Phase II Combination Steroid and Anti-VEGF for Persistent DME

NCT01945866 | Completed Phase 2 Results DMC

• 4 other identifiers: DRCR.net Protocol UEY14231EY23207EY18817
• Study Type: interventional
• Target: 129
• Locations: 1 country
• Sites: 56

Brief Summary

Although anti-vascular endothelial growth factor (VEGF) therapy is generally effective as treatment for center-involved diabetic macular edema (DME), a substantial proportion of anti-VEGF-treated eyes with DME do not achieve vision of 20/20 or complete resolution of retinal thickening. Indeed, over 50% of ranibizumab-treated eyes did not achieve a 2 or more line improvement in visual acuity from baseline at 2 years in Protocol I, a previous DRCR.net (Diabetic Retinopathy Clinical Research Network) study. Furthermore, 27% of ranibizumab-treated eyes still had central subfield (CSF) thickness on time-domain optical coherence tomography (OCT) ≥ 300 at 1 year, and more than 40% of ranibizumab-treated eyes did not achieve complete resolution of retinal thickening (\< 250 microns) by 2 years. Thus, there is a need for alternative or additional treatments that will improve vision by reducing retinal edema in eyes with persistent DME following previous anti-VEGF therapy. Intravitreal steroid is not as efficacious as ranibizumab in eyes with DME overall, but it has been shown to have a positive effect for DME in some eyes and might add benefit in eyes that are already receiving anti-VEGF. The main objective of this study is to assess the short-term effects of combination steroid+anti-VEGF therapy on visual acuity and retinal thickness on OCT in comparison with that of continued anti-VEGF therapy alone in eyes with persistent central-involved DME and visual acuity impairment despite previous anti-VEGF treatment. This study will provide important information for the design of a future confirmatory phase III clinical trial on the efficacy of combination steroid and anti-VEGF in eyes with persistent DME and vision impairment following previous anti-VEGF therapy. The primary outcome for efficacy will be the mean change in visual acuity at 24 weeks. Each study eye is required to complete a 12-week run-in phase. The run-in phase will identify study eyes that truly have persistent DME despite anti-VEGF therapy by requiring an additional 3 injections while also collecting standardized visual acuity and OCT measurements. At the enrollment, 4-week and 8-week visits of the run-in phase, enrolled eyes will receive an intravitreal injection of ranibizumab 3mg. Then at the 12-week run-in visit, if the eye still has persistent DME, it will be randomized to receive either intravitreal sham+intravitreal ranibizumab 0.3 or intravitreal dexamethasone+intravitreal ranibizumab 0.3 injections. The randomized study duration is 24 week, during which a protocol visit takes place every month. The combination injections of sham+ranibizumab or dexamethasone +ranibizumab will be given at the randomization visit (baseline) and at the 12-week visit after randomization. In between, an intravitreal injection of ranibizumab only will be given to study eyes at the 4, 8, 16 and 20 week visits.

Conditions

Diabetic Macular Edema

Keywords

Diabetic Macular Edema; Anti-vascular endothelial growth factor; Dexamethasone Intravitreal implant; Ranibizumab intravitreal injection

Outcome Measures

Primary Outcomes (1)

• Mean Change in Visual Acuity Letter Score

  At 24 weeks after randomization, mean change in visual acuity letter score, adjusted for visual acuity at time of randomization

  24 weeks after randomization

Secondary Outcomes (6)

• At 24 Weeks After Randomization, Number of Eyes With at Least 10 and at Least 15 Letter Gain (Increase) or Loss (Decrease) in E-ETDRS Letter Score Visual Acuity.

  24 weeks weeks after randomization

• Visual Acuity Area Under the Curve (AUC) Between Randomization and 24 Weeks

  24 weeks after randomization

• Mean Change in OCT CSF Thickness, Adjusted for Thickness at Time of Randomization

  24 weeks after randomization

• Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness

  24 weeks after randomization

• Eyes With OCT CSF Thickness < the Gender-specific Spectral Domain OCT Equivalent of 250 Microns on Zeiss Stratus

  24 weeks after randomization

Study Arms (2)

Sham + intravitreal ranibizumab 0.3 mg

ACTIVE COMPARATOR

Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria.

Drug: intravitreal ranibizumab 0.3 mg; Procedure: Sham injection

Intravitreal dexamethasone+intravitreal ranibizumab 0.3mg

EXPERIMENTAL

The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first.

Drug: intravitreal ranibizumab 0.3 mg; Drug: dexamethasone intravitreal implant

Interventions

intravitreal ranibizumab 0.3 mg DRUG

Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria

Also known as: Lucentis

Intravitreal dexamethasone+intravitreal ranibizumab 0.3mg; Sham + intravitreal ranibizumab 0.3 mg

dexamethasone intravitreal implant DRUG

The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first.

Also known as: Ozurdex

Intravitreal dexamethasone+intravitreal ranibizumab 0.3mg

Sham injection PROCEDURE

No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.

Sham + intravitreal ranibizumab 0.3 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years i) Individuals \<18 years old are not being included because DME is so rare in this age group that the diagnosis of DME may be questionable.
• 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:
• Current regular use of insulin for the treatment of diabetes
• Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes
• Documented diabetes by ADA (American Diabetes Association) and/or WHO (World Health Organization) criteria
• At least one eye meets the study eye criteria listed below.
• Fellow eye (if not a study eye) meets criteria.
• Able and willing to provide informed consent.
• Meets all of the following ocular criteria in at least the one eye:
• At least 3 injections of anti-VEGF drug (ranibizumab, bevacizumab, or aflibercept) within the prior 20 weeks.
• Visual acuity letter score in study eye ≤ 78 and ≥24 (approximate Snellen equivalent 20/32 to 20/320).
• On clinical exam, definite retinal thickening due to DME involving the center of the macula.
• OCT CSF thickness, within 8 days of enrollment:
• i) On Zeiss Cirrus ≥ 290 microns in women; ≥ 305 in men ii) On Heidelberg Spectralis: ≥ 305 microns in women; ≥ 320 in men

You may not qualify if:

• History of chronic renal failure requiring dialysis or kidney transplant.
• 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).
• 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.
• Participation in an investigational trial within 30 days of enrollment that involved treatment with any drug that has not received regulatory approval for the indication being studied. Note: study participants cannot receive another investigational drug while participating in the study.
• Known allergy to any component of the study drugs (including povidone iodine prep).
• Blood pressure \> 180/110 (systolic above 180 OR diastolic above 110). If blood pressure is brought below 180/110 by anti-hypertensive treatment, the individual can become eligible.
• Myocardial infarction, other acute cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 1 month prior to enrollment.
• Systemic steroid, anti-VEGF or pro-VEGF treatment within 4 months prior to enrollment or anticipated use during the study. These drugs cannot be used during the study.
• For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 9 months. 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.
• Individual is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the next 9 months.
• Macular edema is considered to be due to a cause other than DME. 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 the primary cause of the macular edema.
• An ocular condition is present such that, in the opinion of the investigator, visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, non-retinal condition, etc.).
• 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.).
• Substantial posterior capsule opacity that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e., opacity would be reducing acuity to 20/40 or worse if eye was otherwise normal).
• History of intravitreal anti-VEGF drug within 21 days prior to enrollment.

Sponsors & Collaborators

• Jaeb Center for Health Research: lead
• Allergan: collaborator
• Genentech, Inc.: collaborator
• National Eye Institute (NEI): collaborator

Study Sites (56)

Retina-Vitreous Associates Medical Group

Beverly Hills, California, 90211, United States

Location

Atlantis Eye Care

Huntington Beach, California, 92647, United States

Location

Loma Linda University Health Care, Dept. of Ophthalmology

Loma Linda, California, 92354, United States

Location

Northern California Retina Vitreous Associates

Mountain View, California, 94040, United States

Location

Retina Consultants of Southern California

Redlands, California, 92374, United States

Location

Retinal Consultants Medical Group, Inc.

Sacramento, California, 95841, United States

Location

California Retina Consultants

Santa Barbara, California, 93103, United States

Location

Bay Area Retina Associates

Walnut Creek, California, 94598, United States

Location

Retina Group of New England

New London, Connecticut, 06320, United States

Location

New England Retina Associates

Norwich, Connecticut, 06360, United States

Location

National Ophthalmic Research Institute

Fort Myers, Florida, 33912, United States

Location

University of Florida College of Med., Department of Ophthalmology

Jacksonville, Florida, 32209, United States

Location

Central Florida Retina Institute

Lakeland, Florida, 33805, United States

Location

Ocala Eye Retina Consultants

Ocala, Florida, 34474, United States

Location

Sarasota Retina Institute

Sarasota, Florida, 34239, United States

Location

Retina Associates of Florida, P.A.

Tampa, Florida, 33609, United States

Location

Southeast Retina Center, P.C.

Augusta, Georgia, 30909, United States

Location

Thomas Eye Group

Sandy Springs, Georgia, 30328, United States

Location

Raj K. Maturi, M.D., P.C.

Indianapolis, Indiana, 46290, United States

Location

Medical Associates Clinic, P.C.

Dubuque, Iowa, 52002, United States

Location

Wolfe Eye Clinic

West Des Moines, Iowa, 50266, United States

Location

Retina Associates, P.A.

Shawnee Mission, Kansas, 66204, United States

Location

Elman Retina Group, P.A.

Baltimore, Maryland, 21237, United States

Location

National Eye Institute/National Institutes of Health

Bethesda, Maryland, 20892-2510, United States

Location

Ophthalmic Consultants of Boston

Boston, Massachusetts, 02114, United States

Location

Joslin Diabetes Center

Boston, Massachusetts, 02215, United States

Location

Retina Vitreous Center

Grand Blanc, Michigan, 48439, United States

Location

Retina Specialists of Michigan

Grand Rapids, Michigan, 49525, United States

Location

Retina Center, PA

Minneapolis, Minnesota, 55404, United States

Location

The Retina Institute

St Louis, Missouri, 63128, United States

Location

The Institute of Ophthalmology and Visual Science (IOVS)

Newark, New Jersey, 07103, United States

Location

MaculaCare

New York, New York, 10021, United States

Location

Retina Associates of Western New York

Rochester, New York, 14618, United States

Location

University of Rochester

Rochester, New York, 14642, United States

Location

Charlotte Eye Ear Nose and Throat Assoc, PA

Charlotte, North Carolina, 28210, United States

Location

Retina Associates of Cleveland, Inc.

Beachwood, Ohio, 44122, United States

Location

Case Western Reserve University

Cleveland, Ohio, 44106, United States

Location

Retina Northwest, PC

Portland, Oregon, 97210, United States

Location

Casey Eye Institute

Portland, Oregon, 97239, United States

Location

University of Pennsylvania Scheie Eye Institute

Philadelphia, Pennsylvania, 19104, United States

Location

Southeastern Retina Associates, P.C.

Knoxville, Tennessee, 37909, United States

Location

Southwest Retina Specialists

Amarillo, Texas, 79106, United States

Location

Austin Retina Associates

Austin, Texas, 78705, United States

Location

Retina Research Center

Austin, Texas, 78705, United States

Location

Retina and Vitreous of Texas

Houston, Texas, 77025, United States

Location

Baylor Eye Physicians and Surgeons

Houston, Texas, 77030, United States

Location

Retina Consultants of Houston, PA

Houston, Texas, 77030, United States

Location

Texas Retina Associates

Lubbock, Texas, 79424, United States

Location

Valley Retina Institute

McAllen, Texas, 78503, United States

Location

Retinal Consultants of San Antonio

San Antonio, Texas, 78240, United States

Location

Retina Associates of Utah, P.C.

Salt Lake City, Utah, 84107, United States

Location

Virginia Retina Center

Leesburg, Virginia, 20176, United States

Location

Retina Institute of Virginia

Richmond, Virginia, 23235, United States

Location

University of Washington Medical Center

Seattle, Washington, 98195, United States

Location

Spokane Eye Clinic

Spokane, Washington, 99204, United States

Location

University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service

Madison, Wisconsin, 53705, United States

Location

Related Publications (1)

• Maturi RK, Glassman AR, Liu D, Beck RW, Bhavsar AR, Bressler NM, Jampol LM, Melia M, Punjabi OS, Salehi-Had H, Sun JK; Diabetic Retinopathy Clinical Research Network. Effect of Adding Dexamethasone to Continued Ranibizumab Treatment in Patients With Persistent Diabetic Macular Edema: A DRCR Network Phase 2 Randomized Clinical Trial. JAMA Ophthalmol. 2018 Jan 1;136(1):29-38. doi: 10.1001/jamaophthalmol.2017.4914.

  PMID: 29127949 RESULT

MeSH Terms

Interventions

Ranibizumab; Dexamethasone; Calcium Dobesilate; salicylhydroxamic acid

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Results Point of Contact

• Title: Adam Glassman
• Organization: Jaeb Center for Health Research

drcrnet@jaeb.org

8139758690

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 12, 2013
• First Posted: September 19, 2013
• Study Start: February 1, 2014
• Primary Completion: June 5, 2017
• Study Completion: June 5, 2017
• Last Updated: September 25, 2018
• Results First Posted: September 25, 2018

Record last verified: 2018-09

Locations

US (56)