Intravitreal Ranibizumab for Vitreous Hemorrhage Due to Proliferative Diabetic Retinopathy (N) (N)

An Evaluation of Intravitreal Ranibizumab for Vitreous Hemorrhage Due to Proliferative Diabetic Retinopathy

This study is being conducted to determine if intravitreal injections of ranibizumab decrease the proportion of eyes in which vitrectomy is performed compared with saline injections in eyes presenting with vitreous hemorrhage from proliferative diabetic retinopathy.

Study Overview

• Status: Completed
• Conditions: Proliferative Diabetic Retinopathy; Vitreous Hemorrhage
• Intervention / Treatment: Drug: Saline; Drug: Ranibizumab

Detailed Description

In mild to moderate cases of vitreous hemorrhage, panretinal photocoagulation (PRP) is performed when possible to achieve regression of new vessels or at least stabilization of the neovascularization with no further growth in order to decrease the probability of subsequent vitreous hemorrhage while spontaneous absorption of the hemorrhage occurs. In cases in which the hemorrhage is too dense to apply PRP, vitrectomy is considered to remove the hemorrhage and provide a clear media for application of PRP (often as endolaser photocoagulation) as well as eliminate extensive neovascularization and relieve traction retinal detachments. Pars plana vitrectomy was introduced in the 1970s as a surgical intervention in diabetes for non-clearing vitreous hemorrhage, traction retinal detachment or very severe proliferative diabetic retinopathy (PDR). The goal of vitrectomy in such eyes is to remove the hemorrhage and provide a clear media for application of PRP (often as endolaser photocoagulation) as well as eliminate extensive neovascularization and relieve traction retinal detachments. Many advances in instrumentation and technique have resulted in a dramatic reduction in complications over the last few decades, but surgical complications remain including the following: neovascular glaucoma, retinal detachment, fibrinoid syndrome, endophthalmitis and hypotony with subsequent phthisis bulbi. Recovery for the subject can take up to 6 weeks.

Increased vascular endothelial growth factor (VEGF) levels have been demonstrated in the retina and vitreous of human eyes with diabetic retinopathy, especially PDR. VEGF has been demonstrated to increase vessel permeability by increasing the phosphorylation of tight junction proteins, and has been shown to increase retinal vascular permeability in in vivo models. Anti-VEGF therapy, therefore, may represent a useful therapeutic modality which targets the underlying pathogenesis of PDR while vitreous hemorrhage clears to facilitate the placement of PRP, potentially avoiding vitrectomy.

This study is designed to determine if intravitreal injections of ranibizumab will facilitate clearing of vitreous hemorrhage and avoidance of vitrectomy and its potential complications. Compared with a surgical intervention, use of an intravitreal agent associated with fewer vitrectomies would be preferable because of the reduced costs, reduced time to treatment, reduced intervention time, relatively low risk of side effects, and reduced recovery time. An intravitreal agent also would be a useful alternative for patients who are unwilling to undergo surgery. Furthermore, the study will determine the safety of this medication in the setting of PDR.

• Study Type: Interventional
• Enrollment (Actual): 261
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85014
      • Retinal Consultants of AZ
  • California
    • Irvine, California, United States, 92697
      • University of California, Irvine
    • Loma Linda, California, United States, 92354
      • Loma Linda University Health Care, Dept. of Ophthalmology
    • Palm Springs, California, United States, 92262
      • Southern California Desert Retina Consultants, MC
    • Walnut Creek, California, United States, 94598
      • Bay Area Retina Associates
    • Westlake Village, California, United States, 91361
      • Retinal Consultants of Southern California Medical Group, Inc.
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Health Medical Center
  • Connecticut
    • Trumbull, Connecticut, United States, 06611
      • New England Retina Associates, PC
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • The George Washington University, Department of Ophthalmology
  • Florida
    • Fort Myers, Florida, United States, 33912
      • Retina Consultants of Southwest Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Med., Department of Ophthalmology
    • Lakeland, Florida, United States, 33805
      • Florida Retina Consultants
    • Orlando, Florida, United States, 32803
      • Magruder Eye Institute
    • Sarasota, Florida, United States, 34239
      • Sarasota Retina Institute
    • Venice, Florida, United States, 34285
      • Retina Associates of Sarasota
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Eye Center
    • Atlanta, Georgia, United States, 30342
      • Georgia Retina, P.C.
    • Augusta, Georgia, United States, 30909
      • Southeast Retina Center, P.C.
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Retina Associates of Hawaii, Inc.
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • Raj K. Maturi, M.D., P.C.
    • New Albany, Indiana, United States, 47150
      • American Eye Institute
  • Iowa
    • Dubuque, Iowa, United States, 52002
      • Medical Associates Clinic, P.C.
    • West Des Moines, Iowa, United States, 50266
      • Wolfe Eye Clinic
  • Kansas
    • Leawood, Kansas, United States, 66211
      • Sabates Eye Centers Research Division
  • Kentucky
    • Lexington, Kentucky, United States, 40509-1802
      • Retina and Vitreous Associates of Kentucky
    • Paducah, Kentucky, United States, 42001
      • Paducah Retinal Center
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • Elman Retina Group, P.A.
    • Baltimore, Maryland, United States, 21287-9277
      • Wilmer Eye Institute at Johns Hopkins
    • Baltimore, Maryland, United States, 21287-9177
      • Wilmer Eye Institute at Johns Hopkins
    • Salisbury, Maryland, United States, 21804
      • Retina Consultants of Delmarva, P.A.
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System, Dept of Ophthalmology and Eye Care Services
    • Grand Rapids, Michigan, United States, 49525
      • Vitreo-Retinal Associates
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Retina Center, PA
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Barnes Retina Institute
  • New Jersey
    • Lawrenceville, New Jersey, United States, 08648
      • Delaware Valley Retina Associates
  • New York
    • New York, New York, United States, 10003
      • The New York Eye and Ear Infirmary/Faculty Eye Practice
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine, Dept. of Ophthalmology
    • Orchard Park, New York, United States, 14127
      • Retina Consultants of Western New York
    • Plattsburgh, New York, United States, 12901
      • Eye Care for the Adirondacks
    • Syracuse, New York, United States, 13224
      • Retina-Vitreous Surgeons of Central New York, PC
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7040
      • University of North Carolina, Dept of Ophthalmology
    • Charlotte, North Carolina, United States, 28210
      • Charlotte Eye Ear Nose and Throat Assoc, PA
    • Greensboro, North Carolina, United States, 27401
      • Piedmont Retina Specialists, PA
    • Kansas City, North Carolina, United States, 64111
      • Mid-America Retina Consultants, P.A.
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Eye Center
  • Ohio
    • Beachwood, Ohio, United States, 44122
      • Retina Associates of Cleveland, Inc.
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
    • Columbus, Ohio, United States, 43212
      • OSU Eye Physicians and Surgeons, LLC.
  • Oregon
    • Portland, Oregon, United States, 97210
      • Retina Northwest, PC
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17601-2644
      • Family Eye Group
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Scheie Eye Institute
  • South Carolina
    • Columbia, South Carolina, United States, 29223
      • Carolina Retina Center
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • Southeastern Retina Associates, PC
    • Knoxville, Tennessee, United States, 37909
      • Southeastern Retina Associates, P.C.
  • Texas
    • Abilene, Texas, United States, 79605
      • West Texas Retina Consultants P.A.
    • Austin, Texas, United States, 78705
      • Retina Research Center
    • Houston, Texas, United States, 77025
      • Retina and Vitreous of Texas
    • Houston, Texas, United States, 77030
      • Baylor Eye Physicians and Surgeons
    • Lubbock, Texas, United States, 79424
      • Texas Retina Associates
    • McAllen, Texas, United States, 78503
      • Valley Retina Institute
    • San Antonio, Texas, United States, 78240
      • Medical Center Ophthalmology Associates
    • San Antonio, Texas, United States, 78240
      • Retinal Consultants of San Antonio
  • Virginia
    • Leesburg, Virginia, United States, 20176
      • Virginia Retina Center
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wiconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Subject-level Criteria

Inclusion

To be eligible, the following inclusion criteria must be met:

Age >= 18 years Diagnosis of diabetes mellitus (type 1 or type 2) At least one eye meets the study eye criteria listed below Able and willing to provide informed consent.

Exclusion

A subject is not eligible if any of the following exclusion criteria are present:

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).

A condition that, in the opinion of the investigator, would preclude subject undergoing elective vitrectomy surgery if indicated during the study.

Participation in an investigational trial that involved treatment with any drug within 30 days of randomization that has not received regulatory approval at the time of study entry.

Known allergy to any component of the study drug. Blood pressure > 180/110 (systolic above 180 or diastolic above 110). Myocardial infarction, other cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 4 months prior to randomization.

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

For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 4 months.

Subject is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the 12 months of the study.

Study Eye Criteria

The subject must have at least one eye meeting all of the inclusion criteria and none of the exclusion criteria listed below.

A subject can have only one study eye. If both eyes are eligible at the time of randomization, the study eye will be selected by the investigator and subject before randomization.

The eligibility criteria for a study eye are as follows:

Inclusion

Vitreous hemorrhage causing vision impairment, presumed to be from proliferative diabetic retinopathy, and precluding completion of panretinal photocoagulation (or precluding assessment of completeness of prior PRP).

Immediate vitrectomy not required (investigator and subject are willing to wait at least 8 weeks to see if hemorrhage clears sufficiently without having to proceed to vitrectomy).

Visual acuity is light perception or better.

Exclusion

Prompt vitrectomy indicated, such as because of signs of rhegmatogenous retinal detachment or traction detachment involving the macula present on ultrasound.

Exam evidence of neovascular glaucoma, angle neovascularization, or active neovascularization of the iris (small iris tufts not an exclusion).

History of intravitreal anti-VEGF treatment for vitreous hemorrhage at any time in the past or for an indication other than vitreous hemorrhage in the past 2 months.

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

History of vitrectomy. History of yttrium aluminum garnet capsulotomy performed within 2 months prior to randomization.

Aphakia. Uncontrolled glaucoma (in investigator's judgment). Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Saline Injection; Saline injection at baseline, 4 and 8 weeks	Drug: Saline; Saline injection of 0.5mg at baseline, 4 and 8 weeks
ACTIVE_COMPARATOR: Ranibizumab; Intravitreal injection of 0.5 mg ranibizumab (Lucentis™) at baseline, 4 and 8 weeks	Drug: Ranibizumab; Intravitreal injection of 0.5 mg ranibizumab (Lucentis™) at baseline, 4 and 8 weeks; Other Names: Lucentis

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment or "Failure" Defined as Vitrectomy	The cumulative probabilities of vitrectomy by 16 weks (112 days) in each group were computed using the life-table method. The treatment group comparison was made using the log-rank test. Data were censored at the time point of the participant's last completed visit.	within 112 days of randomization
Safety (Injected-related, Ocular Drug-related and Systemic Drug-related)		Baseline to 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ability to Complete Panretinal Photocoagulation (PRP) in the Absence of Vitrectomy	The proportion of eyes with "complete" panretinal photocoagulation by 16 weeks in abscence of vitrectomy was computed using the life-table method and treatment groups were compared using the log-rank test.	within 112 days of randomization
Extent of Vitreous Hemorrhage Measured by Optical Coherence Tomography Signal Strength	Optical coherence tomography signal strength was evaluated as a potential indicator of vitreous hemorrhage density in an exploratory analysis. This analysis included only eyes with Optical Coherence Tomography (OCT) signal strength equals to 0 at baseline.	4, 8 and 12 weeks
Visual Acuity Adjusted for the Baseline Acuity Regardless of Vitrectomy Status	Visual acuity was analyzed using a longitudinal mixed regression model adjusting for baseline visual acuity.Unit of measure is based on the E-ETDRS visual acuity letter score scale, 0-97, where 0 = worst and 97 = best.	4, 8 and 12 weeks
Visual Acuity Better Than 20/40 and no Vitrectomy Prior to the Visit		4, 8 and 12 weeks
Severe Visual Acuity Loss (Defined as <20/200)		4,8 and 12 weeks
Very Severe Visual Acuity Loss (Defined as <20/800)		4,8 and 12 weeks

Collaborators and Investigators

• Sponsor: Jaeb Center for Health Research
• Collaborators: National Eye Institute (NEI)
• Investigators: Study Director: Adam R. Glassman, MS, Jaeb Center for Health Research; Study Chair: Abdhish Bhavsar, MD, Retina Center, PA

Publications and helpful links

General Publications

• Bhavsar AR, Torres K, Glassman AR, Jampol LM, Kinyoun JL; Diabetic Retinopathy Clinical Research Network. Evaluation of results 1 year following short-term use of ranibizumab for vitreous hemorrhage due to proliferative diabetic retinopathy. JAMA Ophthalmol. 2014 Jul;132(7):889-90. doi: 10.1001/jamaophthalmol.2014.287. No abstract available.
• Diabetic Retinopathy Clinical Research Network*. Randomized clinical trial evaluating intravitreal ranibizumab or saline for vitreous hemorrhage from proliferative diabetic retinopathy. JAMA Ophthalmol. 2013 Mar;131(3):283-93. doi: 10.1001/jamaophthalmol.2013.2015.

Helpful Links

• Jaeb Center for Health Research

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (ACTUAL): February 1, 2012
• Study Completion (ACTUAL): January 1, 2013

Study Registration Dates

• First Submitted: October 14, 2009
• First Submitted That Met QC Criteria: October 14, 2009
• First Posted (ESTIMATE): October 16, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): August 26, 2016
• Last Update Submitted That Met QC Criteria: August 25, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: intravitreal; hemorrhage; Lucentis; vitrectomy; retinopathy; ranibizumab; saline; diabetic; vitreous; proliferative
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Endocrine System Diseases; Diabetic Angiopathies; Diabetes Complications; Diabetes Mellitus; Eye Hemorrhage; Retinal Diseases; Diabetic Retinopathy; Hemorrhage; Vitreous Hemorrhage; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: NEI-151; U10EY018817-03 (U.S. NIH Grant/Contract); U10EY014231-09 (U.S. NIH Grant/Contract)