye should not be considered eligible if: (1) the macular edema is considered to be related to ocular surgery such as cataract extraction or (2) clinical exam and/or OCT suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or epiretinal membrane) are contributing to the macular edema.

2. An ocular condition is present such that, in the opinion of the investigator, any visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, nonretinal condition).

3. An ocular condition is present (other than DME) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.).

4. Cataract is present that, in the opinion of the investigator, may alter visual acuity during the course of the study.

5. Any history of prior laser or other surgical, intravitreal, or peribulbar treatment for DME (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids, or anti-VEGF).

6. History of topical steroid or nonsteroidal anti-inflammatory drugs (NSAID) treatment within 30 days prior to randomization.

7. History of intravitreal or peribulbar corticosteroid within 4 months prior to randomization for an ocular condition other than DME.

8. Any history of or anticipated need for intravitreal anti-VEGF within the next 6 months for an ocular condition other than DME (e.g. choroidal neovascularization, central retinal vein occlusion, PDR).

9. History of PRP within 4 months prior to randomization or anticipated need for PRP in the 6 months following randomization.

10. Any history of vitrectomy.

11. History of major ocular surgery (cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization.

12. History of YAG capsulotomy performed within 2 months prior to randomization.

13. Aphakia.

14. Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

Related Conditions & MeSH terms

• Diabetic Macular Edema
• Edema
• Macular Edema

Intervention

Procedure:
• Prompt Laser
Focal/grid laser performed at baseline and as needed during follow-up

Drug:
• Prompt aflibercept
Intravitreal injection of 2.0mg aflibercept performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Procedure:
• Deferred laser
Focal/grid laser is initiated while receiving anti-VEGF injections only if certain criteria are met

Drug:
• Deferred aflibercept
Intravitreal injection of 2.0mg aflibercept performed once certain criteria for vision loss are met and then up to every 4 weeks using defined treatment criteria

Locations

Country	Name	City	State
Canada	Alberta Retina Consultants	Edmonton	Alberta
Canada	University Health Network - Toronto Western Hospital	Toronto	Ontario
Canada	UBC/VCHA Eye Care Centre	Vancouver
United States	Eye Associates of New Mexico	Albuquerque	New Mexico
United States	Southwest Retina Specialists	Amarillo	Texas
United States	Kellogg Eye Center, University of Michigan	Ann Arbor	Michigan
United States	Western Carolina Retinal Associates, PA	Asheville	North Carolina
United States	Emory Eye Center	Atlanta	Georgia
United States	Southeast Retina Center, P.C.	Augusta	Georgia
United States	Austin Retina Associates	Austin	Texas
United States	Retina Research Center	Austin	Texas
United States	Elman Retina Group, P.A.	Baltimore	Maryland
United States	Wilmer Eye Institute at Johns Hopkins	Baltimore	Maryland
United States	Retina Associates of Cleveland, Inc.	Beachwood	Ohio
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	Ross Eye Institute, SUNY Buffalo	Buffalo	New York
United States	Retinal Diagnostic Center	Campbell	California
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Charlotte Eye, Ear, Nose and Throat Assoc., PA	Charlotte	North Carolina
United States	Southeastern Retina Associates	Chattanooga	Tennessee
United States	Northwestern Medical Faculty Foundation	Chicago	Illinois
United States	University of Illinois at Chicago Medical Center	Chicago	Illinois
United States	Case Western Reserve University	Cleveland	Ohio
United States	Carolina Retina Center	Columbia	South Carolina
United States	Henry Ford Health System, Dept of Ophthalmology and Eye Care Services	Detroit	Michigan
United States	Medical Associates Clinic, P.C.	Dubuque	Iowa
United States	Retina Vitreous Center	Edmond	Oklahoma
United States	Oregon Retina, LLP	Eugene	Oregon
United States	National Ophthalmic Research Institute	Fort Myers	Florida
United States	NorthShore University HealthSystem	Glenview	Illinois
United States	Retina Vitreous Center	Grand Blanc	Michigan
United States	Retina Specialists of Michigan	Grand Rapids	Michigan
United States	Vitreo-Retinal Associates	Grand Rapids	Michigan
United States	Baylor Eye Physicians and Surgeons	Houston	Texas
United States	Retina and Vitreous of Texas	Houston	Texas
United States	Retina Consultants of Houston, PA	Houston	Texas
United States	Raj Maturi	Indianapolis	Indiana
United States	University of Florida College of Med., Department of Ophthalmology	Jacksonville	Florida
United States	Illinois Retina Associates	Joliet	Illinois
United States	Mid-America Retina Consultants, P.A.	Kansas City	Missouri
United States	Southeastern Retina Associates, PC	Kingsport	Tennessee
United States	Southeastern Retina Associates, P.C.	Knoxville	Tennessee
United States	Florida Retina Consultants	Lakeland	Florida
United States	Family Eye Group	Lancaster	Pennsylvania
United States	Retina and Vitreous Associates of Kentucky	Lexington	Kentucky
United States	Jones Eye Institute/University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Loma Linda University Health Care, Dept. of Ophthalmology	Loma Linda	California
United States	South Coast Retina Center	Long Beach	California
United States	Texas Retina Associates	Lubbock	Texas
United States	University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service	Madison	Wisconsin
United States	Marietta Eye Clinic	Marietta	Georgia
United States	Valley Retina Institute	McAllen	Texas
United States	Bascom Palmer Eye Institute	Miami	Florida
United States	Retina Macula Specialists of Miami	Miami	Florida
United States	Retina Center, PA	Minneapolis	Minnesota
United States	University of Minnesota	Minneapolis	Minnesota
United States	Retina Vitreous Consultants	Monroeville	Pennsylvania
United States	John-Kenyon American Eye Institute	New Albany	Indiana
United States	Retina Group of New England	New London	Connecticut
United States	MaculaCare	New York	New York
United States	The New York Eye and Ear Infirmary/Faculty Eye Practice	New York	New York
United States	The Institute of Ophthalmology and Visual Science (IOVS)	Newark	New Jersey
United States	Retinal and Ophthalmic Consultants, PC	Northfield	New Jersey
United States	New England Retina Associates	Norwich	Connecticut
United States	University Retina and Macula Associates	Oak Forest	Illinois
United States	Ocala Eye Retina Consultants	Ocala	Florida
United States	Magruder Eye Institute	Orlando	Florida
United States	Paducah Retinal Center	Paducah	Kentucky
United States	Southern California Desert Retina Consultants, MC	Palm Desert	California
United States	University of Pennsylvania Scheie Eye Institute	Philadelphia	Pennsylvania
United States	Arizona Retina and Vitreous Consultants	Phoenix	Arizona
United States	Fort Lauderdale Eye Institute	Plantation	Florida
United States	Casey Eye Institute	Portland	Oregon
United States	Retina Northwest, PC	Portland	Oregon
United States	Eyesight Ophthalmic Services, PA	Portsmouth	New Hampshire
United States	University of Kansas Medical Center, Dept. of Ophthalmology	Prairie Village	Kansas
United States	Retina Consultants of Southern California	Redlands	California
United States	Retina Institute of Virginia	Richmond	Virginia
United States	Virginia Commonwealth University, Dept. of Ophthalmology	Richmond	Virginia
United States	Mayo Clinic Department of Ophthalmology	Rochester	Minnesota
United States	Retina Associates of Western New York	Rochester	New York
United States	University of Rochester	Rochester	New York
United States	Retinal Consultants Medical Group, Inc.	Sacramento	California
United States	Andersen Eye Associates	Saginaw	Michigan
United States	The Retina Institute	Saint Louis	Missouri
United States	Retina Associates of Utah, P.C.	Salt Lake City	Utah
United States	Retinal Consultants of San Antonio	San Antonio	Texas
United States	Thomas Eye Group	Sandy Springs	Georgia
United States	California Retina Consultants	Santa Barbara	California
United States	Center for Sight	Sarasota	Florida
United States	Sarasota Retina Institute	Sarasota	Florida
United States	University of Washington Medical Center	Seattle	Washington
United States	Retina Associates, P.A.	Shawnee Mission	Kansas
United States	Spokane Eye Clinic	Spokane	Washington
United States	Retina-Vitreous Surgeons of Central New York, PC	Syracuse	New York
United States	Retina Associates of Florida, P.A.	Tampa	Florida
United States	University of Arizona Medical Center/Department of Ophthalmology	Tucson	Arizona
United States	Carle Foundation Hospital	Urbana	Illinois
United States	Bay Area Retina Associates	Walnut Creek	California
United States	Palmetto Retina Center	West Columbia	South Carolina
United States	Wolfe Eye Clinic	West Des Moines	Iowa
United States	Retinal Consultants of Southern California Medical Group, Inc.	Westlake Village	California
United States	Vitreo-Retinal Associates, PC	Worcester	Massachusetts

Sponsors (4)

Lead Sponsor	Collaborator
Jaeb Center for Health Research	National Eye Institute (NEI), National Institutes of Health (NIH), Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (2)

Baker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, Grover S, Jampol LM, Jhaveri CD, Melia M, Stockdale CR, Martin DF, Sun JK; DRCR Retina Network. Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation — View Citation

Glassman AR, Baker CW, Beaulieu WT, Bressler NM, Punjabi OS, Stockdale CR, Wykoff CC, Jampol LM, Sun JK; DRCR Retina Network. Assessment of the DRCR Retina Network Approach to Management With Initial Observation for Eyes With Center-Involved Diabetic Macular Edema and Good Visual Acuity: A Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2020 Feb 20. doi: 10.1001/jamaophthalmol.2019.6035. [Epub ahead of print] — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Eyes With at Least 5-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).	2 years
Secondary	Number of Eyes With at Least 5-letter Increase or at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).	1 year
Secondary	Change in E-ETDRS Visual Acuity Letter Score From Baseline	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).	1 year
Secondary	Change in E-ETDRS Visual Acuity Letter Score From Baseline Over 2 Years (Area Under the Curve)	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800). The area under the curve (units = letters·years) was divided by 2 years (units = years) to obtain an average change in letter score (units = letters) over the 2-year follow-up.	2 year
Secondary	Change in OCT Central Subfield Thickness From Baseline		2 years
Secondary	Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening	Logarithmic transformation of optical coherence tomography central subfield thickness (CST) is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounding to the nearest hundredth. The change is the change in the log values.	1 year
Secondary	Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease	Center-involved diabetic macular edema defined as follows by central subfield thickness according to optical coherence tomography machine and sex: Heidelberg Spectralis = 305 µm in women and = 320 µm in men, and Zeiss Cirrus = 290 µm in women and = 305 µm in men.	1 year
Secondary	Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant		1 year
Secondary	Number of Eyes With = 2-step Worsening of Diabetic Retinopathy	Includes eyes with baseline severity level of 75 (high-risk proliferative diabetic retinopathy) or less based on reading center grading of color fundus photographs using the Early Treatment Diabetic Retinopathy Study severity scale.	2 years
Secondary	For Eyes Randomized to Initial Laser Photocoagulation and Initial Observation Groups, the Percentage Receiving Aflibercept Treatment		2 years
Secondary	Number of Eyes With at Least 5-, 10-, or 15-letter Decrease in E-ETDRS Visual Acuity Letter Score From Baseline	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).	2 years
Secondary	Change in E-ETDRS Visual Acuity Letter Score From Baseline	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/12) to 0 letters (Snellen equivalent of 20/800).	2 years
Secondary	Change in OCT Central Subfield Thickness From Baseline	Measured using spectral-domain optical coherence tomography (OCT).	1 year
Secondary	Number of Eyes With at Least 1 or 2 Logarithmic-step Central Subfield Thickness Improvement and Worsening	Logarithmic transformation of optical coherence tomography central subfield thickness is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounding to the nearest hundredth. The change is the change in the log values.	2 years
Secondary	Number of Eyes With no Center-involved Diabetic Macular Edema and at Least 10% Central Subfield Thickness Decrease	Center-involved diabetic macular edema defined as follows by central subfield thickness according to optical coherence tomography machine and sex: Heidelberg Spectralis = 305 µm in women and = 320 µm in men, and Zeiss Cirrus = 290 µm in women and = 305 µm in men.	2 years
Secondary	Cumulative Number of Focal/Grid Photocoagulation Sessions Performed Per Participant		2 years
Secondary	Number of Eyes With = 2-step Improvement of Diabetic Retinopathy	Includes eyes with baseline severity level of 35 (mild non-proliferative diabetic retinopathy) or greater based on reading center grading of color fundus photographs using the Early Treatment Diabetic Retinopathy Study severity scale. Excludes eyes with severity level 60 at baseline since improvement is not possible in these eyes.	2 years
Secondary	Cumulative Number of Intraocular Injections of 2.0-mg Aflibercept Received Per Participant		2 years