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Laser-Ranibizumab-Triamcinolone for Proliferative Diabetic Retinopathy (LRTforDME+PRP)

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ClinicalTrials.gov Identifier: NCT00445003
Recruitment Status : Completed
First Posted : March 8, 2007
Results First Posted : July 13, 2011
Last Update Posted : August 26, 2016
Sponsor:
Collaborators:
National Eye Institute (NEI)
Genentech, Inc.
Allergan
Information provided by (Responsible Party):
Jaeb Center for Health Research

Tracking Information
First Submitted Date  ICMJE March 6, 2007
First Posted Date  ICMJE March 8, 2007
Results First Submitted Date  ICMJE April 14, 2011
Results First Posted Date  ICMJE July 13, 2011
Last Update Posted Date August 26, 2016
Study Start Date  ICMJE March 2007
Actual Primary Completion Date October 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 14, 2011)
Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 14 Weeks [ Time Frame: baseline to 14 weeks ]
Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.
Original Primary Outcome Measures  ICMJE
 (submitted: March 6, 2007)
Visual Acuity at 14 weeks adjusted for the baseline acuity.
Change History Complete list of historical versions of study NCT00445003 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 28, 2011)
  • Additional Treatments for Diabetic Macular Edema [ Time Frame: 14 weeks to 56-weeks ]
    Each combination of treatment is only counted once per treatment eye. Participants could have 2 study eyes, with random assignments to different treatments.
  • Change in Optical Coherence Tomography Central Subfield Thickness [ Time Frame: Baseline to 14 weeks ]
  • Total Optical Coherence Tomography Retinal Volume [ Time Frame: Baseline to 14-weeks ]
    Missing/ungradable as follows: Sham = 49, Ranibizumab = 37, Triamcinolone = 39. Visits occured between 70 days and 153 days from randomization adjusted for baseline optical coherence tomography (OCT) retinal volume, OCT retinal thickness and visual acuity, number of planned panretinal photocoagulation sittings, and correlation between 2 study eyes. Confidence intervals are adjusted for multiple comparisons.
  • Change in Visual Acuity From Baseline [ Time Frame: baseline to 56-weeks ]
    Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.
  • Eyes With Anti-vascular Endothelial Growth Factor Treatment for Diabetic Macular Edema [ Time Frame: 14 weeks to 56-weeks ]
  • Number of Eyes With Additional Number of Treatments for Diabetic Macular Edema [ Time Frame: 14 weeks to 56-weeks ]
    Treatments include any type or combination of treatment for diabetic macular edema. Eyes were only counted once, when receiving a combination of treatments.
  • Change in Optical Coherence Tomography Retinal Volume [ Time Frame: Baseline to 14 weeks ]
    Missing or un-gradable data as follows for the sham plus focal/grid/panretinal photocoagulation laser, triamcinolone plus focal/grid panretinal photocoagulation laser, and Ranibizumab groups were 49, 37, and 39, respectively
Original Secondary Outcome Measures  ICMJE
 (submitted: March 6, 2007)
  • Secondary Outcomes at 14 Weeks:
  • Change in retinal thickening from baseline OCT central subfield and retinal volume
  • Presence and extent of new vessels on fundus photographs
  • Vitreous hemorrhage
  • Additional sessions of scatter photocoagulation due to worsening PDR before 14 week visit after completion of initial session
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Laser-Ranibizumab-Triamcinolone for Proliferative Diabetic Retinopathy
Official Title  ICMJE Intravitreal Ranibizumab or Triamcinolone Acetonide as Adjunctive Treatment to Panretinal Photocoagulation for Proliferative Diabetic Retinopathy
Brief Summary The purpose of the study is to find out if treatment with an intravitreal injection of triamcinolone or an intravitreal injection of ranibizumab can prevent loss of vision caused by panretinal photocoagulation treatment. At the present time, it is not known whether intravitreal steroid or anti-vascular endothelial growth factor (anti-VEGF) injections are beneficial in preventing vision loss after panretinal photocoagulation (PRP) treatment. It is possible that one or both of the types of injections will prevent vision loss after PRP treatment. However, it is not known whether the benefits of the injections will outweigh the risks. It is possible that because of side effects, the injections may not be as good as laser alone in treating the diabetic retinopathy.
Detailed Description

Proliferative diabetic retinopathy (PDR) is manifested in retinal neovascularization at the disc (NVD) or elsewhere (NVE). Vitreous hemorrhage or tractional detachment from PDR is a leading cause of severe visual loss and new onset blindness. Without intervention, 60 percent of individuals with diabetic retinopathy will eventually develop PDR, resulting in significant visual loss in nearly fifty percent.

Proliferative diabetic retinopathy is currently treated with panretinal photocoagulation (PRP) which destroys areas of the retina but preserves central vision. PRP is most effectively seen in a regression of new vessels, stabilization of the neovascularization, and reduced risk of visual loss. However, the treatment is associated with unavoidable side effects including macular edema with transient or permanent central vision loss, diminished vision loss, and night vision loss. The treatment applies laser burns to the peripheral retinal tissue, destroying outer photoreceptors and retinal pigment epithelium of the retina, and is thought to exert its effect by increasing oxygen delivery to the inner retina and decreasing viable hypoxic cells which are producing growth factors such as VEGF. Studies have implicated vascular endothelial growth factor (VEGF) as the substance leading to neovascularization and/or increased vascular permeability. Thus, it is reasonable to expect that inhibition of VEGF could reduce both PDR and transient vision loss from macular edema. There are several anti-VEGF drugs. Ranibizumab is the drug to be evaluated in this trial. In one trial of ranibizumab on DME, ten patients with chronic DME received a series of 0.5 mg intraocular injections. The treatments were well tolerated with no ocular or systemic adverse events. Since intraocular injections of ranibizumab significantly reduced foveal thickness and improved visual acuity in all ten patients, there is strong rationale to consider this drug as adjunctive therapy to PRP in a attempt to reduce the acute, transient edema that may occur with PRP.

Similarly, corticosteroids, a class of substances with anti-inflammatory properties, have demonstrated to inhibit the expression of VEGF. Triamcinolone acetonide is often used as a periocular injection for the treatment of cystoid macular edema (CME) secondary to uveitis. Clinically, triamcinolone acetonide is used in the treatment of proliferative vitreoretinopathy and choroidal neovascularization. Studies on patients with proliferative diabetic retinopathy randomly assigned to receive 4 mg triamcinolone 10 to 15 days prior to PRP treatment showed a reduction in central macular thickening, and fluorescein leakage was greater in the injection group than in the control group at 9 and 12 months follow up. Mean visual acuity improved by one line in the injection group and worsened by two lines in the control group.

In summary, there is strong rationale that using either intravitreal ranibizumab or intravitreal triamcinolone acetonide as an adjunct to PRP could reduce the magnitude of vision loss.

This study is being conducted to determine whether intravitreal injection of an anti-VEGF drug or an intravitreal injection of a corticosteroid can reduce the occurrence of macular edema and visual acuity impairment following PRP. Subjects will be randomly assigned with equal probability to one of the following three injection groups:

  • Intravitreal injection of 0.5 mg ranibizumab (Lucentis™) at baseline and 4 weeks
  • Intravitreal injection of 4 mg triamcinolone acetonide at baseline and sham injection at 4 weeks
  • Sham injection at baseline and 4 weeks

The initial injection (or sham) is given on the day of randomization. Focal (macular) photocoagulation is given 7 to 10 days following the injection. Panretinal (scatter) photocoagulation can be initiated either on the same day as the focal photocoagulation (immediately following the focal photocoagulation) or on a subsequent day but must be initiated within 14 days of the baseline injection. Required follow-up visits occur at 4, 14, 34 and 56 weeks.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Proliferative Diabetic Retinopathy
  • Diabetic Macular Edema
Intervention  ICMJE
  • Drug: Ranibizumab
    Intravitreal injection of 0.5 mg ranibizumab at baseline and 4 weeks
    Other Name: Lucentis™
  • Drug: Triamcinolone Acetonide
    Intravitreal injection of 4 mg triamcinolone acetonide at baseline and sham injection at 4 weeks
    Other Name: corticosteroid
  • Behavioral: Sham injection
    Sham injection at baseline and 4 weeks
  • Procedure: Focal/grid laser
    Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
Study Arms  ICMJE
  • Experimental: Sham injection plus laser
    Sham injection at baseline and 4 weeks. Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
    Interventions:
    • Behavioral: Sham injection
    • Procedure: Focal/grid laser
  • Experimental: 0.5mg Ranibizumab plus laser
    Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks. Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
    Interventions:
    • Drug: Ranibizumab
    • Procedure: Focal/grid laser
  • Active Comparator: 4-mg Triamcinolone Acetonide plus Laser
    4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks. Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
    Interventions:
    • Drug: Triamcinolone Acetonide
    • Procedure: Focal/grid laser
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 15, 2011)
333
Original Enrollment  ICMJE
 (submitted: March 6, 2007)
381
Actual Study Completion Date  ICMJE July 2010
Actual Primary Completion Date October 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

General Inclusion Criteria

  • Age >= 18 years
  • Diagnosis of diabetes mellitus (type 1 or type 2)
  • Fellow eye (if not a study eye) meets criteria.
  • Able and willing to provide informed consent. Study Eye Inclusion Criteria Subjects may have one or two study eyes. Subjects with two study eyes will be randomly assigned to receive sham injection at baseline and 4 weeks in one eye and either ranibizumab or triamcinolone in the other eye.
  • Presence of severe nonproliferative or proliferative diabetic retinopathy for which investigator intends to complete panretinal photocoagulation within 49 days after randomization.
  • Diabetic macular edema(DME) present on clinical exam and central subfield thickness on Optical Coherence Tomography (OCT) >250 microns, within 8 days of randomization.
  • Best corrected Electronic-Early Treatment Diabetic Retinopathy Study visual acuity letter score >=24 (i.e., 20/320 or better), within 8 days of randomization.
  • Media clarity, pupillary dilation, and subject cooperation sufficient to administer panretinal photocoagulation and obtain adequate fundus photographs and OCT.
  • If prior macular photocoagulation has been performed, the investigator believes that the study eye may possibly benefit from additional focal photocoagulation.

General Exclusion Criteria

  • Significant renal disease, defined as a 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).
  • Participation in an investigational trial within 30 days of randomization that involved treatment with any drug that has not received regulatory approval at the time of study entry.
  • Known allergy to any component of the study drugs.
  • Blood pressure > 180/110 (systolic above 180 or diastolic above 110).
  • Major surgery within 28 days prior to randomization or major surgery planned during the next 6 months.
  • 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-vascular endothelial growth factor(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 12 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 Exclusion Criteria, Study eye only:

  • Prior panretinal photocoagulation that was sufficiently extensive that the investigator does not believe that at least 1200 additional burns are needed or possible within 49 days after randomization.
  • Macular edema is considered to be due to a cause other than diabetic macular edema.
  • An ocular condition is present such that, in the opinion of the investigator, preventing visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, non-retinal condition).
  • An ocular condition is present (other than diabetes) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., retinal vein or artery occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.).
  • Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye was otherwise normal).
  • History of treatment for DME at any time in the past 4 months (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids, anti-VEGF drugs, or any other treatment).
  • History of major ocular surgery (including vitrectomy, cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization.
  • History of Yttrium Aluminum Garnet capsulotomy performed within 2 months prior to randomization.
  • Aphakia.
  • Intraocular pressure >= 25 mmHg.
  • History of open-angle glaucoma (either primary open-angle glaucoma or other cause of open-angle glaucoma; note: angle-closure glaucoma is not an exclusion criterion).
  • History of steroid-induced intraocular pressure elevation that required intraocular pressure-lowering treatment.
  • History of prior herpetic ocular infection.
  • Exam evidence of ocular toxoplasmosis.
  • Exam evidence of pseudoexfoliation.
  • Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

Fellow Eye Criteria

  • Intraocular pressure < 25 mmHg.
  • No history of open-angle glaucoma (either primary open-angle glaucoma or other cause of open-angle glaucoma; note: angle-closure glaucoma is not an exclusion criterion).
  • No history of steroid-induced intraocular pressure elevation that required intraocular pressure-lowering treatment.
  • No exam evidence of pseudoexfoliation.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00445003
Other Study ID Numbers  ICMJE NEI-134
U10EY018817-03 ( U.S. NIH Grant/Contract )
U10EY014229-07 ( U.S. NIH Grant/Contract )
U10EY014231-09 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Jaeb Center for Health Research
Study Sponsor  ICMJE Jaeb Center for Health Research
Collaborators  ICMJE
  • National Eye Institute (NEI)
  • Genentech, Inc.
  • Allergan
Investigators  ICMJE
Study Chair: Alexander J. Brucker, M.D. Scheie Eye Institute
Study Chair: Joseph Googe, Jr., M.D. Southeastern Retina Associates, P.C.
PRS Account Jaeb Center for Health Research
Verification Date August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP