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

Phase 3TerminatedNCT03810313

Novartis Pharmaceuticals493 enrolled

Overview

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).

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

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

493

Conditions

Central Retinal Vein Occlusion

Interventions

Brolucizumab 6 mgDRUG

Solution for injection (intravitreal use)

Aflibercept 2 mgDRUG

Solution for injection (Intravitreal use)

Sham injectionOTHER

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.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (120)

Outcomes

Primary Outcomes

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.

Time frame: Baseline, Week 24

Secondary Outcomes

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.

Time frame: 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.

Time frame: Baseline, Week 64 to Week 76

Change From Baseline in BCVA by Visit up to Week 76

Data from ClinicalTrials.gov

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Novartis Investigative Site

Phoenix, Arizona, United States

Novartis Investigative Site

La Jolla, California, United States

Novartis Investigative Site

Mountain View, California, United States

Novartis Investigative Site

Santa Barbara, California, United States

Novartis Investigative Site

Colorado Springs, Colorado, United States

Novartis Investigative Site

Fort Myers, Florida, United States

Novartis Investigative Site

St. Petersburg, Florida, United States

Novartis Investigative Site

Indianapolis, Indiana, United States

Novartis Investigative Site

New Albany, Indiana, United States

Novartis Investigative Site

Leawood, Kansas, United States

...and 110 more locations

Time frame: 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.

Time frame: 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.

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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)

Time frame: 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

Time frame: 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).

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: Baseline, Week 4, Week 12, Week 24, Week 36, Week 52 and Week 76