Clinical trial NCT01969708: Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2)
Official title: Study of COmparative Treatments for REtinal Vein Occlusion 2 [SCORE2]: a Multicenter, Prospective, Randomized Non-inferiority Trial of Eyes With Macular Edema Secondary to Central Retinal Vein Occlusion, Comparing Intravitreal Bevacizumab Every 4 Weeks With Intravitreal Aflibercept Every 4 Weeks.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Central Retinal Vein Occlusion
Lead sponsor: The Emmes Company, LLC
Sponsor class: INDUSTRY
Collaborators: name: National Eye Institute (NEI)
name: Milton S. Hershey Medical Center
name: University of Wisconsin, Madison
First posted: 2013-10-25
Enrollment: 362
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: SCORE2 is a multicenter, prospective, randomized, phase III clinical trial in which all participants enrolled will be followed for up to 2.5 years. SCORE2 is designed as a non-inferiority trial, with study eyes randomized to intravitreal bevacizumab (1.25 mg) every 4 weeks vs. intravitreal aflibercept (2.0 mg) every 4 weeks. SCORE2 aims to determine if bevacizumab is non-inferior to aflibercept for the treatment of macular edema associated with central retinal vein occlusion (CRVO), with the primary outcome of visual acuity measured at Month 6.

Detailed description: The primary objective of SCORE2 is to test for non-inferiority based on mean change from baseline in visual acuity letter score at Month 6 for eyes randomized to intravitreal bevacizumab every 4 weeks compared with eyes randomized to intravitreal aflibercept every 4 weeks using a non-inferiority margin of 5 letters.

Secondary objectives of SCORE2 are to:

* compare the bevacizumab and the aflibercept groups with regards to central retinal thickness, as measured with spectral domain optical coherence tomography (SD-OCT), at Month 6 and change between baseline and Month 6;
* assess Month 12 visual acuity and SD-OCT outcomes associated with different dosing strategies after Month 6 in participants who respond well to treatment;
* assess Month 12 visual acuity and SD-OCT outcomes associated with alternative treatment strategies after Month 6 in participants who respond poorly to treatment;
* compare area of retinal ischemia and rates of neovascular complications of CRVO in the bevacizumab vs. aflibercept groups;
* add to our knowledge of the safety profile of these anti-vascular endothelial growth factor (VEGF) medications in the setting of eyes with macular edema secondary to CRVO;
* conduct a cost effectiveness analysis comparing intravitreal bevacizumab to intravitreal aflibercept to assess the economic implications from a payor perspective using decision analytic methods.

Other exploratory aims of SCORE2 are to:

* investigate the correlation of features identified through SD-OCT segmentation analysis, such as the inner segment-outer segment (IS-OS) junction (also known as the ellipsoid zone), with such characteristics as visual acuity and central retinal thickness;
* investigate the correlation of area of peripheral retinal nonperfusion from widefield fluorescein angiography with visual acuity and central retinal thickness, and the prognostic value of baseline peripheral and central retina perfusion status in predicting disease course and treatment responsiveness;
* investigate the correlation of features on adaptive optics imaging with such characteristics as visual acuity and central retinal thickness.

Eligibility criteria: Inclusion Criteria:

* Participants must have center-involved macular edema secondary to CRVO. Eyes may be enrolled as early as the time of diagnosis of the macular edema. The definition of CRVO used in SCORE will also be used for the purposes of SCORE2: a CRVO is defined as an eye that has retinal hemorrhage or other biomicroscopic evidence of retinal vein occlusion (e.g., telangiectatic capillary bed) and a dilated venous system (or previously dilated venous system) in all 4 quadrants.
* Due to the similarities of a hemiretinal vein occlusion (HRVO) to CRVO,HRVO will be classified as CRVO for the purposes of this clinical trial. Eyes classified as having a HRVO will be limited to no more than 25% of the planned sample size. A HRVO is defined as an eye that has retinal hemorrhage or other biomicroscopic evidence of retinal vein occlusion (e.g. telangiectatic capillary bed) and a dilated venous system (or previously dilated venous system) in 5 or more clock hours but less than all 4 quadrants. Typically, a HRVO is a retinal vein occlusion that involves 2 altitudinal quadrants.
* E-Early Treatment Diabetic Retinopathy Study (ETDRS)visual acuity score of greater than or equal to 19 letters (approximately 20/400) and less than or equal to 73 letters (approximately 20/40) by the ETDRS visual acuity protocol. The investigator must believe that a study eye with visual acuity between 19 and 33 letters is perfused.
* Retinal thickness on SD-OCT measurement, defined as central subfield thickness of 300 µm or greater. If the SD-OCT measurement is taken from a Heidelberg Spectralis Machine, the central subfield thickness should be 320 µm or greater.
* Media clarity, pupillary dilation and participant cooperation sufficient for adequate fundus photographs.

Exclusion Criteria:

* A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., chronic alcoholism or drug abuse, personality disorder or use of major tranquilizers indicating difficulty in long term follow-up, likelihood of survival of less than 12 months).
* Participation in an investigational trial within 30 days of study entry that involved treatment with any drug that has not received regulatory approval at time of study entry.
* History of allergy to any anti-VEGF agent, corticosteroid, or component of the delivery vehicle.
* The participant will be moving out of the area of the clinical site to an area not covered by another clinical site during the 12 months of the study.
* Positive urine pregnancy test: all women of childbearing potential (those who are pre-menopausal and not surgically sterilized) may participate only if they have a negative urine pregnancy test, and if they do not intend to become pregnant during the timeframe of the study. Women who are sexually active with a male partner must agree to use at least one of the following birth control methods: hormonal therapy such as oral, implantable or injectable chemical contraceptives; mechanical therapy such as spermicide in conjunction with a barrier such as a condom or diaphragm; intrauterine device (IUD); or surgical sterilization of partner.
* Women who are breast-feeding.
* Examination evidence of vitreoretinal interface disease (e.g., vitreomacular traction, epiretinal membrane), either on clinical examination or OCT thought to be contributing to macular edema.
* An eye that, in the investigator's opinion, would not benefit from resolution of macular edema such as eyes with foveal atrophy, dense pigmentary changes or dense subfoveal hard exudates.
* Presence of an ocular condition that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., age-related macular degeneration, uveitis or other ocular inflammatory disease, neovascular glaucoma, iris neovascularization, Irvine-Gass Syndrome, prior macula-off rhegmatogenous retinal detachment).
* Presence of a substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e., a 20/40 cataract).
* History of laser photocoagulation for macular edema within 3 months prior to randomization.
* History of intravitreal corticosteroid within 4 months of randomization.
* Intravitreal anti-VEGF injection within 2 months of randomization. Note: Enrollment will be limited to no more than 25% of the planned sample size with any history of anti-VEGF treatment. Once this number of eyes has been enrolled, any history of anti-VEGF treatment will be an exclusion criterion. For enrollment of study eyes with prior intravitreal anti-VEGF agents, in the opinion of the investigator, the treatment response to prior anti-VEGF treatment must be either incomplete or the study eye had developed recurrent CRVO-associated macular edema, such that the study eye would benefit from additional anti-VEGF treatment.
* History of peribulbar or retrobulbar corticosteroid use for any reason within 2 months prior to randomization.
* History of panretinal scatter photocoagulation (PRP) or sector laser photocoagulation within 3 months prior to randomization or anticipated within the next 3 months following randomization.
* History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within 4 months prior to randomization or anticipated within the next 6 months following randomization.
* History of yttrium aluminum garnet (YAG) capsulotomy performed within 2 months prior to randomization.
* Aphakia.
* Presence of an anterior chamber intraocular lens
* Examination evidence of external ocular infection, including conjunctivitis, chalazion or significant blepharitis.
* History of macular detachment.
* Examination evidence of any diabetic retinopathy.

Primary outcomes:
measure: Mean Change From Baseline in Best-corrected Early Treatment Diabetic Retinopathy Study (ETDRS) Visual Acuity Letter Score at Month 6
timeFrame: Month 0 to 6
Secondary outcomes:
measure: Number of Study Eyes With Gain of ≥15 Letters in Visual Acuity Letter Score at Month 6
timeFrame: Month 0 to 6
measure: Number of Study Eyes With Visual Acuity Letter Score of 70 or Better at Month 6
timeFrame: Month 0 to 6
measure: Mean Spectral-domain Optical Coherence Tomography Central Subfield Thickness
timeFrame: Month 0 to 6
measure: Mean Change From Baseline in Spectral Domain Optical Coherence Tomography Central Subfield Thickness at Month 6
timeFrame: Month 0 to 6
measure: Number of Study Eyes With Central Subfield Thickness <300 μm, no Subretinal Fluid, no Intraretinal Fluid, and no Cystoid Spaces
timeFrame: Month 0 to 6
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Retinal Consultants of AZ
state: Arizona
city: Tucson
country: United States
facility: Retina Centers, P.C.
state: Arizona
city: Mountain View
country: United States
facility: Northern California Retina Vitreous Associates
state: California
city: Oakland
country: United States
facility: East Bay Retina Consultants, Inc.
state: California
city: Palm Desert
country: United States
facility: Southern California Desert Retina Consultants
state: California
city: Sacramento
country: United States
facility: University of California Davis, Medical Center
state: California
city: Sacramento
country: United States
facility: Retinal Consultants Medical Group, Inc.
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: New London
country: United States
facility: New England Retina Associates
state: Connecticut
city: Fort Lauderdale
country: United States
facility: Retina Group of Florida
state: Florida
city: Fort Myers
country: United States
facility: National Ophthalmic Research Institute
state: Florida
city: Jacksonville
country: United States
facility: University of Florida, Dept of Ophthalmology
state: Florida
city: Lakeland
country: United States
facility: Florida Retina Consultants
state: Florida
city: Sarasota
country: United States
facility: Sarasota Retina Institute
state: Florida
city: Winter Haven
country: United States
facility: Center for Retina and Macular Disease
state: Florida
city: Winter Haven
country: United States
facility: Florida Retina Consultants
state: Florida
city: Atlanta
country: United States
facility: Emory University Eye Center
state: Georgia
city: Augusta
country: United States
facility: Southeast Retina Center
state: Georgia
city: Marietta
country: United States
facility: Georgia Retina, P.C.
state: Georgia
city: Chicago
country: United States
facility: Illinois Eye and Ear Infirmary UIC Dept. of Ophthalmology
state: Illinois
city: Indianapolis
country: United States
facility: Thomas A. Ciulla, MD, PC
state: Indiana
city: Leawood
country: United States
facility: Sabates Eye Centers
state: Kansas
city: Shawnee Mission
country: United States
facility: Retina Associates, PA
state: Kansas
city: Lexington
country: United States
facility: Retina Associates of Kentucky
state: Kentucky
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Paducah
country: United States
facility: Paducah Retinal Center
state: Kentucky
city: Baltimore
country: United States
facility: Elman Retina Group, PA
state: Maryland
city: Chevy Chase
country: United States
facility: The Retina Group of Washington
state: Maryland
city: Glen Burnie
country: United States
facility: Elman Retina Group, P.A.
state: Maryland
city: Hagerstown
country: United States
facility: Cumberland Valley Retina Consultants
state: Maryland
city: Pikesville
country: United States
facility: Elman Retina Group, P.A.
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Jackson
country: United States
facility: TLC Eyecare & Laser Centers
state: Michigan
city: Minneapolis
country: United States
facility: VitreoRetinal Surgery
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: The Retina Institute
state: Missouri
city: Omaha
country: United States
facility: UNMC Truhlsen Eye Institute
state: Nebraska
city: Las Vegas
country: United States
facility: Retina Consultants of Nevada
state: Nevada
city: Lawrenceville
country: United States
facility: Delaware Valley Retina Associates
state: New Jersey
city: New Brunswick
country: United States
facility: NJ Retina
state: New Jersey
city: New York
country: United States
facility: New York Eye and Ear Infirmary
state: New York
city: Rochester
country: United States
facility: Retina Associates of Western New York
state: New York
city: Rochester
country: United States
facility: University of Rochester Flaum Eye Institute
state: New York
city: Syracuse
country: United States
facility: Retina Vitreous Surgeon of CNY, PC
state: New York
city: Charlotte
country: United States
facility: Charlotte Eye Ear Nose & Throat Associates, P.A.
state: North Carolina
city: Statesville
country: United States
facility: Charlotte Eye Ear Nose & Throat Associates, P.A.
state: North Carolina
city: Cleveland
country: United States
facility: Retina Associates of Cleveland, Inc.
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Oklahoma City
country: United States
facility: Dean McGee Eye Institute
state: Oklahoma
city: Portland
country: United States
facility: Retina Northwest, PC
state: Oregon
city: Portland
country: United States
facility: Casey Eye Institute / OHSU
state: Oregon
city: Monroeville
country: United States
facility: Retina Vitreous Consultants
state: Pennsylvania
city: Philadelphia
country: United States
facility: Scheie Eye Institute
state: Pennsylvania
city: Florence
country: United States
facility: Carolinas Centers for Sight, PC
state: South Carolina
city: West Columbia
country: United States
facility: Palmetto Retina Center
state: South Carolina
city: Rapid City
country: United States
facility: Black Hills Regional Eye Institute
state: South Dakota
city: Knoxville
country: United States
facility: Southeastern Retina Associates, PC
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Retina, PC
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Eye Institute
state: Tennessee
city: Abilene
country: United States
facility: Retina Research Institute of Texas
state: Texas
city: Arlington
country: United States
facility: Texas Retina Associates
state: Texas
city: Austin
country: United States
facility: The Retina Research Center
state: Texas
city: Dallas
country: United States
facility: Texas Retina Associates
state: Texas
city: Houston
country: United States
facility: Charlotte Eye Ear Nose & Throat Associates, P.A.
state: Texas
city: Houston
country: United States
facility: Retina & Vitreous of Texas
state: Texas
city: Houston
country: United States
facility: Retina Consultants of Houston, PA
state: Texas
city: McAllen
country: United States
facility: Valley Retina Institute, PA
state: Texas
city: San Antonio
country: United States
facility: Medical Center Ophthalmology Associates
state: Texas
city: San Antonio
country: United States
facility: Retinal Consultants of San Antonio
state: Texas
city: Fairfax
country: United States
facility: The Retina Group of Washington
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Penn State College of Medicine
name: Ingrid U Scott, M.D., M.P.H.
role: STUDY_CHAIR
References:
citation: Scott IU, VanVeldhuisen PC, Ip MS, Blodi BA, Oden NL, Figueroa M; SCORE2 Investigator Group. SCORE2 Report 1: Techniques to Optimize Recruitment in Phase III Clinical Trials of Patients With Central Retinal Vein Occlusion. Am J Ophthalmol. 2016 Oct;170:25-31. doi: 10.1016/j.ajo.2016.07.011. Epub 2016 Jul 19.
citation: Scott IU, VanVeldhuisen PC, Ip MS, Blodi BA, Oden NL, Figueroa M, Dugel PU; SCORE2 Investigator Group. SCORE2 Report 2: Study Design and Baseline Characteristics. Ophthalmology. 2017 Feb;124(2):245-256. doi: 10.1016/j.ophtha.2016.09.038. Epub 2016 Nov 15.
citation: Scott IU, VanVeldhuisen PC, Ip MS, Blodi BA, Oden NL, King J, Antoszyk AN, Peters MA, Tolentino M; SCORE2 Investigator Group. Baseline Factors Associated With 6-Month Visual Acuity and Retinal Thickness Outcomes in Patients With Macular Edema Secondary to Central Retinal Vein Occlusion or Hemiretinal Vein Occlusion: SCORE2 Study Report 4. JAMA Ophthalmol. 2017 Jun 1;135(6):639-649. doi: 10.1001/jamaophthalmol.2017.1141.
citation: Scott IU, Figueroa MJ, Oden NL, Ip MS, Blodi BA, VanVeldhuisen PC; SCORE2 Investigator Group. SCORE2 Report 5: Vision-Related Function in Patients With Macular Edema Secondary to Central Retinal or Hemiretinal Vein Occlusion. Am J Ophthalmol. 2017 Dec;184:147-156. doi: 10.1016/j.ajo.2017.10.008. Epub 2017 Oct 23.
citation: Scott IU, VanVeldhuisen PC, Ip MS, Blodi BA, Oden NL, Altaweel M, Berinstein DM; SCORE2 Investigator Group. Comparison of Monthly vs Treat-and-Extend Regimens for Individuals With Macular Edema Who Respond Well to Anti-Vascular Endothelial Growth Factor Medications: Secondary Outcomes From the SCORE2 Randomized Clinical Trial. JAMA Ophthalmol. 2018 Apr 1;136(4):337-345. doi: 10.1001/jamaophthalmol.2017.6843.
citation: Peterson JS, Rockwell K Jr, Scott IU, Ip MS, VanVeldhuisen PC, Blodi BA; SCORE2 Investigator Group. LONG-TERM PHYSICAL STABILITY, STERILITY, AND ANTI-VEGF BIOACTIVITY OF REPACKAGED BEVACIZUMAB IN 2-ML GLASS VIALS. Retina. 2019 Sep;39(9):1802-1809. doi: 10.1097/IAE.0000000000002212.
citation: Ip MS, Oden NL, Scott IU, VanVeldhuisen PC, Blodi BA, Ghuman T, Baker CW; SCORE2 Investigator Group. Month 12 Outcomes After Treatment Change at Month 6 Among Poor Responders to Aflibercept or Bevacizumab in Eyes With Macular Edema Secondary to Central or Hemiretinal Vein Occlusion: A Secondary Analysis of the SCORE2 Study. JAMA Ophthalmol. 2019 Mar 1;137(3):281-287. doi: 10.1001/jamaophthalmol.2018.6111.
citation: Etheridge T, Dobson ETA, Wiedenmann M, Papudesu C, Scott IU, Ip MS, Eliceiri KW, Blodi BA, Domalpally A. A semi-automated machine-learning based workflow for ellipsoid zone analysis in eyes with macular edema: SCORE2 pilot study. PLoS One. 2020 Apr 30;15(4):e0232494. doi: 10.1371/journal.pone.0232494. eCollection 2020.
citation: Hendrick A, VanVeldhuisen PC, Scott IU, King J, Blodi BA, Ip MS, Khurana RN, Oden NL; SCORE2 Investigator Group. SCORE2 Report 13: Intraretinal Hemorrhage Changes in Eyes With Central or Hemiretinal Vein Occlusion Managed With Aflibercept, Bevacizumab or Observation. Secondary Analysis of the SCORE and SCORE2 Clinical Trials. Am J Ophthalmol. 2021 Feb;222:185-193. doi: 10.1016/j.ajo.2020.08.030. Epub 2020 Aug 20.
citation: Etheridge T, Dobson ETA, Wiedenmann M, Oden N, VanVeldhuisen P, Scott IU, Ip MS, Eliceiri KW, Blodi BA, Domalpally A. Ellipsoid Zone Defects in Retinal Vein Occlusion Correlates With Visual Acuity Prognosis: SCORE2 Report 14. Transl Vis Sci Technol. 2021 Mar 1;10(3):31. doi: 10.1167/tvst.10.3.31.
citation: Etheridge T, Blodi B, Oden N, Van Veldhuisen P, Scott IU, Ip MS, Mititelu M, Domalpally A. Spectral Domain OCT Predictors of Visual Acuity in the Study of COmparative Treatments for REtinal Vein Occlusion 2: SCORE 2 Report 15. Ophthalmol Retina. 2021 Oct;5(10):991-998. doi: 10.1016/j.oret.2020.12.016. Epub 2020 Dec 26.
citation: Scott IU, VanVeldhuisen PC, Ip MS, Blodi BA, Oden NL, Awh CC, Kunimoto DY, Marcus DM, Wroblewski JJ, King J; SCORE2 Investigator Group. Effect of Bevacizumab vs Aflibercept on Visual Acuity Among Patients With Macular Edema Due to Central Retinal Vein Occlusion: The SCORE2 Randomized Clinical Trial. JAMA. 2017 May 23;317(20):2072-2087. doi: 10.1001/jama.2017.4568.
citation: Scott IU, VanVeldhuisen PC, Oden NL, Ip MS, Blodi BA; SCORE2 Investigator Group. Month 60 Outcomes After Treatment Initiation With Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal or Hemiretinal Vein Occlusion. Am J Ophthalmol. 2022 Aug;240:330-341. doi: 10.1016/j.ajo.2022.04.001. Epub 2022 Apr 21.
citation: Aref AA, Scott IU, VanVeldhuisen PC, King J, Ip MS, Blodi BA, Oden NL; Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) Investigator Group. Intraocular Pressure-Related Events After Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal Vein Occlusion or Hemiretinal Vein Occlusion: SCORE2 Report 16 on a Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2021 Dec 1;139(12):1285-1291. doi: 10.1001/jamaophthalmol.2021.4395.
citation: Khurana RN, Oden NL, VanVeldhuisen PC, Scott IU, Blodi BA, Ip MS; SCORE2 Investigator Group. Association between early and late response in eyes with central or hemiretinal vein occlusion treated with anti-VEGF agents : SCORE2 report 12: secondary analysis of the SCORE2 clinical trial. Graefes Arch Clin Exp Ophthalmol. 2021 Jul;259(7):1839-1851. doi: 10.1007/s00417-020-05018-7. Epub 2021 Jan 7.
citation: Scott IU, Oden NL, VanVeldhuisen PC, Ip MS, Blodi BA, Chan CK; SCORE2 Investigator Group. Month 24 Outcomes After Treatment Initiation With Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal or Hemiretinal Vein Occlusion: SCORE2 Report 10: A Secondary Analysis of the SCORE2 Randomized Clinical Trial. JAMA Ophthalmol. 2019 Dec 1;137(12):1389-1398. doi: 10.1001/jamaophthalmol.2019.3947.
citation: Scott IU, VanVeldhuisen PC, Barton F, Oden NL, Ip MS, Blodi BA, Worrall M, Fish GE; Study of Comparative Treatments for Retinal Vein Occlusion 2 Investigator Group. Patient-Reported Visual Function Outcomes After Anti-Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal or Hemiretinal Vein Occlusion: Preplanned Secondary Analysis of a Randomized Clinical Trial. JAMA Ophthalmol. 2019 Aug 1;137(8):932-938. doi: 10.1001/jamaophthalmol.2019.1519.