Study of Brolucizumab in Adult Patients With Suboptimal Anatomically Controlled Neovascular Age-related Macular Degeneration

Phase 3

Completed

• Conditions: Neovascular Age-Related Macular Degeneration
• Interventions: Drug: RTH258/Brolucizumab

• Registration Number: NCT04264819
• Lead Sponsor: Novartis Pharmaceuticals

Brief Summary

Neovascular age-related macular degeneration is characterized by the presence of choroidal neovascularization (CNV), which consists of abnormal blood vessels originating from the choroid that can lead to hemorrhage, fluid exudation, and fibrosis, resulting in photoreceptor damage and vision loss.

Detailed Description

This is a prospective, single-arm, open-label, multicenter study to evaluate the efficacy and safety of brolucizumab 6 mg in pretreated suboptimal anatomically controlled patients with neovascular age-related macular degeneration (nAMD).

Study Timeline

• Study First Submitted: 2020-02-07
• Study First Submitted QC: 2020-02-07
• Study First Posted: 2020-02-11
• Study Start: 2020-12-14
• Primary Completion: 2022-10-05
• Study Completion: 2023-05-10
• Results First Submitted: 2023-08-23
• Status Verified: 2024-09
• Results First Submitted QC: 2024-09-06
• Last Update Submitted: 2024-09-06
• Results First Posted: 2024-11-07
• Last Update Posted: 2024-11-07

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 295

Inclusion Criteria

1. Patients must provide written informed consent before any study-related procedures are performed.

2. Patients must be 50 years of age or older at Screening/Baseline.

   Study eye:

3. Active CNV lesions secondary to nAMD diagnosed < 18 months prior to Screening/Baseline that affect the central subfield, including retinal angiomatous proliferation (RAP) with a CNV component, confirmed by presence of active leakage from CNV seen by FA and sequelae of CNV, e.g. pigment epithelial detachment (PED), subretinal hemorrhage or sub RPE hemorrhage, blocked fluorescence, or macular edema.

4. Previous treatment with only one licensed anti-VEGF drug (i.e. Lucentis®, Eylea®) with a ≥ Q4 and ≤ Q8 treatment (treatment interval of 26 to 62 days inclusive) with licensed anti-VEGF (a minimal washout period of at least 4 weeks / 26 days is required). Patients must have received at least 3 injections of this anti-VEGF in the 6 months prior to Screening/Baseline.

5. Presence of residual fluid (IRF or SRF that affects the central subfield under, as seen by OCT)

6. BCVA score must be ≤ 83 and ≥ 38 letters at an initial testing distance of 4 meters starting distance using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity charts at Screening/Baseline.

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Exclusion Criteria

Ocular conditions

1. Any active intraocular or periocular infection or active intraocular inflammation (e.g. infectious conjunctivitis, keratitis, scleritis, endophthalmitis, infectious blepharitis), in either eye at Screening/Baseline.

2. Presence of amblyopia, amaurosis, or ocular disorders in the fellow eye with BCVA < 35 ETDRS letters at Screening/Baseline (except when due to conditions whose surgery may improve visual acuity, e.g. cataract).

3. Medical history of intraocular inflammation and/or retinal vascular occlusion within 12 months prior to Screening/Baseline

   Study eye

4. Poor quality of OCT image at Screening/Baseline.

5. Atrophy or fibrosis involving the center of the fovea in the study eye, as assessed by CFP and fundus autofluorescence (FAF).

6. The total area of fibrosis or subretinal blood affecting the foveal center point comprising ≥ 50% of the lesion area in the study eye.

7. Concomitant conditions or ocular disorders in the study eye, including retinal diseases other than nAMD, that, in the judgment of the Investigator, could require medical or surgical intervention during the course of the study to prevent or treat visual loss that might result from that condition, or that limits the potential to gain visual acuity upon treatment with the investigational product.

8. Structural damage within 0.5 disc diameter of the center of the macula in the study eye, e.g. vitreomacular traction, epiretinal membrane, RPE rip/tear scar, laser burn, at the time of Screening/Baseline that in the Investigator's opinion could preclude visual function improvement with treatment.

9. Current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 weeks prior to Screening/Baseline.

10. Uncontrolled glaucoma in the study eye defined as IOP > 25 mmHg on medication or according to the Investigator's judgment, at Screening/Baseline.

11. Aphakia and/or absence of the posterior capsule in the study eye. Ocular treatments (study eye)

12. Patient has received any investigational treatment for nAMD (other than vitamin supplements) in the study eye at any time.

13. Previous use of intraocular or periocular of corticosteroids in the study eye within the 6 month period prior to Screening/Baseline.

14. Previous penetrating keratoplasty or vitrectomy at any time prior to Screening/Baseline.

15. History or evidence of the following in the study eye within the 90-day period prior to Screening/Baseline:

    • Intraocular or refractive surgery.
    • Previous panretinal and peripheral laser photocoagulation.
    • Previous macular surgery or other intraocular surgical intervention

16. Previous laser treatment for nAMD including photodynamic therapy (PDT) laser at any time prior to Screening/Baseline.

17. Previous treatment with investigational drugs.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
RTH258/Brolucizumab	RTH258/Brolucizumab	This is a single arm study in which all patients will be treated with brolucizumab 6mg; 3 loading injections (at Screening/Baseline, week 4 and week 8) followed by treat-to-control phase with adjustable treatment frequency based on disease activity from every 8 to up to 16 weeks; last treatment at week 44/46 based on the treatment regimen.

Primary Outcome Measures

Name	Time	Method
Number of Patients With no Disease Activity at Week 16 in the Study Eye	Week 16	Disease activity criteria were assessed by the Investigator based on whether neovascular age-related macular degeneration (nAMD) was still active or had been re-activated. The disease was defined as active if at least one of the following criteria was observed: * Best-corrected visual acuity (BCVA) decrease ≥ 5 letters from the best value since Baseline due to disease activity; * Any significant increase in central retinal thickness (CRT); * Retinal hemorrhage; * Intraretinal fluid or sub-retinal fluid (SRF) due to disease activity (degenerative cysts allowed); * Increase of sub-retinal pigmented epithelium (RPE) fluid These criteria were for guidance only, Investigators could define disease activity based on their own assessment.

Secondary Outcome Measures

Name	Time	Method
Number of Patients With no Disease Activity at Week 48 in the Study Eye	Week 48	Disease activity criteria were assessed by the Investigator based on whether neovascular age-related macular degeneration (nAMD) was still active or had been re-activated. The disease was defined as active if at least one of the following criteria was observed: * Best-corrected visual acuity (BCVA) decrease ≥ 5 letters from the best value since Baseline due to disease activity; * Any significant increase in central retinal thickness (CRT); * Retinal hemorrhage; * Intraretinal fluid or sub-retinal fluid (SRF) due to disease activity (degenerative cysts allowed); * Increase of sub-retinal pigmented epithelium (RPE) fluid These criteria were for guidance only, Investigators could define disease activity based on their own assessment.
Change From Baseline in CFST (Central Sub-Field Retinal Thickness) as Assessed by OCT (Optical Coherence Tomography) Over Time up to Week 48 in the Study Eye	Baseline, Weeks 4,8,16, 48	Central Subfield Thickness Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.
Absence of IRF (Intraretinal Fluid), SRF (Subretinal Fluid), and Sub-RPE (Retinal Pigmented Epithelium) Fluid as Assessed by OCT Over Time up to Week 48 in the Study Eye	Baseline, Week 4, 8, 16, 48	Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.; At week 8, for 1 patient, the fluid assessment was performed, but result is unknown; at week 16, for 1 patient, the fluid assessment was performed, but result is unknown; at week 48, for 2 patients, the fluid assessment was performed, but result is unknown.
Number of Patients With a Dry Retina (Neither IRF Nor SRF) up to Week 48 in the Study Eye	Baseline, Weeks 4, 8, 16, 48	Assessed by Spectral domain optical coherence tomography (SD-OCT) from the central reading center.
Distribution of the Last Interval With no Disease Activity up to Week 48 in the Study Eye	Intervals of 0,4,5,6,7,8,9,10,11,12,13,14,15,16,17 Weeks	Disease activity criteria were assessed by the Investigator based on whether neovascular age-related macular degeneration (nAMD) was still active or had been re-activated. The disease was defined as active if at least one of the following criteria was observed: * Best-corrected visual acuity (BCVA) decrease ≥ 5 letters from the best value since Baseline due to disease activity; * Any significant increase in central retinal thickness (CRT); * Retinal hemorrhage; * Intraretinal fluid or sub-retinal fluid (SRF) due to disease activity (degenerative cysts allowed); * Increase of sub-retinal pigmented epithelium (RPE) fluid These criteria were for guidance only, Investigators could define disease activity based on their own assessment.
Distribution of the Maximal Intervals With no Disease Activity up to Week 48 in the Study Eye	Intervals of 0,4,5,6,7,8,9,10,11,12,13,14,15,16,17 Weeks	Disease activity criteria were assessed by the Investigator based on whether neovascular age-related macular degeneration (nAMD) was still active or had been re-activated. The disease was defined as active if at least one of the following criteria was observed: * Best-corrected visual acuity (BCVA) decrease ≥ 5 letters from the best value since Baseline due to disease activity; * Any significant increase in central retinal thickness (CRT); * Retinal hemorrhage; * Intraretinal fluid or sub-retinal fluid (SRF) due to disease activity (degenerative cysts allowed); * Increase of sub-retinal pigmented epithelium (RPE) fluid These criteria were for guidance only, Investigators could define disease activity based on their own assessment.
Average Change in BCVA (Best-Corrected Visual Acuity) From Baseline up to Week 48 in the Study Eye	Baseline, Weeks 4, 8, 16, 48	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.; Min and max possible scores are 0-100 respectively. A higher score represents better visual functioning.
Summary of Treatment-emergent Adverse Events - Overall	Adverse events were reported from first dose of study treatment until Week 48, plus 30 days post treatment, up to a maximum duration of 52 weeks.	An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.
Summary of Treatment-emergent Adverse Events Regardless of Study Treatment Relationship by Primary System Organ Class, Preferred Term, and Maximum Severity - Ocular (Study Eye)	Adverse events were reported from first dose of study treatment until Week 48, plus 30 days post treatment, up to a maximum duration of 52 weeks.	An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.
Summary of Treatment-emergent Adverse Events Regardless of Study Treatment Relationship by Primary System Organ Class, Preferred Term, and Maximum Severity - Non-ocular	Adverse events were reported from first dose of study treatment until Week 48, plus 30 days post treatment, up to a maximum duration of 52 weeks.	An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a clinical investigation participant after providing written informed consent for participation in the study.

Trial Locations

Locations (1)

Novartis Investigative Site; 🇫🇷 Vincennes, France