Efficacy and Safety of Ranibizumab With or Without Laser in Comparison to Laser in Branch Retinal Vein Occlusion (BRIGHTER)

A 24-month, Phase IIIb, Open-label, Randomized, Active Controlled, 3-arm, Multicenter Study Assessing the Efficacy and Safety of an Individualized, Stabilization-criteria-driven PRN Dosing Regimen With 0.5-mg Ranibizumab Intravitreal Injections Applied as Monotherapy or With Adjunctive Laser Photocoagulation in Comparison to Laser Photocoagulation in Patients With Visual Impairment Due to Macular Edema Secondary to Branch Retinal Vein Occlusion

This study will generate comparative data for 0.5-mg ranibizumab using PRN dosing administered with or without adjunctive laser treatment versus laser photocoagulation (the current standard of care) up to Month 6 in patients with visual impairment due to ME secondary to BRVO. Additionally the results of this study will provide long-term (24-month) safety and efficacy data for ranibizumab, administered with or without adjunctive laser treatment in this indication.

Study Overview

• Status: Completed
• Conditions: Branch Retinal Vein Occlusion
• Intervention / Treatment: Drug: Ranibizumab; Procedure: Laser

• Study Type: Interventional
• Enrollment (Actual): 455
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Parramatta, New South Wales, Australia, 2150
      • Novartis Investigative Site
    • Sydney, New South Wales, Australia, 2000
      • Novartis Investigative Site
  • Victoria
    • Melbourne, Victoria, Australia, 3002
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2H0C8
      • Novartis Investigative Site
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Novartis Investigative Site
    • Victoria, British Columbia, Canada, V8V 4X3
      • Novartis Investigative Site
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Novartis Investigative Site
  • Ontario
    • London, Ontario, Canada, N6A 4G5
      • Novartis Investigative Site
  • Quebec
    • Boisbriand, Quebec, Canada, J7H 1S6
      • Novartis Investigative Site
    • Montreal, Quebec, Canada, H1T 2M4
      • Novartis Investigative Site
• Czech Republic
  • Olomouc, Czech Republic, 775 20
    • Novartis Investigative Site
  • Praha 10, Czech Republic, 100 34
    • Novartis Investigative Site
• Denmark
  • Glostrup, Denmark, DK-2600
    • Novartis Investigative Site
• France
  • Dijon, France, 21033
    • Novartis Investigative Site
  • Lyon, France, 69003
    • Novartis Investigative Site
  • Nice, France, 06000
    • Novartis Investigative Site
  • Paris, France
    • Novartis Investigative Site
  • Paris Cedex 19, France, 75940
    • Novartis Investigative Site
  • Paris cedex 10, France, 75010
    • Novartis Investigative Site
• Greece
  • Patras, Greece, 26504
    • Novartis Investigative Site
  • Thessaloniki, Greece, GR 54636
    • Novartis Investigative Site
  • GR
    • Athens, GR, Greece, 124 62
      • Novartis Investigative Site
    • Heraklion Crete, GR, Greece, 711 10
      • Novartis Investigative Site
    • Larissa, GR, Greece, 411 10
      • Novartis Investigative Site
    • Thessaloniki, GR, Greece, 546 29
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H-1083
    • Novartis Investigative Site
  • Budapest, Hungary, 1133
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
• Ireland
  • Dublin, Ireland
    • Novartis Investigative Site
  • Dublin 7, Ireland
    • Novartis Investigative Site
• Italy
  • Bari, Italy, 70124
    • Novartis Investigative Site
  • Udine, Italy, 33100
    • Novartis Investigative Site
  • BO
    • Bologna, BO, Italy, 40138
      • Novartis Investigative Site
  • FI
    • Firenze, FI, Italy, 50134
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
    • Milano, MI, Italy, 20100
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00144
      • Novartis Investigative Site
  • TO
    • Torino, TO, Italy, 10122
      • Novartis Investigative Site
• Netherlands
  • Leiden 2333 ZA, Netherlands, 2333
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3011 BH
    • Novartis Investigative Site
  • Tilburg, Netherlands, 5022 GC
    • Novartis Investigative Site
• Poland
  • Bielsko-Biala, Poland, 43-300
    • Novartis Investigative Site
  • Gdansk, Poland, 80-809
    • Novartis Investigative Site
  • Kraków, Poland, 31-501
    • Novartis Investigative Site
  • Lublin, Poland, 20-079
    • Novartis Investigative Site
  • Warszawa, Poland, 02-005
    • Novartis Investigative Site
  • Wroclaw, Poland, 50-556
    • Novartis Investigative Site
• Portugal
  • Coimbra, Portugal, 3000-354
    • Novartis Investigative Site
  • Coimbra, Portugal, 3030-163
    • Novartis Investigative Site
  • Lisboa, Portugal, 1349-019
    • Novartis Investigative Site
  • Lisboa, Portugal, 1050-085
    • Novartis Investigative Site
  • Porto, Portugal, 4099-001
    • Novartis Investigative Site
  • Porto, Portugal, 4200-319
    • Novartis Investigative Site
• Slovakia
  • Banska Bystrica, Slovakia, 975 17
    • Novartis Investigative Site
  • Bratislava, Slovakia, 826 06
    • Novartis Investigative Site
  • Bratislava, Slovakia, 851 07
    • Novartis Investigative Site
  • Slovak Republic
    • Zilina, Slovak Republic, Slovakia, 010 01
      • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28046
    • Novartis Investigative Site
  • Castilla y Leon
    • Valladolid, Castilla y Leon, Spain, 47011
      • Novartis Investigative Site
  • Cataluña
    • Barcelona, Cataluña, Spain
      • Novartis Investigative Site
    • Barcelona, Cataluña, Spain, 08022
      • Novartis Investigative Site
    • L´Hospitalet de Llobregat, Cataluña, Spain, 08907
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Alicante, Comunidad Valenciana, Spain, 03016
      • Novartis Investigative Site
    • Valencia, Comunidad Valenciana, Spain, 46014
      • Novartis Investigative Site
    • Valencia, Comunidad Valenciana, Spain, 46015
      • Novartis Investigative Site
  • Galicia
    • Santiago de Compostela, Galicia, Spain, 15706
      • Novartis Investigative Site
  • Pais Vasco
    • Bilbao, Pais Vasco, Spain, 48006
      • Novartis Investigative Site
• Sweden
  • Örebro, Sweden, 701 85
    • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland, 3012
    • Novartis Investigative Site
  • Lausanne, Switzerland, 1007
    • Novartis Investigative Site
  • Olten, Switzerland, 4600
    • Novartis Investigative Site
  • Zuerich, Switzerland, 8063
    • Novartis Investigative Site
• United Kingdom
  • Belfast, United Kingdom, BT12 6BA
    • Novartis Investigative Site
  • Birmingham, United Kingdom, B9 5SS
    • Novartis Investigative Site
  • Bristol, United Kingdom, BS1 2LX
    • Novartis Investigative Site
  • London, United Kingdom, EC1V 2PD
    • Novartis Investigative Site
  • London, United Kingdom, NW1 5QH
    • Novartis Investigative Site
  • Newcastle upon Tyne, United Kingdom, NE1 4LP
    • Novartis Investigative Site
  • Plymouth, United Kingdom, PL4 6PL
    • Novartis Investigative Site
  • Southampton, United Kingdom, SO16 6YD
    • Novartis Investigative Site
  • Surrey
    • Frimley, Surrey, United Kingdom, GU16 7UJ
      • 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:

• Written informed consent must be obtained before any study assessment is performed
• Diagnosis of visual impairment exclusively due to ME secondary to BRVO
• BCVA score at Screening and Baseline between 73 and 19 letters (ETDRS)

Exclusion Criteria:

• Pregnant or nursing (lactating) women
• Stroke or myocardial infarction less than 3 months before Screening
• Uncontrolled blood pressure defined as systolic value of >160 mm Hg or diastolic value of >100 mm Hg at Screening or Baseline.
• Any active periocular or ocular infection or inflammation at Screening or Baseline in either eye
• Uncontrolled glaucoma at Screening or Baseline or diagnosed within 6 months before Baseline in either eye
• Neovascularization of the iris or neovascular glaucoma in the study eye
• Use of any systemic antivascular endothelial growth factor (anti-VEGF) drugs within 6 months before Baseline
• Panretinal laser photocoagulation within 3 months before Baseline or anticipated or scheduled within the next 3 months following Baseline in the study eye
• Focal or grid laser photocoagulation within 4 months before Baseline in the study eye
• Use of intra- or periocular corticosteroids (including sub-Tenon) within 3 months before Screening in the study eye
• Any use of intraocular corticosteroid implants (eg, dexamethasone [Ozurdex®], fluocinolone acetonide [Iluvien®]) in the study eye

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1-ranibizumab monotherapy; Ranibizumab 0.5 mg	Drug: Ranibizumab; Other Names: Lucentis
Experimental: 2-ranibizumab with laser; Ranibizumab 0.5 mg + laser	Drug: Ranibizumab; Other Names: Lucentis; Procedure: Laser; laser photocoagulation
Active Comparator: 3-laser monotherapy; Laser monotherapy with Ranibizumab 0.5 mg from Month 6	Procedure: Laser; laser photocoagulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Visual Acuity: BCVA Change at Month 6 Compared to Baseline in Patients With Visual Impairment Due to Branch Retinal Vein Occlusion (BRVO)	Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) -like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. For the mean change of best corrected visual acuity at Month 6 compare to Baseline, the 95% confidence interval and P value (related to the null hypothesis that this mean change is equal to zero) based on a t distribution/t test were calculated and assessed by an ANOVA model.	Baseline, 6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Mean Average Change in Visual Acuity From Month 1 Through Month 24 Compared to Baseline	Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. (A positive average change from baseline of BCVA indicates improvement): Mean Average Change: for each patient, first average change is calculated as the average of the changes from baseline to Month 1 over Month 24. Then, mean average change is calculated as the average of average changes across all patients.	Baseline, 24 Months
Number of Ranibizumab Treatments From Day 1 to Month 23 by Treatment Group	Number of injections provided to the patients during the 23 month period and conducted within FAS with LOCF and observed data.	Day 1 through Month 23
Mean Average Change in Visual Acuity (BCVA Letters) From Month 1 Through Month 6	Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) -like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters.(A positive average change from baseline of BCVA indicates improvement): Mean Average Change: for each patient, first average change is calculated as the average of the changes from baseline to Month 1 over Month 6. Then, mean average change is calculated as the average of average changes across all patients.	From Baseline through Month 6
The Mean Change in Visual Acuity BCVA (Letters) From Baseline at Month 12 and Month 24	Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) -like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. For the mean change of best corrected visual acuity at Month 12 and Month 24 compare to Baseline, the 95% confidence interval and P value (related to the null hypothesis that this mean change is equal to zero) based on a t distribution/t test were calculated and were assessed by an ANOVA model.	Baseline, Month 12 and Month 24
The Percent of Patients With a Visual Acuity Gain of ≥1, ≥5, ≥10, ≥15, and ≥30 Letters From Baseline up to Month 6 and Month 24, by Visit	BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An increased score indicates improvement in acuity. This outcome assessed the number of participants who had improvement of ≥1, ≥5, ≥10, ≥15, and ≥30 letters of visual acuity at Month 6 & Month 24 as compared with baseline, was assessed by an ANOVA model. Endpoints related to the proportion of patients with BCVA letter gain or loss from Baseline was analyzed via stratified Cochran-Mantel-Haenszel test with stratification based on baseline BCVA (baseline BCVA less than or equal to 39, 40 to 59, greater than or equal to 60 letters, treatment groups).	Baseline, Month 6 and Month 24
Number of Patients With a BCVA Improvement vs Baseline or Achieving Greater Than or Equal to 73 Letters at Month 6 in the Study Eye	Best Corrected Visual Acuity (BCVA) was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart at baseline and Month 6 while participants were in a sitting position at a testing distance of 4 meters. The range of EDTRS is 0 to 100 letters. BCVA above 73 letters at Month 6 indicates a positive outcome.	Month 6
Number of Patients With a BCVA Improvement vs Baseline or Achieved Greater Than or Equal to 73 Letters at Month 24 in the Study Eye	Best Corrected Visual Acuity (BCVA) was measured using Early Treatment Diabetic Retinopathy Study (ETDRS)-like chart at baseline and Month 12 while participants were in a sitting position at a testing distance of 4 meters. The range of EDTRS is 0 to 100 letters. BCVA above 73 letters at Month 24 indicates a positive outcome.	Month 24
The Mean Change in Central Reading Center-assessed Central Subfield Thickness From Month 12 and Month 24 vs. Baseline by Treatment Arm	Retinal thickness was measured using Optical Coherence Tomography (OCT). The images were reviewed by a central reading center to ensure a standardized evaluation. Stratification was done based on categories of baseline best corrected visual acuity & analysis was based on analysis of variance (ANOVA)	Month 12 and Month 24
The Mean Change in Patient Reported Outcomes in NEI-VFQ-25 Score (Composite Score and Subscales) at Month 6 and Month 24 Compared to Baseline	The survey consists of 25 items representing 11 vision related constructs (general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, color vision, peripheral vision) plus a single-item general health rating question. All items are scored so that a high score represents better functioning. Each item is then converted to a 0 to 100 scale so that the lowest and highest possible scores are set at 0 and 100 points, respectively. In this format scores represent the achieved percentage of the total possible score, e.g. a score of 50 represents 50% of the highest possible score.	Months 6 and 24
BCVA (Letters) Mean Average Change From First Ranibizumab Treatment to Month 24 in the Study Eye for Patients Randomized to the Laser Monotherapy Arm	Best-Corrected Visual Acuity (BCVA) letters was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) -like chart while participants were in a sitting position at a testing distance of 4 meters. The range of ETDRS is 0 to 100 letters. For the mean change of best corrected visual acuity at Month 24 compare to Baseline, the 95% confidence interval and P value (related to the null hypothesis that this mean change is equal to zero) based on a t distribution/t test were calculated and assessed by an ANOVA model.	Month 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Pawloff M, Bogunovic H, Gruber A, Michl M, Riedl S, Schmidt-Erfurth U. SYSTEMATIC CORRELATION OF CENTRAL SUBFIELD THICKNESS WITH RETINAL FLUID VOLUMES QUANTIFIED BY DEEP LEARNING IN THE MAJOR EXUDATIVE MACULAR DISEASES. Retina. 2022 May 1;42(5):831-841. doi: 10.1097/IAE.0000000000003385.
• Tadayoni R, Waldstein SM, Boscia F, Gerding H, Gekkieva M, Barnes E, Das Gupta A, Wenzel A, Pearce I; BRIGHTER Study Group. Sustained Benefits of Ranibizumab with or without Laser in Branch Retinal Vein Occlusion: 24-Month Results of the BRIGHTER Study. Ophthalmology. 2017 Dec;124(12):1778-1787. doi: 10.1016/j.ophtha.2017.06.027. Epub 2017 Aug 12. Erratum In: Ophthalmology. 2018 Mar;125(3):463.
• Tadayoni R, Waldstein SM, Boscia F, Gerding H, Pearce I, Priglinger S, Wenzel A, Barnes E, Gekkieva M, Pilz S, Mones J; BRIGHTER study group. Individualized Stabilization Criteria-Driven Ranibizumab versus Laser in Branch Retinal Vein Occlusion: Six-Month Results of BRIGHTER. Ophthalmology. 2016 Jun;123(6):1332-44. doi: 10.1016/j.ophtha.2016.02.030. Epub 2016 Mar 30.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: May 2, 2012
• First Submitted That Met QC Criteria: May 14, 2012
• First Posted (Estimate): May 16, 2012

Study Record Updates

• Last Update Posted (Estimate): November 10, 2016
• Last Update Submitted That Met QC Criteria: September 21, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Macular Edema, Branch Retinal Vein Occlusion, visual impairment
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Retinal Diseases; Embolism and Thrombosis; Venous Thrombosis; Thrombosis; Retinal Vein Occlusion; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Ranibizumab
• Other Study ID Numbers: CRFB002E2402; 2011-002859-34 (EudraCT Number)