Prompt Panretinal Photocoagulation Versus Ranibizumab+Deferred Panretinal Photocoagulation for Proliferative Diabetic Retinopathy

Proliferative Diabetic Retinopathy Clinical Trial

— Protocol S  

Official title:

Prompt Panretinal Photocoagulation Versus Intravitreal Ranibizumab With Deferred Panretinal Photocoagulation for Proliferative Diabetic Retinopathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01489189
• Other study ID #: DRCR.net Protocol S
• Status: Completed
• Phase: Phase 3
• Start date: March 2012
• Est. completion date: February 5, 2018

Study information

• Verified date: October 2021
• Source: Jaeb Center for Health Research
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of the protocol is to determine if visual acuity outcomes at 2 years in eyes with proliferative diabetic retinopathy (PDR) that receive anti-vascular endothelial growth factor (anti-VEGF) therapy with deferred panretinal photocoagulation (PRP) are non-inferior to those in eyes that receive standard prompt PRP therapy.

Secondary objectives include:

• Comparing other visual function outcomes (including Humphrey visual field testing and study participant self-reports of visual function) in eyes receiving anti-VEGF with deferred PRP with those in eyes receiving prompt PRP.

• Determining percent of eyes not requiring PRP when anti-VEGF is given in the absence of prompt PRP.

• Comparing safety outcomes between treatment groups.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 305
• Est. completion date: February 5, 2018
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Age >= 18 years -Individuals < 18 years old are not being included because proliferative diabetic retinopathy (PDR) is so rare in this age group that the diagnosis of PDR 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 American Diabetes Association (ADA) and/or World Health Organization (WHO) criteria (see Procedures Manual for definitions) Able and willing to provide informed consent.

Meets at least all of the following ocular criteria criteria:

• Presence of PDR which the investigator intends to manage with PRP alone but for which PRP can be deferred for at least 4 weeks in the setting of intravitreal ranibizumab, in the investigator's judgment.

• Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score > 24 (approximate Snellen equivalent 20/320) on the day of randomization.

• Media clarity, pupillary dilation, and study participant cooperation sufficient to administer PRP and obtain adequate fundus photographs and optical coherence tomography (OCT).

• Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality

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).

• Individuals in poor glycemic control who, within the last 4 months, initiated intensive insulin treatment (a pump or multiple daily injections) or plan to do so in the next 4 months should not be enrolled.

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.

• Study participants cannot receive another investigational drug while participating in the study.

Known allergy to any component of the study drug.

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.

Myocardial infarction, other acute 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.

• These drugs should not be used during the study.

For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 3 years.

• 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 Diabetic Retinopathy Clinical Research Network (DRCR.net) certified clinical center during the 3 years of the study.

Individual has any of the following ocular characteristics:

• History of prior panretinal photocoagulation (prior PRP is defined as = 100 burns outside of the posterior pole)

• Tractional retinal detachment involving the macula.

-- A tractional retinal detachment is not an exclusion if it is outside of the posterior pole (not threatening the macula) and in the investigator's judgment, is not a contraindication to intravitreal ranibizumab treatment and also does not preclude deferring PRP for at least 4 weeks in the setting of intravitreal ranibizumab

• Exam evidence of neovascularization of the angle (neovascularization of the iris alone is not an exclusion if it does not preclude deferring PRP for at least 4 weeks in the investigator's judgment).

• If macular edema is present, it is considered to be primarily due to a cause other than diabetic macular edema.

-- An eye should not be considered eligible if:

• macular edema is present that is considered to be related to ocular surgery such as cataract extraction or

• clinical exam and/or OCT suggest that vitreoretinal interface abnormalities disease (e.g., a taut posterior hyaloid or epiretinal membrane) is the primary cause of any macular edema.

• An ocular condition is present (other than diabetic retinopathy) that, in the opinion of the investigator, might 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.).

-- A vitreous or preretinal hemorrhage is not an exclusion if it is out of the visual axis and in the investigator's judgment is not having any affect on visual acuity.

• 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 were otherwise normal).

• History of intravitreal anti-VEGF treatment at any time in the past 2 months.

• History of corticosteroid treatment (intravitreal or peribulbar) at any time in the past 4 months.

--If the investigator believes that there may still be a substantial effect 4 months after prior treatment (e.g., dose of intravitreal triamcinolone higher than 4 mg), the eye should not be included.

• 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) YAG 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

Related Conditions & MeSH terms

• Diabetic Retinopathy
• Proliferative Diabetic Retinopathy
• Retinal Diseases

Intervention

Other:
• Prompt Panretinal Photocoagulation
Panretinal photocoagulation alone at baseline (full session completed within 56 days).

Drug:
• 0.5-mg Ranibizumab
Intravitreal injection of 0.5 mg ranibizumab (Lucentis™) at baseline and up to every 4 weeks using defined retreatment criteria.

Other:
• Deferred panretinal photocoagulation
PRP is deferred until failure/futility criteria for intravitreal injection are met.

Locations

Country	Name	City	State
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	Retina Associates of Cleveland, Inc.	Beachwood	Ohio
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	Carolina Retina Center	Columbia	South Carolina
United States	Texas Retina Associates	Dallas	Texas
United States	Retina Consultants of Southwest Florida	Fort Myers	Florida
United States	North Shore University Health System	Glenview	Illinois
United States	Retina Vitrous Center	Grand Blanc	Michigan
United States	Penn State College of Medicine	Hershey	Pennsylvania
United States	Baylor Eye Physicians and Surgeons	Houston	Texas
United States	Retina and Vitreous of Texas	Houston	Texas
United States	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana
United States	Southeastern Retina Associates, PC	Kingsport	Tennessee
United States	Southeastern Retina Associates, P.C.	Knoxville	Tennessee
United States	Central Florida Retina Institute	Lakeland	Florida
United States	Family Eye Group	Lancaster	Pennsylvania
United States	Retina and Vitreous Associates of Kentucky	Lexington	Kentucky
United States	Eye Surgical Associates	Lincoln	Nebraska
United States	Loma Linda University Health Care, Dept. of Ophthalmology	Loma Linda	California
United States	Texas Retina Associates	Lubbock	Texas
United States	Valley Retina Institute	McAllen	Texas
United States	Medical College of Wiconsin	Milwaukee	Wisconsin
United States	John-Kenyon American Eye Institute	New Albany	Indiana
United States	The New York Eye and Ear Infirmary/Faculty Eye Practice	New York	New York
United States	Ocala Eye Retina Consultants	Ocala	Florida
United States	Paducah Retinal Center	Paducah	Kentucky
United States	Southern California Desert Retina Consultants, MC	Palm Springs	California
United States	Retinal Consultants of AZ	Phoenix	Arizona
United States	Retina Vitrous Consultants	Pittsburgh	Pennsylvania
United States	Fort Lauderdale Eye Institute	Plantation	Florida
United States	Casey Eye Institute	Portland	Oregon
United States	Retina Northwest, PC	Portland	Oregon
United States	University of Rochester	Rochester	New York
United States	Barnes Retina Institute	Saint Louis	Missouri
United States	Retinal Consultants of San Antonio	San Antonio	Texas
United States	California Retina Consultants	Santa Barbara	California
United States	University of Washington Medical Center	Seattle	Washington
United States	Spokane Eye Clinic	Spokane	Washington
United States	Retina-Vitreous Surgeons of Central New York, PC	Syracuse	New York
United States	New England Retina Associates	Trumbull	Connecticut
United States	Retina Associates of Sarasota	Venice	Florida
United States	Bay Area Retina Associates	Walnut Creek	California
United States	Wolfe Eye Clinic	West Des Moines	Iowa
United States	Vitreo-Retinal Associates, PC	Worcester	Massachusetts

Sponsors (3)

Lead Sponsor	Collaborator
Jaeb Center for Health Research	Genentech, Inc., National Eye Institute (NEI)

Country where clinical trial is conducted

United States, 

References & Publications (15)

Beaulieu WT, Bressler NM, Melia M, Owsley C, Mein CE, Gross JG, Jampol LM, Glassman AR; Diabetic Retinopathy Clinical Research Network. Panretinal Photocoagulation Versus Ranibizumab for Proliferative Diabetic Retinopathy: Patient-Centered Outcomes From a Randomized Clinical Trial. Am J Ophthalmol. 2016 Oct;170:206-213. doi: 10.1016/j.ajo.2016.08.008. Epub 2016 Aug 12. — View Citation

Bressler SB, Beaulieu WT, Glassman AR, Gross JG, Jampol LM, Melia M, Peters MA, Rauser ME; Diabetic Retinopathy Clinical Research Network. Factors Associated with Worsening Proliferative Diabetic Retinopathy in Eyes Treated with Panretinal Photocoagulation or Ranibizumab. Ophthalmology. 2017 Apr;124(4):431-439. doi: 10.1016/j.ophtha.2016.12.005. Epub 2017 Feb 1. Erratum in: Ophthalmology. 2017 Sep;124(9):1427-1430. — View Citation

Bressler SB, Beaulieu WT, Glassman AR, Gross JG, Melia M, Chen E, Pavlica MR, Jampol LM; Diabetic Retinopathy Clinical Research Network. Panretinal Photocoagulation Versus Ranibizumab for Proliferative Diabetic Retinopathy: Factors Associated with Vision and Edema Outcomes. Ophthalmology. 2018 Nov;125(11):1776-1783. doi: 10.1016/j.ophtha.2018.04.039. Epub 2018 Jul 3. — View Citation

Bressler SB, Beaulieu WT, Glassman AR, Gross JG, Melia M, Chen E, Pavlica MR, Jampol LM; Diabetic Retinopathy Clinical Research Network. PHOTOCOAGULATION VERSUS RANIBIZUMAB FOR PROLIFERATIVE DIABETIC RETINOPATHY: Should Baseline Characteristics Affect Choice of Treatment? Retina. 2019 Sep;39(9):1646-1654. doi: 10.1097/IAE.0000000000002377. — View Citation

Glassman AR, Beaulieu WT, Stockdale CR, Beck RW, Bressler NM, Labriola LT, Melia M, Oliver K, Sun JK. Effect of telephone calls from a centralized coordinating center on participant retention in a randomized clinical trial. Clin Trials. 2020 Apr;17(2):195-201. doi: 10.1177/1740774519894229. Epub 2020 Jan 27. — View Citation

Gross JG, Glassman AR, Klein MJ, Jampol LM, Ferris FL 3rd, Bressler NM, Beck RW. Interim Safety Data Comparing Ranibizumab With Panretinal Photocoagulation Among Participants With Proliferative Diabetic Retinopathy. JAMA Ophthalmol. 2017 Jun 1;135(6):672-673. doi: 10.1001/jamaophthalmol.2017.0969. — View Citation

Gross JG, Glassman AR, Liu D, Sun JK, Antoszyk AN, Baker CW, Bressler NM, Elman MJ, Ferris FL 3rd, Gardner TW, Jampol LM, Martin DF, Melia M, Stockdale CR, Beck RW; Diabetic Retinopathy Clinical Research Network. Five-Year Outcomes of Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA Ophthalmol. 2018 Oct 1;136(10):1138-1148. doi: 10.1001/jamaophthalmol.2018.3255. Erratum in: JAMA Ophthalmol. 2019 Apr 1;137(4):467. — View Citation

Gross JG, Glassman AR. A Novel Treatment for Proliferative Diabetic Retinopathy: Anti-Vascular Endothelial Growth Factor Therapy. JAMA Ophthalmol. 2016 Jan;134(1):13-4. doi: 10.1001/jamaophthalmol.2015.5079. — View Citation

Gross JG, Glassman AR. Panretinal Photocoagulation vs Anti-Vascular Endothelial Growth Factor for Proliferative Diabetic Retinopathy-Reply. JAMA Ophthalmol. 2016 Jun 1;134(6):716. doi: 10.1001/jamaophthalmol.2016.0703. — View Citation

Hutton DW, Stein JD, Bressler NM, Jampol LM, Browning D, Glassman AR; Diabetic Retinopathy Clinical Research Network. Cost-effectiveness of Intravitreous Ranibizumab Compared With Panretinal Photocoagulation for Proliferative Diabetic Retinopathy: Secondary Analysis From a Diabetic Retinopathy Clinical Research Network Randomized Clinical Trial. JAMA Ophthalmol. 2017 Jun 1;135(6):576-584. doi: 10.1001/jamaophthalmol.2017.0837. — View Citation

Hutton DW, Stein JD, Glassman AR, Bressler NM, Jampol LM, Sun JK; DRCR Retina Network. Five-Year Cost-effectiveness of Intravitreous Ranibizumab Therapy vs Panretinal Photocoagulation for Treating Proliferative Diabetic Retinopathy: A Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2019 Dec 1;137(12):1424-1432. doi: 10.1001/jamaophthalmol.2019.4284. — View Citation

Jampol LM, Odia I, Glassman AR, Baker CW, Bhorade AM, Han DP, Jaffe GJ, Melia M, Bressler NM, Tanna AP; Diabetic Retinopathy Clinical Research Network. PANRETINAL PHOTOCOAGULATION VERSUS RANIBIZUMAB FOR PROLIFERATIVE DIABETIC RETINOPATHY: Comparison of Peripapillary Retinal Nerve Fiber Layer Thickness in a Randomized Clinical Trial. Retina. 2019 Jan;39(1):69-78. doi: 10.1097/IAE.0000000000001909. — View Citation

Maguire MG, Liu D, Glassman AR, Jampol LM, Johnson CA, Baker CW, Bressler NM, Gardner TW, Pieramici D, Stockdale CR, Sun JK; DRCR Retina Network. Visual Field Changes Over 5 Years in Patients Treated With Panretinal Photocoagulation or Ranibizumab for Proliferative Diabetic Retinopathy. JAMA Ophthalmol. 2020 Mar 1;138(3):285-293. doi: 10.1001/jamaophthalmol.2019.5939. — View Citation

Sun JK, Glassman AR, Beaulieu WT, Stockdale CR, Bressler NM, Flaxel C, Gross JG, Shami M, Jampol LM; Diabetic Retinopathy Clinical Research Network. Rationale and Application of the Protocol S Anti-Vascular Endothelial Growth Factor Algorithm for Proliferative Diabetic Retinopathy. Ophthalmology. 2019 Jan;126(1):87-95. doi: 10.1016/j.ophtha.2018.08.001. Epub 2018 Aug 7. — View Citation

Writing Committee for the Diabetic Retinopathy Clinical Research Network, Gross JG, Glassman AR, Jampol LM, Inusah S, Aiello LP, Antoszyk AN, Baker CW, Berger BB, Bressler NM, Browning D, Elman MJ, Ferris FL 3rd, Friedman SM, Marcus DM, Melia M, Stockdale — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Change in Visual Acuity From Baseline	Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart.	2-years
Secondary	Mean Visual Acuity	Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart.	2-years
Secondary	Number of Eyes With Greater Than or Equal to 10 Letter Vision Gain		2-years
Secondary	Humphrey Visual Field Test Cumulative Score Change From Baseline	Visual fields, collected using the Humphrey Visual Field analyzer, measured the total point score (sum of retinal sensitivities of all points) tested on 30-2 and 60-4 patterns, which included the mid-peripheral and peripheral visual fields. A lower score indicates greater visual field loss.The cumulative score is the sum of all visual field sensitivity values for each of the four individual quadrants of the visual field (the quadrants are divided by the horizontal and vertical lines). The range can be from 0 to about 600 for the 30-2 test [for each quadrant], and from 0 to about 400 or 450 for the peripheral test.	2-years
Secondary	Frequency of Vitrectomy		2-years
Secondary	Mean Change in OCT Central Subfield Thickness From Baseline	All baseline and 2-year optical coherence tomography (OCT) scans were evaluated by the OCT reading center.	2-years
Secondary	Development of Central DME With Vision Impairment by 2-years		2-years
Secondary	Number of Eyes With Vitreous Hemorrhage		2-years
Secondary	Number of Eyes Without Active or Regressed Neovascularization on Fundus Photography at 2-years		2-years
Secondary	Number of Eyes With Greater Than or Equal to 10 Letter Vision Loss		2-year