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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of brolucizumab in treatment of patients with visual impairment due to diabetic macular edema (DME).

Detailed Description
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In this 2-year, randomized, double-masked, multicenter, active controlled study, consenting patients will be randomized in a 1:1 ratio to one of the two treatment arms and attend 28 planned visits.

Official Title
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A Two-Year, Two-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

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: Brolucizumab
* Drug: Aflibercept


Participation Criteria
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Eligibility Criteria
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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 the 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Brolucizumab 6 mg<br>Brolucizumab 6 mg/0.05 mL, 5 loading doses, with subsequent doses per protocol-specified maintenance schedule | Drug: Brolucizumab<br>* Intravitreal injection<br>* Other names: RTH258, ESBA1008;|
| Active Comparator: Aflibercept 2 mg<br>Aflibercept 2 mg/0.05 mL, as labeled, 5 loading doses, with subsequent doses every 8 weeks | Drug: Aflibercept<br>* Intravitreal injection<br>* Other names: Eylea;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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 | Assessed with ETDRS visual acuity testing charts | Baseline up to Week 52 | 
| Proportion of patients maintained at q12w up to Weeks 52 and 100 | Positive treatment status is defined as IVT injections per planned dosing regimen [every 12 weeks (q12w)]. This outcome measure is pre-specified for brolucizumab treatment arm only. | Up to Week 100 | 
| Proportion of patients maintained at q12w up to Week 52 within those patients that qualified for q12w at Week 36 | This outcome measure is pre-specified for brolucizumab treatment arm only. | Up to Week 52 | 
| Change from baseline in BCVA at each visit up to Week 100 | Assessed with ETDRS visual acuity testing charts | Baseline up to Week 100 | 
| Average change from baseline in BCVA over the period Week 4 to Week 52/100 | Assessed with ETDRS visual acuity testing charts | Baseline up to Week 100 | 
| Average change from baseline in BCVA over the period Week 20 to Week 52/100 and Week 28 to Week 52/100 | Assessed with ETDRS visual acuity testing charts | Baseline up to Week 100 | 
| Gain in BCVA of ≥5, ≥10, and ≥15 ETDRS letters from baseline to each post-baseline visit | Assessed with ETDRS visual acuity testing charts | Baseline up to Week 100 | 
| Time to achieve gain in BCVA of ≥5, ≥10, and ≥15 ETDRS letters from baseline (or reaching a score of 84 or more) | Assessed with ETDRS visual acuity testing charts | Baseline up to Week 100 | 
| Loss in BCVA of ≥5, ≥10, and ≥15 ETDRS letters from baseline to each post-baseline visit | Assessed with ETDRS visual acuity testing charts | Baseline up to Week 100 | 
| Absolute BCVA ≥73 ETDRS letters at each post-baseline visit | Assessed with ETDRS visual acuity testing charts | Baseline up to Week 100 | 
| Proportion of patients maintained at q12w up to Week 64 (after three q12w- treatment intervals) |  | Up to Week 64 | 
| Proportion of patients maintained at q12w up to Week 64 (after three q12w- treatment intervals), within those patients that qualified for q12w at Week 36 | This outcome measure is pre-specified for brolucizumab treatment arm only | Up to Week 64 | 
| Proportion of patients maintained at q12w/q16w up to Week 100, within those patients that qualified for q12w at Week 36 | This outcome measure is pre-specified for brolucizumab treatment arm only | Up to Week 100 | 
| Proportion of patients with disease activity at Week 32 (eg ≥5 letters loss in BCVA compared to Week 28) | This outcome measure is pre-specified for brolucizumab treatment arm only | Week 28, Week 32 | 
| Proportion of patients maintained on q16w up to Week 100 within the patients on q12 at Week 68 and on q16w at Week 76 |  | Up to Week 100 | 
| Proportion of patients re-assigned and maintained on q12w up to Week 100 within the patients on q8w at Week 68 and on q12w at Week 80 |  | Up to Week 100 | 
| Proportion of patients with injections per planned dosing regimen (every 8, 12 or 16 weeks) | This outcome measure is pre-specified for brolucizumab treatment arm only | Up to Week 100 | 
| Change from baseline in central subfield thickness (CSFT) at each assessment visit | Assessed by Spectral Domain Optical Coherence Tomography (SD-OCT) | Baseline up to Week 100 | 
| Average change from baseline in CSFT over the period Week 40 through Week 52 / Week 88 through Week 100 | Assessed by SD-OCT | Baseline up to Week 100 | 
| Average change from baseline in CSFT over the period Week 4 to Week 52 / 96 | Assessed by SD-OCT | Baseline up to Week 96 | 
| Patient status regarding normal CSFT thickness (<280 microns) at each assessment visit | Assessed by SD-OCT | Baseline up to Week 100 | 
| Change from baseline in central subfield thickness-neurosensory (CSFTns) at each assessment visit | Assessed by SD-OCT | Baseline up to Week 100 | 
| Average change from baseline in CSFTns over the period Week 40 through Week 52 / Week 88 through Week 100 | Assessed by SD-OCT | Baseline up to Week 100 | 
| Average change from baseline in CSFTns over the period Week 4 to Week 52 / 100 |  | Baseline up to Week 100 | 
| Proportion of patients with presence of subretinal fluid (SRF) at each assessment visit | Assessed by SD-OCT, angiography, and/or color fundus photography | Baseline up to Week 100 | 
| Proportion of patients with presence of intraretinal fluid (IRF) at each assessment visit | Assessed by SD-OCT, angiography, and/or color fundus photography | Baseline up to Week 100 | 
| Proportion of patients with simultaneous absence of SRF and IRF at each assessment visit | Assessed by SD-OCT, angiography, and/or color fundus photography | Baseline up to Week 100 | 
| Proportion of patients with presence of leakage on fluorescein angiography (FA) at Weeks 52 and 100 | Assessed by fluorescein angiography | Up to Week 100 | 
| Change from baseline in ETDRS Diabetic Retinopathy Severity Scale (ETDRS-DRSS) score at each assessment visit | The Diabetic Retinopathy Disease Severity Scale measures the 5 levels of diabetic retinopathy - none, mild, moderate, severe, and proliferative | Baseline up to Week 100 | 
| Number of patients with progression to proliferative diabetic retinopathy (PDR) as assessed by ETDRS-DRSS Score of at least 61 by Week 52 and Week 100 | ETDRS-DRSS | Baseline up to Week 100 | 
| Change from baseline in patient reported outcomes (VFQ-25) total and subscale scores up to Week 100 | The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) measures the influence of visual disability and visual symptoms on general health domains | Baseline up to Week 100 | 
| Systemic brolucizumab/aflibercept concentration | Blood draw | Up to Week 24 | 
| Anti-Drug Antibody (ADA) status | Blood draw | Up to Week 100 | 
| Average change from baseline in BCVA from the period Week 88 to 100 | Assessed with ETDRS visual acuity testing charts | Baseline up to Week 100 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetic Macular Edema, intravitreal injection, brolucizumab, aflibercept, double-masked