Clinical trial NCT03917472: Efficacy and Safety of Brolucizumab vs Aflibercept in Patients With Visual Impairment Due to Diabetic Macular Edema
Official title: A 12-Month, 2-Arm, Randomized, Double-Masked, Multicenter Phase III Study Assessing the Efficacy and Safety of Brolucizumab vs. Aflibercept in Patients With Visual Impairment Due to Diabetic Macular Edema (KINGFISHER)
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: 2019-04-17
Enrollment: 517
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 vs. aflibercept in the treatment of patients with visual impairment due to diabetic macular edema (DME).

Detailed description: This study was designed as a Phase III, multi-center, randomized, double-masked, active controlled, parallel group prospective study to evaluate if brolucizumab 6 mg dosed q4w is safe and effective in the treatment of subjects with visual impairment due to diabetic macular edema (DME). Subjects who met all the inclusion and none of the exclusion criteria were randomized in a 2:1 ratio to one of two treatment arms i.e., brolucizumab 6 mg and aflibercept 2 mg. Only one eye was selected as study eye and treated with study medication.

The study included a screening period of up to 2 weeks to assess eligibility, followed by a double-masked treatment period (Day 1 to Week 48). For all subjects, the last study assessment was performed at the Week 52/end of study (EOS) visit. All subjects had study visits q4w through Week 52. The primary analysis was performed at the EOS visit (Week 52).

To ensure masking was maintained, the investigational site had both masked and unmasked staff to perform the masked and unmasked study assessments/procedures accordingly.

Eligibility criteria: Inclusion Criteria:

* Signed informed consent must be obtained prior to participation in the study.
* Patients with type 1 or type 2 diabetes mellitus (DM) and Hemoglobin A1c (HbA1c) ≤ 12% at screening.
* Study eye: Visual impairment due to DME with:

  * Best-corrected visual acuity (BCVA) score between 73 and 23 letters, inclusive, using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing charts at an initial testing distance of 4 meters
  * DME involving the center of the macula, with Central Subfield Thickness (CSFT) ≥ 320 µm on Spectral Domain Optical Coherence Tomography (SD-OCT)

Exclusion Criteria:

* High-risk proliferative diabetic retinopathy (PDR) in the study eye
* Concomitant conditions or ocular disorders in the study eye which confound interpretation of study results, compromise visual acuity or require medical or surgical intervention
* Any active intraocular or periocular infection or active intraocular inflammation in the either eye
* Uncontrolled glaucoma in the study eye
* Presence of amblyopia, amaurosis or ocular disorders in the fellow eye with BCVA \<20/200
* Use of anti-VEGF therapies, intraocular surgery or laser photocoagulation (macular or panretinal) in the study eye during the 3-month period prior to baseline
* Use of intraocular or periocular corticosteroids in the study eye during the 6-month period prior to baseline, and use of fluocinolone acetonide intravitreal (IVT) implant (Iluvien) at any time prior to baseline
* Prior investigational drugs in either eye, vitreoretinal surgery in the study eye at any time prior to baseline

Primary outcomes:
measure: Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 52
timeFrame: Baseline, Week 52
Secondary outcomes:
measure: Change From Baseline in Central Subfield Thickness (CSFT) at Each Post-baseline Visit
timeFrame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
measure: Number and Percentage of Participants With Fluid-free Macula in the Study Eye at Each Post-baseline Visit
timeFrame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
measure: Number and Percentage of Participants With Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) at Each Post-baseline Visit for the Study Eye
timeFrame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
measure: Time to First Fluid-free Macula - Time-to-first Absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the Study Eye - Number of Subjects With Absence of SRF / IRF and Number of Subjects Censored by Visit
timeFrame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
measure: Time to First Fluid-free Macula - Time-to-first Absence of Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) in the Study Eye - Kaplan-Meier Analysis - Probability of Absence of SRF/IRF by Visit
timeFrame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
measure: Time to First Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the Study Eye at Each Post-baseline Visit - Number of Subjects With Probability of Absence of DME and Number Censored by Visit
timeFrame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
measure: Time to First Absence of Diabetic Macular Edema (DME) (CSFT < 280 μm) in the Study Eye at Each Post-baseline Visit - Kaplan-Meier Analysis - Probability of Absence of DME by Visit
timeFrame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
measure: Best Corrected Visual Acuity (Letters Read): Change From Baseline in Best-corrected Visual Acuity (BCVA) at Each Post-baseline Visit for the Study Eye
timeFrame: Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
measure: Gain in Best-corrected Visual Acuity (BCVA) (Letters Read): Number (%) of Subjects Who Gained ≥ 5, 10, or 15 Letters in BCVA From Baseline or Reached BCVA ≥ 84 Letters in the Study Eye at Week 52
timeFrame: Baseline, Week 52
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
timeFrame: Baseline, Weeks 12, 24 and 52
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
timeFrame: Baseline, Weeks 12, 24 and 52
measure: Anti-Drug Antibody (ADA): Frequency Distribution of Pre-existing ADA Status in the Brolucizumab Arm
timeFrame: Baseline
measure: Ocular AEs (Greater Than or Equal to 2% in Any Treatment Arm) by Preferred Term in the Study Eye
timeFrame: Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.
measure: Number of Subjects With Non-ocular AEs (Greater Than or Equal to 2% in Any Treatment Arm)
timeFrame: Adverse events were reported from first dose of study treatment until end of study treatment plus 30 days post treatment, up to a maximum duration of approximately 52 weeks.
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Phoenix
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Tucson
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Beverly Hills
country: United States
facility: Novartis Investigative Site
state: California
city: Campbell
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facility: Novartis Investigative Site
state: California
city: Fresno
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facility: Novartis Investigative Site
state: California
city: Huntington Beach
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facility: Novartis Investigative Site
state: California
city: Loma Linda
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facility: Novartis Investigative Site
state: California
city: Mountain View
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facility: Novartis Investigative Site
state: California
city: Oakland
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facility: Novartis Investigative Site
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city: Pasadena
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facility: Novartis Investigative Site
state: California
city: Poway
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facility: Novartis Investigative Site
state: California
city: Rancho Cordova
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state: California
city: Redlands
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state: California
city: Riverside
country: United States
facility: Novartis Investigative Site
state: California
city: Sacramento
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facility: Novartis Investigative Site
state: California
city: Sacramento
country: United States
facility: Novartis Investigative Site
state: California
city: San Francisco
country: United States
facility: Novartis Investigative Site
state: California
city: Santa Ana
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facility: Novartis Investigative Site
state: California
city: Santa Barbara
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facility: Novartis Investigative Site
state: California
city: Torrance
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facility: Novartis Investigative Site
state: California
city: Ventura
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facility: Novartis Investigative Site
state: California
city: Altamonte Springs
country: United States
facility: Novartis Investigative Site
state: Florida
city: Deerfield Beach
country: United States
facility: Novartis Investigative Site
state: Florida
city: Fort Lauderdale
country: United States
facility: Novartis Investigative Site
state: Florida
city: Fort Myers
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facility: Novartis Investigative Site
state: Florida
city: Orlando
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facility: Novartis Investigative Site
state: Florida
city: Pinellas Park
country: United States
facility: Novartis Investigative Site
state: Florida
city: Saint Petersburg
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facility: Novartis Investigative Site
state: Florida
city: Tampa
country: United States
facility: Novartis Investigative Site
state: Florida
city: Atlanta
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facility: Novartis Investigative Site
state: Georgia
city: Marietta
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facility: Novartis Investigative Site
state: Georgia
city: 'Aiea
country: United States
facility: Novartis Investigative Site
state: Hawaii
city: Bloomington
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Oak Forest
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facility: Novartis Investigative Site
state: Illinois
city: Springfield
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facility: Novartis Investigative Site
state: Illinois
city: Indianapolis
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facility: Novartis Investigative Site
state: Indiana
city: New Albany
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state: Indiana
city: West Des Moines
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facility: Novartis Investigative Site
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city: Leawood
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state: Kansas
city: Lenexa
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facility: Novartis Investigative Site
state: Kansas
city: Hagerstown
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Boston
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facility: Novartis Investigative Site
state: Massachusetts
city: Royal Oak
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state: Michigan
city: Minneapolis
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facility: Novartis Investigative Site
state: Minnesota
city: Kansas City
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state: Missouri
city: Reno
country: United States
facility: Novartis Investigative Site
state: Nevada
city: Bloomfield
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Teaneck
country: United States
facility: Novartis Investigative Site
state: New Jersey
city: Rochester
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facility: Novartis Investigative Site
state: New York
city: Hickory
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Southern Pines
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Cleveland
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Columbus
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Dublin
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Eugene
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Kingston
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Chattanooga
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Germantown
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Abilene
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: Austin
country: United States
facility: Novartis Investigative Site
state: Texas
city: Bellaire
country: United States
facility: Novartis Investigative Site
state: Texas
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: Fort Worth
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: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: San Antonio
country: United States
facility: Novartis Investigative Site
state: Texas
city: Southlake
country: United States
facility: Novartis Investigative Site
state: Texas
city: Norfolk
country: United States
facility: Novartis Investigative Site
state: Virginia
city: Morgantown
country: United States
facility: Novartis Investigative Site
state: West Virginia
city: Madison
country: United States
facility: Novartis Investigative Site
state: Wisconsin
city: Pecs
country: Hungary
facility: Novartis Investigative Site
state: Baranya
city: Zalaegerszeg
country: Hungary
facility: Novartis Investigative Site
state: Zala
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Szeged
country: Hungary
facility: Novartis Investigative Site
city: Haifa
country: Israel
facility: Novartis Investigative Site
city: Haifa
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: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Arecibo
country: Puerto Rico
facility: Novartis Investigative Site
city: Banska Bystrica
country: Slovakia
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
city: Bratislava
country: Slovakia
facility: Novartis Investigative Site
city: Poprad
country: Slovakia
facility: Novartis Investigative Site
city: Trebisov
country: Slovakia
facility: Novartis Investigative Site
city: Trencin
country: Slovakia
facility: Novartis Investigative Site
city: Zvolen
country: Slovakia
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: