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

Study Overview
=================
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. The safety and efficacy of brolucizumab were assessed in 2 randomized, multicenter, double-masked, active treatment-controlled Phase 3 studies in nAMD patients (the HAWK study (RTH258-C001 [NCT02307682]) and the HARRIER study (RTH258-C002 [NCT02434328]). Accordingly, a new Phase 3b study (TALON, CRTH258A2303) is being conducted to evaluate the efficacy and safety of brolucizumab in a Treat-to-Control (TtC) regimen for the treatment of naïve patients with nAMD. In this TtC regimen, patients receive 3 consecutive injections every 4 weeks and then the injection interval is extended by 4 weeks up to a maximum of a 16-week interval. The decision to extend or reduce the injection interval is taken by the Investigator at each visit based on his/her judgment of disease activity, according to the patient visual and/or anatomic outcomes. If there is no disease activity, the injection interval can be extended by 4 weeks ; if disease activity occurs or recurs, the injection interval should be shortened accordingly by 4 weeks at a time or to a minimal interval of 8 weeks. The injection interval can also be maintained if the Investigator deems that the patient do not benefit from injection interval adjustment. Since all these studies were conducted in a naïve nAMD patient population, no data are available on the efficacy and safety of brolucizumab in pretreated nAMD patients who still present active exudation.

Official Title
-----------------
A One-year, Single-arm, Open-label, Multicenter Study Assessing the Effect of Brolucizumab on Disease Control in Adult Patients With Suboptimal Anatomically Controlled Neovascular Age-related Macular Degeneration (SWIFT)

Conditions
-----------------
Neovascular Age-Related Macular Degeneration

Intervention / Treatment
-----------------
* Drug: RTH258/Brolucizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must provide written informed consent before any study-related procedures are performed. Patients must be 50 years of age or older at Screening/Baseline. Study eye: 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. 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. Presence of residual fluid (IRF or SRF that affects the central subfield under, as seen by OCT) 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. Exclusion Criteria: Ocular conditions 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. 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). Medical history of intraocular inflammation and/or retinal vascular occlusion within 12 months prior to Screening/Baseline Study eye Poor quality of OCT image at Screening/Baseline. Atrophy or fibrosis involving the center of the fovea in the study eye, as assessed by CFP and fundus autofluorescence (FAF). The total area of fibrosis or subretinal blood affecting the foveal center point comprising ≥ 50% of the lesion area in the study eye. 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. 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. Current vitreous hemorrhage or history of vitreous hemorrhage in the study eye within 4 weeks prior to Screening/Baseline. Uncontrolled glaucoma in the study eye defined as IOP > 25 mmHg on medication or according to the Investigator's judgment, at Screening/Baseline. Aphakia and/or absence of the posterior capsule in the study eye. Ocular treatments (study eye) Patient has received any investigational treatment for nAMD (other than vitamin supplements) in the study eye at any time. Previous use of intraocular or periocular of corticosteroids in the study eye within the 6 month period prior to Screening/Baseline. Previous penetrating keratoplasty or vitrectomy at any time prior to Screening/Baseline. 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 Previous laser treatment for nAMD including photodynamic therapy (PDT) laser at any time prior to Screening/Baseline. Previous treatment with investigational drugs. Systemic conditions or treatments End-stage renal disease requiring dialysis or renal transplant. Systemic medications known to be toxic to the lens, retina or optic nerve (e.g. deferoxamine, chloroquine/hydroxychloroquine, tamoxifen, phenothiazines and ethambutol) used during the 6-month period prior to Baseline, except temporary use for COVID-19 treatment. Participation in an investigational drug, biologic, or device study within 30 days or the duration of 5 half-lives of the investigational product (whichever is longer) prior to Baseline. Note: observational clinical studies solely involving over-the-counter vitamins, supplements, or diets are not exclusionary. Systemic anti-VEGF therapy at any time. Stroke or myocardial infarction in the 6-month period prior to Screening/Baseline. Uncontrolled blood pressure defined as a systolic value ≥ 160 mmHg or diastolic value ≥ 100 mmHg. (In case there is an elevated blood pressure measurement, it should be repeated after 20 minutes. If the repeat measurement is elevated, then the patient is not eligible to be enrolled into the study). History of a medical condition (disease, metabolic dysfunction with exception of type 1 or 2 diabetes mellitus, physical examination finding, or clinical laboratory finding) that, in the judgment of the Investigator, would preclude scheduled study visits, completion of the study, or a safe administration of investigational product. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. History of hypersensitivity to the study drug or its excipients or to drugs of similar classes, or clinically relevant sensitivity to fluorescein dye, as assessed by the Investigator. Other Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) pregnancy test. Women of childbearing potential, defined as all women less than 1 year postmenopausal or less than 6 weeks since sterilization. Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of childbearing potential. Patients mentioned in Articles L.1121-5 to L.1121-8 and L.1122-1-2 of the Code de Santé Publique (e.g. minors, protected adults, etc.)

Ages Eligible for Study
-----------------
Minimum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Single-arm, open-label study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RTH258/Brolucizumab<br>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. | Drug: RTH258/Brolucizumab<br>* Brolucizumab is a new generation of anti-VEGF (vascular endothelial growth factor). All patients will be treated with brolucizumab 6mg: 3 loading injections (at Screening/Baseline, Week 4 and Week 8), followed by Treat-to-Control regimen up to Week 44/46.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with no disease activity at Week 16 | To evaluate the effect of brolucizumab 6 mg on disease control | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with no disease activity at Week 48 | To evaluate the long term effects of brolucizumab 6 mg on disease control | Week 48 | 
| Change from Baseline in CFST (Central Sub-Field Retinal Thickness) as assessed by OCT (Optical Coherence Tomography) over time up to Week 48 | To evaluate the effect of brolucizumab 6 mg on anatomical parameters | Week 48 | 
| 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 | To evaluate the effect of brolucizumab 6 mg on anatomical parameters | Week 48 | 
| Proportion of patients with a dry retina (neither IRF nor SRF) up to Week 48 | To evaluate the effect of brolucizumab 6 mg on anatomical parameters | Week 48 | 
| Distribution of the last interval with no disease activity up to Week 48 | To evaluate the durability of brolucizumab 6 mg | Week 48 | 
| Distribution of the maximal intervals with no disease activity up to Week 48 | To evaluate the durability of brolucizumab 6 mg | Week 48 | 
| Average change in BCVA (Best-Corrected Visual Acuity) from Baseline up to Week 48 | To evaluate functional outcomes | Week 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
age-related macular degeneration, wetAMD, nAMD, neovascular, choroidal neovascularization, disease control