Clinical trial NCT03481634: Study of Efficacy and Safety of Brolucizumab vs. Aflibercept in Patients With Visual Impairment Due to Diabetic Macular Edema
Official title: A Two-year, Three-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 Diabetic Macular Edema
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Diabetic Macular Edema
Keywords: Diabetic Macular Edema
intravitreal injection
brolucizumab
aflibercept
double-masked
Diabetic Macular Edema (DME)
macular edema
diabetic retinopathy
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-03-29
Enrollment: 566
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: The purpose of this study was to evaluate the efficacy and safety of brolucizumab in treatment of patients with visual impairment due to diabetic macular edema (DME).

Detailed description: This was a Phase III, randomized, double-masked, multi-center, active-controlled, three-arm study designed to evaluate the efficacy and safety of brolucizumab 6 mg and 3 mg compared to the active control, aflibercept 2 mg used per authorized label, in subjects with diabetic macular edema (DME). The study included a screening period of up to 2 weeks to assess eligibility, followed by a doublemasked treatment period (Day 1 to Week 96). The baseline visit was defined as Day 1/Visit 1, and end of treatment visit as Visit 27 (Week 96). After the last treatment visit, a post-treatment follow-up period was planned from Week 96 to Week 100.

Subjects were assigned to one of three treatment arms in a 1:1:1 ratio: brolucizumab 6 mg/0.05 mL administered 5 x every 6 weeks (q6w) during loading phase then q12w/every 8 weeks (q8w) during maintenance phase, brolucizumab 3 mg/0.05 mL administered 5 x every 6 weeks (q6w) during loading phase then q12w/q8w during maintenance phase or aflibercept 2 mg/0.05 mL administered 5 x every 4 weeks (q4w) during loading phase then q8w during maintenance phase.

Disease Activity Assessments (DAAs) were conducted by the masked investigator for each treatment arm at Week 32 and Week 36, i.e. 8 and 12 weeks after the end of the loading phase for subjects receiving brolucizumab. Assessments were also performed at Week 48, and will then continue to be performed from Week 60 up to Week 96, every 12 weeks. Subjects in the brolucizumab arms who qualified for q12w during the initial q12w interval continued on a q12w treatment frequency unless disease activity was identified at any of the subsequent DAA visits, in which case subjects were switched to a q8w treatment interval until the end of the study.

To fulfil the double-masking requirement, each investigational site had masked and unmasked staff. The investigator who performed the injection was unmasked to the treatments as were any other site personnel who had been delegated responsibility for working with the Investigational Product (IP). The unmasked site personnel and unmasked injecting investigator did not perform Best-corrected visual acuity (BCVA), complete ophthalmic examination (with the exception of post-injection safety assessment), DAAs or administer the Visual Functioning Questionnaire-25 (VFQ-25). Also, the unmasked site personnel and unmasked injecting physician did not perform assessment of any ocular or non-ocular safety parameters, or assess causality of Adverse event (AEs) for subjects during the course of the study except an event reported immediately following Intravitreal treatment (IVT). Once the designated roles were determined, the unmasked investigator/site personnel roles were not switched at any time after randomization to masked role. Every effort was made to limit the number of unmasked study personnel to ensure the integrity of this masked study.

Eligibility criteria: Inclusion Criteria:

* Written informed consent before any assessment
* Patients with type 1 or type 2 diabetes mellitus and HbA1c of ≤10% at screening
* Medication for the management of diabetes stable within 3 months prior to randomization and is expected to remain stable during the course of the study

Exclusion Criteria:

* Active proliferative diabetic retinopathy in the study eye
* Active intraocular or periocular infection or active intraocular inflammation in study eye
* Uncontrolled glaucoma in the study eye defined as intraocular pressure (IOP) \> 25 millimeters mercury (mmHg)
* Previous treatment with anti-VEGF drugs or investigational drugs in the study eye
* Stroke or myocardial infarction during the 6-month period prior to baseline
* Uncontrolled blood pressure defined as a systolic value ≥160 mmHg or diastolic value ≥100 mmHg

Other protocol-specified inclusion/exclusion criteria may apply

Primary outcomes:
measure: Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 52
timeFrame: Baseline, Week 52
Secondary outcomes:
measure: Average Change From Baseline in BCVA Over the Period Week 40 Through Week 52
timeFrame: Baseline and Week 40 through Week 52 (average)
measure: Patients Maintained at q12w - Probability of Maintaining on q12w
timeFrame: Baseline (Week 0), Weeks 32, 36 and 48
measure: Patients Maintained at q12w (for Those Patients Who Qualified for q12w at Week 36) - Probability of Maintaining on q12w
timeFrame: Weeks 36 and 48
measure: Change From Baseline in BCVA at Each Visit up to Week 52
timeFrame: Baseline (Week 0), Weeks 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, and 52
measure: BCVA (Letters Read): ANOVA Results for Average Change From Baseline Over the Period Week 88 Through Week 100 for the Study Eye (FAS - LOCF)
timeFrame: Baseline, and Week 88 through Week 100 (average)
measure: Patients Maintained at q12w up to Week 64 (After Three q12w- Treatment Intervals) and Week 100 - Probability of Maintaining on q12w
timeFrame: Baseline (Week 0), Weeks 32, 36, 48, 60, 72, 84, and 96
measure: Secondary: Patients Maintained at q12w up to Week 64 (After Three q12w- Treatment Intervals) and Week 100, Within Those Patients That Qualified for q12w at Week 36 - Probability of Maintaining on q12w
timeFrame: Baseline (Week 0), Weeks 32, 36, 48, 60, 72, 84, and 96
measure: Change From Baseline in Central Subfield Thickness (CSFT) at Each Visit up to Week 52 - Pairwise ANOVA Results
timeFrame: Baseline up to week 52
measure: Central Subfield Thickness (CSFT) (Micrometers): ANOVA Results for Average Change From Baseline Over the Period Week 88 Through Week 100 for the Study Eye (Full Analysis Set - LOCF)
timeFrame: Baseline, and Week 88 through Week 100 (average)
measure: Number of Patients With Presence of Subretinal Fluid (SRF) at Each Assessment Visit
timeFrame: Baseline up to Week 52 and Week 100
measure: Number of Patients With Presence of Intraretinal Fluid (IRF) at Each Assessment Visit
timeFrame: Baseline, up to Week 52 and Week 100
measure: Number of Patients With Presence of SRF and/or IRF in the Study Eye by Visit
timeFrame: Baseline, up to Week 52 and Week 100
measure: Number of Patients With Presence of Leakage on Fluorescein Angiography (FA) at Week 52
timeFrame: Week 52
measure: Number of Patients With Presence of Leakage on Fluorescein Angiography (FA) at Week 100
timeFrame: Week 100
measure: Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Number of Subjects With >=2-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye - Number of Subjects
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Proportion of Subjects With >=2-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye - Percentage Estimates
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Number of Subjects With >=3-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye - Number of Subjects
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS): Proportion of Subjects With >=3-step Improvement From Baseline in the DRSS Score at Each Assessment Visit for the Study Eye - Percentage Estimates
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Composite Score
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - General Vision
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Ocular Pain
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Near Activities
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Distance Activities
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Social Functioning
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Mental Health
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Role Difficulties
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Dependency
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Driving
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Color Vision
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Peripheral Vision
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - General Health Rating
timeFrame: Baseline, Weeks 28, 52, 76, 100
measure: Ocular Adverse Events (AEs) (>=2% in Any Treatment Arm) by Preferred Term for the Study Eye
timeFrame: Adverse events were reported from first dose of study treatment until Week 96, plus 30 days post treatment, up to a maximum duration of 100 weeks.
measure: Number of Subjects With Non-ocular Adverse Events (AEs) (>=2% in Any Treatment Arm)
timeFrame: Adverse events were reported from first dose of study treatment until Week 96, plus 30 days post treatment, up to a maximum duration of 100 weeks.
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Beverly Hills
country: United States
facility: Novartis Investigative Site
state: California
city: La Jolla
country: United States
facility: Novartis Investigative Site
state: California
city: Mountain View
country: United States
facility: Novartis Investigative Site
state: California
city: Santa Barbara
country: United States
facility: Novartis Investigative Site
state: California
city: Colorado Springs
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Danbury
country: United States
facility: Novartis Investigative Site
state: Connecticut
city: Miami
country: United States
facility: Novartis Investigative Site
state: Florida
city: Pensacola
country: United States
facility: Novartis Investigative Site
state: Florida
city: Stuart
country: United States
facility: Novartis Investigative Site
state: Florida
city: 'Aiea
country: United States
facility: Novartis Investigative Site
state: Hawaii
city: Urbana
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Wheaton
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Indianapolis
country: United States
facility: Novartis Investigative Site
state: Indiana
city: New Albany
country: United States
facility: Novartis Investigative Site
state: Indiana
city: Leawood
country: United States
facility: Novartis Investigative Site
state: Kansas
city: Lenexa
country: United States
facility: Novartis Investigative Site
state: Kansas
city: Paducah
country: United States
facility: Novartis Investigative Site
state: Kentucky
city: Springfield
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Stoneham
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Reno
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Cincinnati
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Cleveland
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Cleveland
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Kingston
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Memphis
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Nashville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Austin
country: United States
facility: Novartis Investigative Site
state: Texas
city: Austin
country: United States
facility: Novartis Investigative Site
state: Texas
city: Austin
country: United States
facility: Novartis Investigative Site
state: Texas
city: Bellaire
country: United States
facility: Novartis Investigative Site
state: Texas
city: Harlingen
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: San Antonio
country: United States
facility: Novartis Investigative Site
state: Texas
city: Tyler
country: United States
facility: Novartis Investigative Site
state: Texas
city: Silverdale
country: United States
facility: Novartis Investigative Site
state: Washington
city: Spokane
country: United States
facility: Novartis Investigative Site
state: Washington
city: Madison
country: United States
facility: Novartis Investigative Site
state: Wisconsin
city: Ciudad Autonoma de Bs As
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Provincia De Santa Fe
city: Caba
country: Argentina
facility: Novartis Investigative Site
city: Caba
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Liverpool
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Parramatta
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Sydney
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Clayton
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Nedlands
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Graz
country: Austria
facility: Novartis Investigative Site
city: Innsbruck
country: Austria
facility: Novartis Investigative Site
city: Vienna
country: Austria
facility: Novartis Investigative Site
city: Ottawa
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Quebec
country: Canada
facility: Novartis Investigative Site
city: Medellin
country: Colombia
facility: Novartis Investigative Site
state: Antioquia
city: Medellin
country: Colombia
facility: Novartis Investigative Site
state: Antioquia
city: Bogota
country: Colombia
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Kfar Saba
country: Israel
facility: Novartis Investigative Site
city: Petach Tikva
country: Israel
facility: Novartis Investigative Site
city: Rehovot
country: Israel
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Chieti
country: Italy
facility: Novartis Investigative Site
state: CH
city: Catania
country: Italy
facility: Novartis Investigative Site
state: CT
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Nagoya-city
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Kurume-city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Amagasaki city
country: Japan
facility: Novartis Investigative Site
state: Hyogo
city: Tsuchiura
country: Japan
facility: Novartis Investigative Site
state: Ibaragi
city: Ishioka
country: Japan
facility: Novartis Investigative Site
state: Ibaraki
city: Kagoshima city
country: Japan
facility: Novartis Investigative Site
state: Kagoshima
city: Matsumoto-city
country: Japan
facility: Novartis Investigative Site
state: Nagano
city: Saitama-shi
country: Japan
facility: Novartis Investigative Site
state: Saitama
city: Shimotsuke
country: Japan
facility: Novartis Investigative Site
state: Tochigi
city: Chiyoda-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Hachioji-city
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Shinjuku ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Taito-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Kumamoto
country: Japan
facility: Novartis Investigative Site
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Tilburg
country: Netherlands
facility: Novartis Investigative Site
city: Coimbra
country: Portugal
facility: Novartis Investigative Site
city: Coimbra
country: Portugal
facility: Novartis Investigative Site
city: Leiria
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Porto
country: Portugal
facility: Novartis Investigative Site
city: Santa Maria da Feira
country: Portugal
facility: Novartis Investigative Site
city: Vila Franca de Xira
country: Portugal
facility: Novartis Investigative Site
city: Arecibo
country: Puerto Rico
facility: Novartis Investigative Site
city: Valladolid
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Sant Cugat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Zaragoza
country: Spain
facility: Novartis Investigative Site
city: Frimley
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: Hull
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: