Back to results

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

Primary Purpose

Diabetic Macular Edema

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Brolucizumab

Aflibercept

About this trial

This is an interventional treatment trial for Diabetic Macular Edema focused on measuring Diabetic Macular Edema, intravitreal injection, brolucizumab, aflibercept, double-masked, Diabetic Macular Edema (DME), macular edema, diabetic retinopathy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Arm Label

Brolucizumab 3 mg

Brolucizumab 6 mg

Aflibercept 2 mg

Arm Description

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).

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).

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).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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

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

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.

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.

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

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

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

Number of Patients With Presence of Leakage on Fluorescein Angiography (FA) at Week 52

Assessed by angiography.

Number of Patients With Presence of Leakage on Fluorescein Angiography (FA) at Week 100

Assessed by angiography.

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

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.

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

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.

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.

Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - General Vision

Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Ocular Pain

Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Near Activities

Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Distance Activities

Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Social Functioning

Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Mental Health

Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Role Difficulties

Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Dependency

Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Driving

Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Color Vision

Change From Baseline in Patient Reported Outcomes Visual Functioning Questionnaire-25 (VFQ-25) Total Scores up to Week 52 and Week 100 - Peripheral Vision

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

Ocular Adverse Events (AEs) (>=2% in Any Treatment Arm) by Preferred Term for the Study Eye

Number of Subjects With Non-ocular Adverse Events (AEs) (>=2% in Any Treatment Arm)

Full Information

NCT ID

NCT03481634

First Posted

March 13, 2018

Last Updated

January 27, 2023

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT03481634

Brief Title

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

Acronym

KESTREL

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

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Completed

Study Start Date

July 23, 2018 (Actual)

Primary Completion Date

November 11, 2020 (Actual)

Study Completion Date

October 18, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diabetic Macular Edema

Keywords

Diabetic Macular Edema, intravitreal injection, brolucizumab, aflibercept, double-masked, Diabetic Macular Edema (DME), macular edema, diabetic retinopathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

566 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Brolucizumab 3 mg

Arm Type

Experimental

Arm Description

Arm Title

Brolucizumab 6 mg

Arm Type

Experimental

Arm Description

Arm Title

Aflibercept 2 mg

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Brolucizumab

Other Intervention Name(s)

RTH258, ESBA1008

Intervention Description

Intravitreal injection

Intervention Type

Drug

Intervention Name(s)

Aflibercept

Other Intervention Name(s)

Eylea

Intervention Description

Intravitreal injection

Primary Outcome Measure Information:

Title

Change From Baseline in Best-corrected Visual Acuity (BCVA) at Week 52

Description

Time Frame

Baseline, Week 52

Secondary Outcome Measure Information:

Title

Average Change From Baseline in BCVA Over the Period Week 40 Through Week 52

Description

Time Frame

Baseline and Week 40 through Week 52 (average)

Title

Patients Maintained at q12w - Probability of Maintaining on q12w

Description

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.

Time Frame

Baseline (Week 0), Weeks 32, 36 and 48

Title

Patients Maintained at q12w (for Those Patients Who Qualified for q12w at Week 36) - Probability of Maintaining on q12w

Description

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.

Time Frame

Weeks 36 and 48

Title

Change From Baseline in BCVA at Each Visit up to Week 52

Description

Time Frame

Baseline (Week 0), Weeks 4, 6, 8, 12, 16, 18, 20, 24, 28, 32, 36, 40, 44, 48, and 52

Title

BCVA (Letters Read): ANOVA Results for Average Change From Baseline Over the Period Week 88 Through Week 100 for the Study Eye (FAS - LOCF)

Description

Time Frame

Baseline, and Week 88 through Week 100 (average)

Title

Patients Maintained at q12w up to Week 64 (After Three q12w- Treatment Intervals) and Week 100 - Probability of Maintaining on q12w

Description

This outcome measure is pre-specified for brolucizumab treatment arms only

Time Frame

Baseline (Week 0), Weeks 32, 36, 48, 60, 72, 84, and 96

Title

Description

This outcome measure is pre-specified for brolucizumab treatment arms only

Time Frame

Baseline (Week 0), Weeks 32, 36, 48, 60, 72, 84, and 96

Title

Change From Baseline in Central Subfield Thickness (CSFT) at Each Visit up to Week 52 - Pairwise ANOVA Results

Description

Time Frame

Baseline up to week 52

Title

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)

Description

Time Frame

Baseline, and Week 88 through Week 100 (average)

Title

Number of Patients With Presence of Subretinal Fluid (SRF) at Each Assessment Visit

Description

Subretinal Fluid (SRF) status in the central subfield: proportion of subjects with presence of SRF in the study eye by visit

Time Frame

Baseline up to Week 52 and Week 100

Title

Number of Patients With Presence of Intraretinal Fluid (IRF) at Each Assessment Visit

Description

Intraretinal Fluid (IRF) status in the central subfield: proportion of subjects with presence of IRF in the study eye by visit

Time Frame

Baseline, up to Week 52 and Week 100

Title

Number of Patients With Presence of SRF and/or IRF in the Study Eye by Visit

Description

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

Time Frame

Baseline, up to Week 52 and Week 100

Title

Number of Patients With Presence of Leakage on Fluorescein Angiography (FA) at Week 52

Description

Assessed by angiography.

Time Frame

Week 52

Title

Number of Patients With Presence of Leakage on Fluorescein Angiography (FA) at Week 100

Description

Assessed by angiography.

Time Frame

Week 100

Title

Description

Time Frame