Assessing the Efficacy and Safety of Brolucizumab Versus Aflibercept in Patients With Visual Impairment Due to Macular Edema Secondary to Central Retinal Vein Occlusion (RAVEN)

An Eighteen-Month, Two-Arm, Randomized, Double Masked, Multicenter, Phase III Study Assessing the Efficacy and Safety of Brolucizumab Versus Aflibercept in Adult Patients With Visual Impairment Due to Macular Edema Secondary to Central Retinal Vein Occlusion

The purpose of this study was to evaluate the efficacy and safety of brolucizumab in treatment of patients with macular edema (ME) secondary to central retinal vein occlusion (CRVO).

Study Overview

• Status: Terminated
• Conditions: Central Retinal Vein Occlusion
• Intervention / Treatment: Drug: Brolucizumab 6 mg; Other: Sham injection; Drug: Aflibercept 2 mg

Detailed Description

The study included Screening Period (Day -28 to Day -1), double-masked treatment period (Day 1 to Week 72), and post-treatment follow-up period (Week 72 to Week 76). Treatment visits were scheduled in 4-week intervals. After 6 initial monthly injections of brolucizumab or aflibercept (loading phase), subjects entered a one-year individualized flexible treatment (IFT) phase. During the IFT phase, an assessment of disease stability was performed at each monthly visit and subjects received either an active or a sham injection. Treatment with active was interrupted when disease stability was reached.

• Study Type: Interventional
• Enrollment (Actual): 493
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Albury, New South Wales, Australia, 2640
      • Novartis Investigative Site
    • Parramatta, New South Wales, Australia, 2150
      • Novartis Investigative Site
    • Strathfield, New South Wales, Australia, 2135
      • Novartis Investigative Site
    • Sydney, New South Wales, Australia, 2000
      • Novartis Investigative Site
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3002
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Canada
  • Quebec, Canada, G1S 4L8
    • Novartis Investigative Site
  • Alberta
    • Calgary, Alberta, Canada, T2H0C8
      • Novartis Investigative Site
  • Ontario
    • London, Ontario, Canada, N6A 4V2
      • Novartis Investigative Site
    • Ottawa, Ontario, Canada, K1H 8L6
      • Novartis Investigative Site
    • Ottawa, Ontario, Canada, K1Z 8R2
      • Novartis Investigative Site
• China
  • Beijing, China, 100044
    • Novartis Investigative Site
  • Beijing, China, 100730
    • Novartis Investigative Site
  • Chongqing, China, 400038
    • Novartis Investigative Site
  • Shanghai, China, 200080
    • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Novartis Investigative Site
    • Shantou, Guangdong, China, 515041
      • Novartis Investigative Site
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150001
      • Novartis Investigative Site
  • Hubei
    • Wuhan, Hubei, China, 430070
      • Novartis Investigative Site
  • Jiangsu
    • Wuxi, Jiangsu, China, 214002
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
  • Tianjin
    • Tianjin, Tianjin, China, 300020
      • Novartis Investigative Site
    • Tianjin, Tianjin, China, 300070
      • Novartis Investigative Site
  • Zhejiang
    • Wenzhou, Zhejiang, China, 325027
      • Novartis Investigative Site
• Czechia
  • Pardubice, Czechia, 532 03
    • Novartis Investigative Site
  • Praha, Czechia, 12808
    • Novartis Investigative Site
  • Praha 10, Czechia, 100 34
    • Novartis Investigative Site
  • CZE
    • Hradec Kralove, CZE, Czechia, 500 05
      • Novartis Investigative Site
• France
  • Creteil, France, 94000
    • Novartis Investigative Site
  • Dijon, France, 21034
    • Novartis Investigative Site
  • Nantes, France, 44000
    • Novartis Investigative Site
  • Paris Cedex 19, France, 75940
    • Novartis Investigative Site
  • Paris cedex 10, France, 75010
    • Novartis Investigative Site
• Germany
  • Duesseldorf, Germany, 40225
    • Novartis Investigative Site
  • Freiburg, Germany, 79106
    • Novartis Investigative Site
  • Gottingen, Germany, 37075
    • Novartis Investigative Site
  • Hannover, Germany, 30625
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Leipzig, Germany, 04103
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • Muenster, Germany, 48145
    • Novartis Investigative Site
  • Ulm, Germany, 89075
    • Novartis Investigative Site
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • Novartis Investigative Site
• Greece
  • Heraklion Crete, Greece, 711 10
    • Novartis Investigative Site
  • GR
    • Larissa, GR, Greece, 411 10
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, 1083
    • Novartis Investigative Site
  • Debrecen, Hungary, 4012
    • Novartis Investigative Site
  • Szeged, Hungary, H 6725
    • Novartis Investigative Site
  • Baranya
    • Pecs, Baranya, Hungary, 7621
      • Novartis Investigative Site
• Israel
  • Jerusalem, Israel, 9112001
    • Novartis Investigative Site
  • Petach Tikva, Israel, 4941492
    • Novartis Investigative Site
  • Rehovot, Israel, 7610001
    • Novartis Investigative Site
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Italy
  • BA
    • Bari, BA, Italy, 70124
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
    • Milano, MI, Italy, 20122
      • Novartis Investigative Site
    • Milano, MI, Italy, 20100
      • Novartis Investigative Site
• Japan
  • Aichi
    • Nagakute-city, Aichi, Japan, 480-1195
      • Novartis Investigative Site
  • Fukushima
    • Koriyama, Fukushima, Japan, 963-8052
      • Novartis Investigative Site
  • Kagawa
    • Kita-gun, Kagawa, Japan, 761-0793
      • Novartis Investigative Site
  • Mie
    • Tsu-city, Mie, Japan, 514-8507
      • Novartis Investigative Site
  • Nagano
    • Matsumoto-city, Nagano, Japan, 390-8621
      • Novartis Investigative Site
  • Nagasaki
    • Nagasaki-city, Nagasaki, Japan, 852-8501
      • Novartis Investigative Site
  • Tokyo
    • Chiyoda-ku, Tokyo, Japan, 101-8309
      • Novartis Investigative Site
    • Hachioji-city, Tokyo, Japan, 193-0944
      • Novartis Investigative Site
    • Taito-ku, Tokyo, Japan, 111-0051
      • Novartis Investigative Site
• Malaysia
  • Selangor
    • Batu Caves, Selangor, Malaysia, 68100
      • Novartis Investigative Site
    • Shah Alam, Selangor, Malaysia, 40000
      • Novartis Investigative Site
• Netherlands
  • Tilburg, Netherlands, 5022 GC
    • Novartis Investigative Site
• Puerto Rico
  • Arecibo, Puerto Rico, 00612
    • Novartis Investigative Site
• Russian Federation
  • Cheboksary, Russian Federation, 428028
    • Novartis Investigative Site
  • Ekaterinburg, Russian Federation, 620109
    • Novartis Investigative Site
  • Kazan, Russian Federation, 420066
    • Novartis Investigative Site
  • St-Petersburg, Russian Federation, 197022
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08025
    • Novartis Investigative Site
  • Barcelona, Spain, 8022
    • Novartis Investigative Site
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Valencia, Spain, 46004
    • Novartis Investigative Site
  • Zaragoza, Spain, 50009
    • Novartis Investigative Site
  • Pais Vasco
    • San Sebastian, Pais Vasco, Spain, 20080
      • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Hat Yai
    • Songkhla, Hat Yai, Thailand, 90110
      • Novartis Investigative Site
  • THA
    • Khon Kaen, THA, Thailand, 40002
      • Novartis Investigative Site
• Turkey
  • Ankara, Turkey, 06100
    • Novartis Investigative Site
• United Kingdom
  • Leeds, United Kingdom, LS9 7TF
    • Novartis Investigative Site
  • Liverpool, United Kingdom, L7 8XP
    • Novartis Investigative Site
  • London, United Kingdom, EC1V 2PD
    • Novartis Investigative Site
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • Novartis Investigative Site
  • Suffolk
    • Bury Saint Edmonds, Suffolk, United Kingdom, IP33 2QZ
      • Novartis Investigative Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85020
      • Novartis Investigative Site
  • California
    • La Jolla, California, United States, 92093
      • Novartis Investigative Site
    • Mountain View, California, United States, 94040
      • Novartis Investigative Site
    • Santa Barbara, California, United States, 93103
      • Novartis Investigative Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • Novartis Investigative Site
  • Florida
    • Fort Myers, Florida, United States, 33912-7125
      • Novartis Investigative Site
    • Saint Petersburg, Florida, United States, 33711
      • Novartis Investigative Site
  • Indiana
    • Indianapolis, Indiana, United States, 46280
      • Novartis Investigative Site
    • New Albany, Indiana, United States, 47150
      • Novartis Investigative Site
  • Kansas
    • Leawood, Kansas, United States, 66211
      • Novartis Investigative Site
    • Lenexa, Kansas, United States, 66215
      • Novartis Investigative Site
  • Massachusetts
    • Stoneham, Massachusetts, United States, 02180
      • Novartis Investigative Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55435
      • Novartis Investigative Site
  • Nevada
    • Reno, Nevada, United States, 89502
      • Novartis Investigative Site
  • New Jersey
    • Bloomfield, New Jersey, United States, 07003
      • Novartis Investigative Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Novartis Investigative Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Novartis Investigative Site
    • Cleveland, Ohio, United States, 44122
      • Novartis Investigative Site
  • Pennsylvania
    • Monroeville, Pennsylvania, United States, 15146
      • Novartis Investigative Site
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Novartis Investigative Site
    • Nashville, Tennessee, United States, 37203
      • Novartis Investigative Site
  • Texas
    • Abilene, Texas, United States, 79606
      • Novartis Investigative Site
    • Arlington, Texas, United States, 76012
      • Novartis Investigative Site
    • Austin, Texas, United States, 78731
      • Novartis Investigative Site
    • Austin, Texas, United States, 78750
      • Novartis Investigative Site
    • Bellaire, Texas, United States, 77401
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
    • Houston, Texas, United States, 77025
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78240
      • Novartis Investigative Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53705-3611
      • Novartis Investigative Site

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

Inclusion Criteria:

• Signed informed consent must be obtained prior to participation in the study.
• Patients with visual impairment due to ME secondary to CRVO diagnosed < 6 months prior to screening.
• BCVA score between 78 and 23 letters, inclusive, using ETDRS visual acuity testing charts (approximate Snellen equivalent of 20/32 to 20/320) at both screening and baseline visits.

Exclusion criteria

• Concomitant conditions or ocular disorders in the study eye at screening or baseline which could, in the opinion of the investigator, prevent response to study treatment or may confound interpretation of study results, compromise visual acuity or require medical or surgical intervention during the first 12-month study period (e.g. structural damage of the fovea, vitreous hemorrhage, retinal vascular occlusion other than CRVO, retinal detachment, macular hole, or choroidal neovascularization of any cause, diabetic retinopathy (except mild non-proliferative) and diabetic macular edema).
• Any active intraocular or periocular infection or active intraocular inflammation (e.g. infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis, uveitis) in study eye at screening or baseline
• Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) > 25 mmHg on medication, or according to investigator's judgment, at screening or baseline
• Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with BCVA < 20/200 at screening (except when due to conditions whose surgery may improve VA, e.g. cataract)
• Previous treatment with any anti-VEGF therapy or investigational drugs in the study eye at any time prior to baseline
• Previous use of intraocular or periocular steroids in study eye at any time prior to baseline
• Macular laser photocoagulation (focal/grid) in the study eye at any time prior to baseline and peripheral laser photocoagulation in the study eye within 3 months prior to the baseline
• Intraocular surgery in the study eye during the 3-month period prior to baseline
• Vitreoretinal surgery in the study eye at any time prior to baseline
• Aphakia with the absence of posterior capsule in the study eye

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Brolucizumab 6 mg; 1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individual flexible treatment (IFT)	Drug: Brolucizumab 6 mg; Solution for injection (intravitreal use); Other Names: RTH258; ESBA1008; Other: Sham injection; Empty sterile syringe without a needle administered as a sham injection for masking. From Week 24 to Week 72 inclusive, a sham treatment was performed to maintain subject masking in case treatment with brolucizumab or aflibercept was not deemed necessary by the investigator.
Active Comparator: Aflibercept 2 mg; 1 intravitreal injection every 4 weeks for a total of 6 injections, followed by 48 weeks of individual flexible treatment (IFT)	Other: Sham injection; Empty sterile syringe without a needle administered as a sham injection for masking. From Week 24 to Week 72 inclusive, a sham treatment was performed to maintain subject masking in case treatment with brolucizumab or aflibercept was not deemed necessary by the investigator.; Drug: Aflibercept 2 mg; Solution for injection (Intravitreal use); Other Names: EYLEA®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 24	BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. Missing and censored BCVA values were imputed by Last observation carried forward (LOCF) as the primary approach. Observed values from both scheduled and unscheduled post-baseline visits were used for the LOCF imputation. For subjects with no post-baseline BCVA value, the baseline value was carried forward.	Baseline, Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in BCVA Averaged Over Week 40 to Week 52	An average BCVA over week 40 to week 52 was calculated. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning.	Baseline, Week 40 to Week 52
Change From Baseline in BCVA Averaged Over Week 64 to Week 76	An average BCVA over week 64 to week 76 was calculated. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning.	Baseline, Week 64 to Week 76
Change From Baseline in BCVA by Visit up to Week 76	BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning.	Baseline and every 4 weeks from baseline up to Week 76
Proportion of Participants With a Gain ≥ 5, 10 and 15 Letters in BCVA by Visit Compared to Baseline	The summary by visit was conducted based on the BCVA observed from each of the corresponding visits. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. Every 5 letters represents 1 line of vision on the reading chart.	Baseline and every 4 weeks from baseline up to Week 76
Proportion of Participants With a Loss ≥ 5, 10 and 15 Letters in BCVA by Visit Compared to Baseline	The summary by visit was conducted based on the BCVA observed from each of the corresponding visit. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters. Min and max possible scores are 0-100 letters read respectively. A higher score represents better visual functioning. Every 5 letters represents 1 line of vision on the reading chart.	Baseline and every 4 weeks from baseline up to Week 76
Change From Baseline in CSFT Averaged Over Week 40 to Week 52	Change from baseline in central subfield thickness (CSFT) averaged over Week 40 to Week 52, measured in μm by Spectral Domain Optical Coherence Tomography (SD-OCT)	Baseline, Week 40 to Week 52
Change From Baseline in CSFT Averaged Over Week 64 to Week 76	Change from baseline in central subfield thickness (CSFT) averaged over Week 64 to Week 76, measured in μm by Spectral Domain Optical Coherence Tomography (SD-OCT)	Baseline, Week 64 to Week 76
Change From Baseline in CSFT by Visit up to Week 76	Change from baseline in central subfield thickness (CSFT) measured in μm by Spectral Domain Optical Coherence Tomography (SD-OCT)	Baseline, and every 4 weeks from baseline up to Week 76
Proportion of Subjects With Presence of Retinal Fluid (Intra- and/or Subretinal Fluid) in the Study Eye by Visit up to Week 76	Presence of retinal fluid (intra- and/or subretinal fluid) assessed by Spectral Domain Optical Coherence Tomography (SD-OCT)	Every 4 weeks from week 4 up to Week 76
Proportion of Subjects With a CSFT < 300 μm for the Study Eye by Visit up to Week 76	Central subfield thickness (CSFT) is measured in μm by Spectral Domain Optical Coherence Tomography (SD-OCT)	Every 4 weeks from week 4 up to Week 76
Number of Injections Between Week 24 and Week 52 and Between Week 24 and Week 72	Number of administered injections during the individualized flexible treatment (IFT) period, between Week 24 and Week 52 and between Week 24 and Week 72 are presented	Week 24 to Week 52 and Week 24 to Week 72
Time to Recurrence After Week 20 and up to Week 76	Recurrence is defined as the need for injection while showing a lack of disease stability for the first time after Week 20 and up to Week 76. For subjects with recurrence after the Week 20 visit, time-to-event is calculated as (first time with the lack of disease stability - the injection date on Week 20 visit + 1). For subjects without recurrence after Week 20, the censoring time will be calculated as (last visit with disease stability assessment - the injection date on Week 20 visit + 1).	Week 20 to Week 76
Number of Subjects With Ocular and Non-ocular AEs up to Week 52 and Week 76	Number of subjects with at least one ocular or non-ocular Adverse Events (AEs).	Baseline to Week 76
Change From Baseline in Patient Reported Outcomes (NEI VFQ-25) at Week 24, Week 52 and Week 76	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures a patient's subjective assessment of vision-related Quality of Life (QoL). The 11 subscales in the VFQ-25 are general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated better vision-related quality of life.	Baseline, Week 24, Week 52 and Week 76
Number of Subjects According to Their Anti-drug Antibody (ADA) Titer at Screening and Week 4, Week 12, Week 24, Week 36, Week 52 and Week 76	Anti-drug antibodies (ADA) levels were assessed from subjects assigned to brolucizumab treatment only.	Baseline, Week 4, Week 12, Week 24, Week 36, Week 52 and Week 76

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CRTH258C2302 from the Novartis Clinical Trials Website
• A Plain Language Trial Summary is available on novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): July 3, 2019
• Primary Completion (Actual): July 26, 2021
• Study Completion (Actual): July 26, 2021

Study Registration Dates

• First Submitted: January 17, 2019
• First Submitted That Met QC Criteria: January 17, 2019
• First Posted (Actual): January 18, 2019

Study Record Updates

• Last Update Posted (Estimate): January 30, 2023
• Last Update Submitted That Met QC Criteria: January 27, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: VEGF; anti-VEGF; CRVO; Vascular endothelial growth factor; Aflibercept; Macular edema; Central retinal vein occlusion; Brolucizumab; Visual impairment
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Retinal Degeneration; Retinal Diseases; Embolism and Thrombosis; Venous Thrombosis; Thrombosis; Macular Degeneration; Sensation Disorders; Macular Edema; Retinal Vein Occlusion; Vision, Low; Vision Disorders; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept
• Other Study ID Numbers: CRTH258C2302; 2018-001788-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No