Efficacy and Safety of Brolucizumab vs Aflibercept in Patients With Visual Impairment Due to Diabetic Macular Edema

Diabetic Macular Edema Clinical Trial

— KINGFISHER  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03917472
• Other study ID #: CRTH258B2305
• Secondary ID: 2019-001004-37
• Status: Completed
• Phase: Phase 3
• Start date: July 17, 2019
• Est. completion date: March 24, 2021

Study information

• Verified date: August 2022
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 517
• Est. completion date: March 24, 2021
• Est. primary completion date: March 24, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetic Macular Edema
• Edema
• Macular Edema
• Vision Disorders
• Vision, Low

Intervention

Drug:
• Brolucizumab
Intravitreal injection
• Aflibercept
Intravitreal injection

Locations

Country	Name	City	State
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Pecs	Baranya
Hungary	Novartis Investigative Site	Szeged
Hungary	Novartis Investigative Site	Zalaegerszeg	Zala
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Haifa
Israel	Novartis Investigative Site	Kfar Saba
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Tel Aviv
Puerto Rico	Novartis Investigative Site	Arecibo
Slovakia	Novartis Investigative Site	Banska Bystrica
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Poprad
Slovakia	Novartis Investigative Site	Trebisov
Slovakia	Novartis Investigative Site	Trencin
Slovakia	Novartis Investigative Site	Zvolen
United States	Novartis Investigative Site	'Aiea	Hawaii
United States	Novartis Investigative Site	Abilene	Texas
United States	Novartis Investigative Site	Altamonte Springs	Florida
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Austin	Texas
United States	Novartis Investigative Site	Austin	Texas
United States	Novartis Investigative Site	Austin	Texas
United States	Novartis Investigative Site	Bellaire	Texas
United States	Novartis Investigative Site	Beverly Hills	California
United States	Novartis Investigative Site	Bloomfield	New Jersey
United States	Novartis Investigative Site	Bloomington	Illinois
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Campbell	California
United States	Novartis Investigative Site	Chattanooga	Tennessee
United States	Novartis Investigative Site	Cleveland	Ohio
United States	Novartis Investigative Site	Columbus	Ohio
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Deerfield Beach	Florida
United States	Novartis Investigative Site	Dublin	Ohio
United States	Novartis Investigative Site	Eugene	Oregon
United States	Novartis Investigative Site	Fort Lauderdale	Florida
United States	Novartis Investigative Site	Fort Myers	Florida
United States	Novartis Investigative Site	Fort Worth	Texas
United States	Novartis Investigative Site	Fresno	California
United States	Novartis Investigative Site	Germantown	Tennessee
United States	Novartis Investigative Site	Hagerstown	Maryland
United States	Novartis Investigative Site	Harlingen	Texas
United States	Novartis Investigative Site	Hickory	North Carolina
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Huntington Beach	California
United States	Novartis Investigative Site	Indianapolis	Indiana
United States	Novartis Investigative Site	Kansas City	Missouri
United States	Novartis Investigative Site	Kingston	Pennsylvania
United States	Novartis Investigative Site	Leawood	Kansas
United States	Novartis Investigative Site	Lenexa	Kansas
United States	Novartis Investigative Site	Loma Linda	California
United States	Novartis Investigative Site	Madison	Wisconsin
United States	Novartis Investigative Site	Marietta	Georgia
United States	Novartis Investigative Site	Minneapolis	Minnesota
United States	Novartis Investigative Site	Morgantown	West Virginia
United States	Novartis Investigative Site	Mountain View	California
United States	Novartis Investigative Site	New Albany	Indiana
United States	Novartis Investigative Site	Norfolk	Virginia
United States	Novartis Investigative Site	Oak Forest	Illinois
United States	Novartis Investigative Site	Oakland	California
United States	Novartis Investigative Site	Orlando	Florida
United States	Novartis Investigative Site	Pasadena	California
United States	Novartis Investigative Site	Phoenix	Arizona
United States	Novartis Investigative Site	Phoenix	Arizona
United States	Novartis Investigative Site	Pinellas Park	Florida
United States	Novartis Investigative Site	Poway	California
United States	Novartis Investigative Site	Rancho Cordova	California
United States	Novartis Investigative Site	Redlands	California
United States	Novartis Investigative Site	Reno	Nevada
United States	Novartis Investigative Site	Riverside	California
United States	Novartis Investigative Site	Rochester	New York
United States	Novartis Investigative Site	Royal Oak	Michigan
United States	Novartis Investigative Site	Sacramento	California
United States	Novartis Investigative Site	Sacramento	California
United States	Novartis Investigative Site	Saint Petersburg	Florida
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Francisco	California
United States	Novartis Investigative Site	Santa Ana	California
United States	Novartis Investigative Site	Santa Barbara	California
United States	Novartis Investigative Site	Southern Pines	North Carolina
United States	Novartis Investigative Site	Southlake	Texas
United States	Novartis Investigative Site	Springfield	Illinois
United States	Novartis Investigative Site	Tampa	Florida
United States	Novartis Investigative Site	Teaneck	New Jersey
United States	Novartis Investigative Site	Torrance	California
United States	Novartis Investigative Site	Tucson	Arizona
United States	Novartis Investigative Site	Ventura	California
United States	Novartis Investigative Site	West Des Moines	Iowa

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Hungary,  Israel,  Puerto Rico,  Slovakia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Best-corrected Visual Acuity (BCVA) at 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 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included.; Min and max possible scores are 0-100 respectively. A higher score represents better functioning.; Last observation carried forward (LOCF) was used for the imputation of missing values.	Baseline, Week 52
Secondary	Change From Baseline in Central Subfield Thickness (CSFT) at Each Post-baseline Visit	Central Subfield Thickness assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Secondary	Number and Percentage of Participants With Fluid-free Macula in the Study Eye at Each Post-baseline Visit	Subretinal Fluid (SRF) and Intraretinal Fluid (IRF) status in the central subfield: proportion of subjects with simultaneous absence of SRF and IRF in the study eye by visit. Events and censoring after 52 weeks are included in week 52 row.	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Secondary	Number and Percentage of Participants With Absence of Diabetic Macular Edema (DME) (CSFT < 280 µm) at Each Post-baseline Visit for the Study Eye	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Secondary	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	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Secondary	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	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. Fluid status assessments after start of alternative DME treatment in the study eye are censored. Time to first fluid-free macula analysis is based on the subset of subjects with fluid present at baseline and at least one post-baseline assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Secondary	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	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Secondary	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	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center. CSFT assessments after start of alternative DME treatment in the study eye are censored. Time to first absence of DME based on subjects with valid baseline and at least one post-baseline CSFT assessment. Time (week) was calculated by (study day / 7). Events and censoring after 52 weeks were included in week 52 row.	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Secondary	Best Corrected Visual Acuity (Letters Read): Change From Baseline in Best-corrected Visual Acuity (BCVA) at Each Post-baseline Visit for the Study Eye	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 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included.; Min and max possible scores are 0-100 respectively. A higher score represents better functioning.	Baseline, Weeks 4,8,12,16,20,24,28,32,36,40,44,48 and 52
Secondary	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	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 73 to 23 (per the inclusion criteria) (approximate Snellen equivalent of 20/40 to 20/320) in the study eye were included.; Min and max possible scores are 0-100 respectively. A higher score represents better functioning.	Baseline, Week 52
Secondary	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	The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative.; Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the =2-step and =3-step change from baseline for each post-baseline assessment".; A lower score represents better functioning.; Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded.; DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.	Baseline, Weeks 12, 24 and 52
Secondary	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	The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative.; Severity of Diabetic retinopathy was evaluated using the ETDRS DRSS score assessed by the Central Reading Center based on color fundus photography images in the study eye. When the ETDRS-DR severities were evaluable, they were categorized on the original scale with scores varying from 10 (DR absent) to 85 (very advanced PDR). All DRSS values were then converted into a 12-level scale, allowing the derivation of the =2-step and =3-step change from baseline for each post-baseline assessment".; A lower score represents better functioning.; Subjects who had full/partial panretinal photocoagulation or local photocoagulation for new vessel (DRSS score 60) at any visit were excluded.; DRSS scores after start of alternative DME treatment in the study eye are censored and replaced by the last value prior to start of this alternative treatment.	Baseline, Weeks 12, 24 and 52
Secondary	Anti-Drug Antibody (ADA): Frequency Distribution of Pre-existing ADA Status in the Brolucizumab Arm		Baseline
Secondary	Ocular AEs (Greater Than or Equal to 2% in Any Treatment Arm) by Preferred Term in the Study Eye		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.
Secondary	Number of Subjects With Non-ocular AEs (Greater Than or Equal to 2% in Any Treatment Arm)		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.

External Links

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