Study of Efficacy and Safety of Brolucizumab vs. Aflibercept in Patients With Visual Impairment Due to Diabetic Macular Edema (KESTREL)

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

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).

Study Overview

• Status: Completed
• Conditions: Diabetic Macular Edema
• Intervention / Treatment: Drug: Brolucizumab; Drug: Aflibercept

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.

• Study Type: Interventional
• Enrollment (Actual): 566
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Caba, Argentina
    • Novartis Investigative Site
  • Caba, Argentina, 1425
    • Novartis Investigative Site
  • Cordoba, Argentina, X5000AAJ
    • Novartis Investigative Site
  • Buenos Aires
    • Ciudad Autonoma de Bs As, Buenos Aires, Argentina, C1015ABO
      • Novartis Investigative Site
  • Provincia De Santa Fe
    • Rosario, Provincia De Santa Fe, Argentina
      • Novartis Investigative Site
• Australia
  • New South Wales
    • Liverpool, New South Wales, Australia, 2170
      • Novartis Investigative Site
    • Parramatta, New South Wales, Australia, 2150
      • Novartis Investigative Site
    • Sydney, New South Wales, Australia, 2000
      • Novartis Investigative Site
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Novartis Investigative Site
    • Melbourne, Victoria, Australia, 3002
      • Novartis Investigative Site
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Novartis Investigative Site
• Austria
  • Graz, Austria, A-8036
    • Novartis Investigative Site
  • Innsbruck, Austria, 6020
    • Novartis Investigative Site
  • Vienna, Austria, 1090
    • Novartis Investigative Site
• Canada
  • Quebec, Canada, G1S 4L8
    • Novartis Investigative Site
  • Ontario
    • Ottawa, Ontario, Canada, K1Z 8R2
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5C 2T2
      • Novartis Investigative Site
• Colombia
  • Bogota, Colombia, 110221
    • Novartis Investigative Site
  • Antioquia
    • Medellin, Antioquia, Colombia
      • Novartis Investigative Site
    • Medellin, Antioquia, Colombia, 001
      • Novartis Investigative Site
• Israel
  • Haifa, Israel, 3339419
    • Novartis Investigative Site
  • Haifa, Israel, 3436212
    • Novartis Investigative Site
  • Haifa, Israel, 3109601
    • Novartis Investigative Site
  • Jerusalem, Israel, 9112001
    • Novartis Investigative Site
  • Kfar Saba, Israel, 4428164
    • Novartis Investigative Site
  • Petach Tikva, Israel, 4941492
    • Novartis Investigative Site
  • Rehovot, Israel, 7610001
    • Novartis Investigative Site
  • Tel Aviv, Israel, 6423906
    • Novartis Investigative Site
• Italy
  • CH
    • Chieti, CH, Italy, 66100
      • Novartis Investigative Site
  • CT
    • Catania, CT, Italy, 95124
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
    • Milano, MI, Italy, 20100
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35128
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00144
      • Novartis Investigative Site
• Japan
  • Kumamoto, Japan
    • Novartis Investigative Site
  • Osaka, Japan, 543-0027
    • Novartis Investigative Site
  • Aichi
    • Nagoya, Aichi, Japan, 466 8560
      • Novartis Investigative Site
    • Nagoya, Aichi, Japan, 457-8511
      • Novartis Investigative Site
    • Nagoya, Aichi, Japan, 455-8530
      • Novartis Investigative Site
    • Nagoya-city, Aichi, Japan, 462-0825
      • Novartis Investigative Site
  • Fukuoka
    • Kurume-city, Fukuoka, Japan, 830-8543
      • Novartis Investigative Site
  • Hyogo
    • Amagasaki city, Hyogo, Japan, 660 8550
      • Novartis Investigative Site
  • Ibaragi
    • Tsuchiura, Ibaragi, Japan, 300-0817
      • Novartis Investigative Site
  • Ibaraki
    • Ishioka, Ibaraki, Japan, 315-0037
      • Novartis Investigative Site
  • Kagoshima
    • Kagoshima city, Kagoshima, Japan, 890 8520
      • Novartis Investigative Site
  • Nagano
    • Matsumoto-city, Nagano, Japan, 390-8621
      • Novartis Investigative Site
  • Saitama
    • Saitama-shi, Saitama, Japan, 336-0963
      • Novartis Investigative Site
  • Tochigi
    • Shimotsuke, Tochigi, Japan, 329-0498
      • Novartis Investigative Site
  • Tokyo
    • Chiyoda-ku, Tokyo, Japan, 101-8309
      • Novartis Investigative Site
    • Hachioji-city, Tokyo, Japan, 193-0944
      • Novartis Investigative Site
    • Shinjuku ku, Tokyo, Japan, 162 8666
      • Novartis Investigative Site
    • Taito-ku, Tokyo, Japan, 111-0051
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3011 BH
    • Novartis Investigative Site
  • Tilburg, Netherlands, 5022 GC
    • Novartis Investigative Site
• Portugal
  • Coimbra, Portugal, 3000-548
    • Novartis Investigative Site
  • Coimbra, Portugal, 3030-363
    • Novartis Investigative Site
  • Leiria, Portugal, 2410-187
    • Novartis Investigative Site
  • Porto, Portugal, 4099-001
    • Novartis Investigative Site
  • Porto, Portugal, 4200 319
    • Novartis Investigative Site
  • Santa Maria da Feira, Portugal, 4520 211
    • Novartis Investigative Site
  • Vila Franca de Xira, Portugal, 2600-009
    • Novartis Investigative Site
• Puerto Rico
  • Arecibo, Puerto Rico, 00612
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08025
    • Novartis Investigative Site
  • Zaragoza, Spain, 50009
    • Novartis Investigative Site
  • Castilla Y Leon
    • Valladolid, Castilla Y Leon, Spain, 47011
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
    • Sant Cugat, Catalunya, Spain, 08190
      • Novartis Investigative Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46014
      • Novartis Investigative Site
• United Kingdom
  • Birmingham, United Kingdom, B18 7QH
    • Novartis Investigative Site
  • Hull, United Kingdom, HU3 2JZ
    • Novartis Investigative Site
  • London, United Kingdom, NW10 7NS
    • Novartis Investigative Site
  • Nottingham, United Kingdom, NG7 2UH
    • Novartis Investigative Site
  • Surrey
    • Frimley, Surrey, United Kingdom, GU16 7UJ
      • Novartis Investigative Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85053
      • Novartis Investigative Site
  • California
    • Beverly Hills, California, United States, 90211
      • Novartis Investigative Site
    • 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
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Novartis Investigative Site
  • Florida
    • Miami, Florida, United States, 33136
      • Novartis Investigative Site
    • Pensacola, Florida, United States, 32503
      • Novartis Investigative Site
    • Stuart, Florida, United States, 34994
      • Novartis Investigative Site
  • Hawaii
    • 'Aiea, Hawaii, United States, 96701
      • Novartis Investigative Site
  • Illinois
    • Urbana, Illinois, United States, 61801
      • Novartis Investigative Site
    • Wheaton, Illinois, United States, 60187
      • 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
  • Kentucky
    • Paducah, Kentucky, United States, 42001
      • Novartis Investigative Site
  • Massachusetts
    • Springfield, Massachusetts, United States, 01107
      • Novartis Investigative Site
    • Stoneham, Massachusetts, United States, 02180
      • Novartis Investigative Site
  • Nevada
    • Reno, Nevada, United States, 89502
      • Novartis Investigative Site
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Novartis Investigative Site
    • Cleveland, Ohio, United States, 44195
      • Novartis Investigative Site
    • Cleveland, Ohio, United States, 44122
      • Novartis Investigative Site
  • Pennsylvania
    • Kingston, Pennsylvania, United States, 95403
      • Novartis Investigative Site
    • Philadelphia, Pennsylvania, United States, 19107
      • Novartis Investigative Site
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Novartis Investigative Site
    • Nashville, Tennessee, United States, 37232
      • Novartis Investigative Site
  • Texas
    • Austin, Texas, United States, 78705
      • 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
    • Harlingen, Texas, United States, 78550
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78240
      • Novartis Investigative Site
    • Tyler, Texas, United States, 75701
      • Novartis Investigative Site
  • Washington
    • Silverdale, Washington, United States, 98383
      • Novartis Investigative Site
    • Spokane, Washington, United States, 99204
      • 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:

• 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Brolucizumab 3 mg; Brolucizumab 3 mg/0.05 mL, 5 loading doses, with subsequent doses per protocol-specified maintenance schedule. 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).	Drug: Brolucizumab; Intravitreal injection; Other Names: RTH258; ESBA1008
Experimental: Brolucizumab 6 mg; Brolucizumab 6 mg/0.05 mL, 5 loading doses, with subsequent doses per protocol-specified maintenance schedule. 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).	Drug: Brolucizumab; Intravitreal injection; Other Names: RTH258; ESBA1008
Active Comparator: Aflibercept 2 mg; Aflibercept 2 mg/0.05 mL, as labeled, 5 loading doses, with subsequent doses every 8 weeks. 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).	Drug: Aflibercept; Intravitreal injection; 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 52	BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual Function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 78 to 23 (approximate Snellen equivalent of 20/32 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning. This endpoint was analyzed via the pairwise ANOVA method where the 2 dose groups of Brolucizumab are compared to Aflibercept.	Baseline, Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Change From Baseline in BCVA Over the Period Week 40 Through Week 52	BCVA will be assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 78 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/32 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning. This endpoint was analyzed via the pairwise ANOVA method where the 2 dose groups of Brolucizumab are compared to Aflibercept.	Baseline and Week 40 through Week 52 (average)
Patients Maintained at q12w - Probability of Maintaining on q12w	Positive treatment status is defined as intravitreal (IVT) injections per planned dosing regimen [every 12 weeks (q12w)]. This outcome measure is pre-specified for brolucizumab treatment arms only.	Baseline (Week 0), Weeks 32, 36 and 48
Patients Maintained at q12w (for Those Patients Who Qualified for q12w at Week 36) - Probability of Maintaining on q12w	Positive treatment status is defined as intravitreal (IVT) injections per planned dosing regimen [every 8 weeks (q8w)]. This outcome measure is pre-specified for brolucizumab treatment arms only.	Weeks 36 and 48
Change From Baseline in BCVA at Each Visit up to Week 52	BCVA was assessed using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. Visual function of the study eye was assessed using the ETDRS protocol. Participants with a BCVA ETDRS letter score of 78 to 23 (approximate Snellen equivalent of 20/32 to 20/320) in the study eye were included. Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning.	Baseline (Week 0), Weeks 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, and 52
BCVA (Letters Read): ANOVA Results for Average Change From Baseline Over the Period Week 88 Through Week 100 for the Study Eye (FAS - LOCF)	Visual acuity was assessed at every study visit using best correction determined from protocol refraction (BCVA). BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts. LS Mean estimates are reported, comparing the 2 Brolucizumab arms to Aflibercept. Results do not apply to the Brolucizumab 6 mg arm when Brolucizumab 3mg is compared to Aflibercept. Likewise, results do not apply to the Brolucizumab 3 mg arm when Brolucizumab 6 mg is compared to Aflibercept.	Baseline, and Week 88 through Week 100 (average)
Patients Maintained at q12w up to Week 64 (After Three q12w- Treatment Intervals) and Week 100 - Probability of Maintaining on q12w	This outcome measure is pre-specified for brolucizumab treatment arms only	Baseline (Week 0), Weeks 32, 36, 48, 60, 72, 84, and 96
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	This outcome measure is pre-specified for brolucizumab treatment arms only	Baseline (Week 0), Weeks 32, 36, 48, 60, 72, 84, and 96
Change From Baseline in Central Subfield Thickness (CSFT) at Each Visit up to Week 52 - Pairwise ANOVA Results	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. LS Mean estimates are reported, comparing the 2 Brolucizumab arms to Aflibercept. Results do not apply to the Brolucizumab 6 mg arm when Brolucizumab 3mg is compared to Aflibercept. Likewise, results do not apply to the Brolucizumab 3 mg arm when Brolucizumab 6 mg is compared to Aflibercept.	Baseline up to week 52
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)	Central subfield thickness (average thickness of circular 1mm area centered around fovea measured from RPE to ILM, inclusively). Assessed with Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts. LS Mean estimates are reported, comparing the 2 Brolucizumab arms to Aflibercept. Results do not apply to the Brolucizumab 6 mg arm when Brolucizumab 3mg is compared to Aflibercept. Likewise, results do not apply to the Brolucizumab 3 mg arm when Brolucizumab 6 mg is compared to Aflibercept.	Baseline, and Week 88 through Week 100 (average)
Number of Patients With Presence of Subretinal Fluid (SRF) at Each Assessment Visit	Subretinal Fluid (SRF) status in the central subfield: proportion of subjects with presence of SRF in the study eye by visit	Baseline up to Week 52 and Week 100
Number of Patients With Presence of Intraretinal Fluid (IRF) at Each Assessment Visit	Intraretinal Fluid (IRF) status in the central subfield: proportion of subjects with presence of IRF in the study eye by visit	Baseline, up to Week 52 and Week 100
Number of Patients With Presence of SRF and/or IRF in the Study Eye by Visit	Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) status in the central subfield: proportion of subjects with presence of SRF and/or IRF in the study eye by visit	Baseline, up to Week 52 and Week 100
Number of Patients With Presence of Leakage on Fluorescein Angiography (FA) at Week 52	Assessed by angiography.	Week 52
Number of Patients With Presence of Leakage on Fluorescein Angiography (FA) at Week 100	Assessed by angiography.	Week 100
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	Severity of Diabetic Retinopathy (DR) was evaluated using the ETDRS DRSS score assessed by the Central Reading Center (CRC) based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR). A lower score represents better visual functioning.	Baseline, Weeks 28, 52, 76, 100
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	Severity of Diabetic Retinopathy (DR) was evaluated using the ETDRS DRSS score assessed by the Central Reading Center (CRC) based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR). A lower score represents better visual functioning.; estimates are reported, comparing the 2 Brolucizumab arms to Aflibercept. Results do not apply to the Brolucizumab 6 mg arm when Brolucizumab 3mg is compared to Aflibercept. Likewise, results do not apply to the Brolucizumab 3 mg arm when Brolucizumab 6 mg is compared to Aflibercept.; estimates represent the % of participants who were estimated to have a ">=2-step Improvement From Baseline in the DRSS Score" from pairwise logistic regression models adjusting for baseline DRSS score categories (<=4, ≥5), age categories (<65, ≥65 years) and treatment as fixed effect factors. Abbreviation: Proportion Estimates = P.E.	Baseline, Weeks 28, 52, 76, 100
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	Severity of Diabetic Retinopathy (DR) was evaluated using the ETDRS DRSS score assessed by the Central Reading Center (CRC) based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR). A lower score represents better visual functioning.	Baseline, Weeks 28, 52, 76, 100
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	Severity of Diabetic Retinopathy (DR) was evaluated using the ETDRS DRSS score assessed by the Central Reading Center (CRC) based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on a 12-level scale, from 1 (DR absent) to 12 (very advanced PDR). A lower score represents better visual functioning.; estimates are reported, comparing the 2 Brolucizumab arms to Aflibercept. Results do not apply to the Brolucizumab 6 mg arm when Brolucizumab 3mg is compared to Aflibercept. Likewise, results do not apply to the Brolucizumab 3 mg arm when Brolucizumab 6 mg is compared to Aflibercept.; estimates represent the % of participants who were estimated to have a ">=3-step Improvement From Baseline in the DRSS Score" from pairwise logistic regression models adjusting for baseline DRSS score categories (<=4, ≥5), age categories (<65, ≥65 years) and treatment as fixed effect factors. Abbreviation: Proportion Estimates = P.E.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Composite Score	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - General Vision	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Ocular Pain	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Near Activities	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Distance Activities	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Social Functioning	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Mental Health	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Role Difficulties	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Dependency	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Driving	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Color Vision	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Peripheral Vision	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
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	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains. The NEI VFQ-25 consists of a base set of 25 vision-targeted questions representing 11 vision-related constructs, plus an additional single-item general health rating question. All items are scored so that a high score represents better visual 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. A composite score is derived based on the average of the 11 subscales.	Baseline, Weeks 28, 52, 76, 100
Ocular Adverse Events (AEs) (>=2% in Any Treatment Arm) by Preferred Term for the Study Eye		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.
Number of Subjects With Non-ocular Adverse Events (AEs) (>=2% in Any Treatment Arm)		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.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2018
• Primary Completion (Actual): November 11, 2020
• Study Completion (Actual): October 18, 2021

Study Registration Dates

• First Submitted: March 13, 2018
• First Submitted That Met QC Criteria: March 27, 2018
• First Posted (Actual): March 29, 2018

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: macular edema; intravitreal injection; Diabetic Macular Edema; diabetic retinopathy; aflibercept; brolucizumab; Diabetic Macular Edema (DME); double-masked
• Additional Relevant MeSH Terms: Nervous System Diseases; Eye Diseases; Neurologic Manifestations; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Sensation Disorders; Macular Edema; Edema; Vision, Low; Vision Disorders; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept
• Other Study ID Numbers: CRTH258B2301; 2017-004742-23 (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