Clinical trial NCT04239027: A Study to Assess the Effects of Brolucizumab in Adult Patients With Neovascular Age Related Macular Degeneration
Official title: A One-year, Single-arm, Open-label, Multicenter Study Assessing the Anatomic Outcomes of Brolucizumab Assessed by OCT-A in Adult Patients With Neovascular Age Related Macular Degeneration
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Neovascular Age Related Macular Degeneration
Keywords: age-related macular degeneration, wetAMD, nAMD, neovascular, choroidal neovascularization, CNV, OCT-angiography
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-01-23
Enrollment: 210
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single-arm, open-label study
Primary purpose: TREATMENT

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

The safety and efficacy of brolucizumab has been demonstrated in 2 randomized, multicenter, double-masked, active controlled Phase 3 studies in nAMD patients (RTH258-C001 and RTH258-C002). Anatomical changes were evaluated in these studies using spectral domain optical coherence tomography (SD-OCT), which relied on indirect parameters for the diagnosis of active CNV. The OCT-angiography (OCT A) that directly visualize retinal circulation and image CNV and vascular diseases of the retina was not included in previous brolucizumab studies.

This single-arm, open-label, multicenter study was performed to evaluate the efficacy and safety of brolucizumab 6 mg in patients with nAMD.

OCT-A was used in this study to assess the morphological response of patients to brolucizumab in terms of percentage change in CNV lesion area in the short term (i.e. at Week 12) and in the long term (i.e. at Week 48), as well as changes in other OCT-A features up to Week 48.

Detailed description: This was a prospective, single-arm, open-label, multicenter study to evaluate the efficacy and safety of brolucizumab 6 mg in patients with neovascular age-related macular degeneration (nAMD). Patients were required to attend 6 mandatory study visits: Screening/Baseline Visit (Day 1), Week 4, Week 8, Week 12, Week 16 and Week 48 visits. The timing of the interim visits between Week 16 and Week 48 depended on the patient's injection regimen, i.e. every 12 weeks (q12w) or every 8 weeks (q8w). Patients who consented and met all the inclusion and none of the exclusion criteria were screened to evaluate eligibility. After confirmation of eligibility, patients were included and treated with brolucizumab 6 mg. The maximum study duration for 1 patient was 48 weeks, including Screening. There were 2 periods in this study:

* Open-label treatment period: from Screening/Baseline (Day 1) to Week 40/Week 44 (depending on assigned regimen)
* Follow-up period: Week 40/Week 44 to Week 48

A Safety Review Committee (SRC) was established for this study to provide an independent, systematic, standardized and unbiased assessment of the review of intraocular inflammation (IOI), retinal vasculitis (RV) and/or retinal vascular occlusion (RO).

Eligibility criteria: 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 AMD that affect the central subfield, including retinal angiomatous proliferation (RAP) with a CNV component, confirmed by presence of active leakage from CNV seen by fluorescein angiography and sequellae of CNV, e.g. pigment epithelial detachment (PED), subretinal hemorrhage or sub-retinal pigment epithelium (sub-RPE) hemorrhage, blocked fluorescence, macular edema.
4. Intra- and/or subretinal fluid affecting the central subfield of the study eye at Screening/Baseline.
5. BCVA between 83 and 23 letters, inclusive, in the study eye at Screening/Baseline using early treatment diabetic retinopathy study (ETDRS) at an initial testing distance of 4 meters.

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 (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-A and SD-OCT images at Screening/Baseline.
5. Atrophy or fibrosis involving the center of the fovea in the study eye, as assessed by color fundus photography and fundus autofluorescence (FAF) at Screening/Baseline.
6. The total area of fibrosis or subretinal blood affecting the foveal center point comprising ≥ 50% of the lesion area in the study eye at Screening/Baseline.
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, retinal pigment epithelium (RPE) rip/tear scar, laser burn, at the time of Screening 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 at Screening/Baseline.

    Ocular treatments (study eye):
12. Patient has received any approved or investigational treatment for nAMD (other than vitamin supplements) in the study eye at any time.
13. Intraocular or periocular use of corticosteroids in the study eye during 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 photocoagulation.
    * Previous submacular surgery, other surgical intervention or laser treatment for nAMD including photodynamic therapy (PDT).

    Systemic conditions or treatments:
16. End stage renal disease requiring dialysis or renal transplant.
17. 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 Screening/Baseline except temporary use for COVID-19 treatment.
18. 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 Screening/Baseline. Note: observational clinical studies solely involving over-the-counter vitamins, supplements, or diets are not exclusionary.
19. Systemic anti-VEGF therapy at any time.
20. Stroke or myocardial infarction in the 6-month period prior to Screening/Baseline.
21. Uncontrolled blood pressure defined as a systolic value ≥ 160 mmHg or diastolic value ≥ 100 mmHg at Screening/Baseline. (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).
22. 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.
23. 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.
24. History of hypersensitivity to any component of the test article, control article, or clinically relevant sensitivity to fluorescein dye, as assessed by the investigator.

    Other:
25. 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.
26. Women of childbearing potential, defined as all women less than 1 year postmenopausal or less than 6 weeks since sterilization at Screening/Baseline 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.
27. 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.)

Primary outcomes:
measure: Percentage Change in Choroidal Neovascularization (CNV) Lesion Area Measured by Optical Coherence Tomography-Angiograph (OCT-A) From Baseline to Week 12
timeFrame: Baseline, Week 12
Secondary outcomes:
measure: Percentage Change in Choroidal Neovascularization (CNV) Lesion Area Measured by Optical Coherence Tomography-Angiograph (OCT-A) From Baseline to Week 48
timeFrame: Baseline, Weeks 4, 8, 48
measure: Change in Choroidal Neovascularization (CNV) Lesion Area Measured by Optical Coherence Tomography-Angiograph (OCT-A) From Baseline to Week 48
timeFrame: Baseline, Weeks 4, 8, 12, 48
measure: Presence of Choroidal Neovascularization (CNV) Lesion Area Measured by Optical Coherence Tomography-Angiograph (OCT-A) From Baseline to Week 48
timeFrame: Baseline, Week 48
measure: Change in Best Corrected Visual Acuity (BCVA) From Baseline up to Week 48
timeFrame: Baseline, Weeks 4, 8, 12, 48
measure: Percentage of Patients Who Are Maintained on an Exclusive Treatment Interval Every 12 Weeks (q12w) Following the Loading Phase to Week 48
timeFrame: Weeks 20, 32, 44, 48
measure: The Probability of the First q12w Interval for Determining Successful q12w Maintenance
timeFrame: Weeks 0,4,5,8,9,15,16,17,18,20,21,22,24,32,33,34,35,40,41,43,44,48
measure: Time From Last Intravitreal (IVT) Injection in the Initiation Phase to First Visit With no Disease Activity - Probability of no Disease Activity
timeFrame: Week 8 until Week 41
measure: Change From Baseline up to Week 48 in SD-OCT Assessed by Qualitative and Quantitative Criteria: Central Sub-Field Retinal Thickness (CSFT)
timeFrame: Baseline, Weeks 4, 8, 12, 48
measure: Change From Baseline up to Week 48 in SD-OCT and FA Features Assessed by Qualitative and Quantitative Criteria: Sub and Intraretinal Fluid, Sub-RPE (Retinal Pigmented Epithelium) - Study Eye
timeFrame: Baseline, Weeks 4, 8, 12, 48
measure: Incidence of Adverse Events (AEs) (Serious and Nonserious) Reported in Patients Treated With Brolucizumab.
timeFrame: Up to Week 48
measure: Incidence of AEs (Serious and Nonserious) Reported in Patients Treated With Brolucizumab, by Primary System Organ Class (SOC) and Preferred Term (PT) - Ocular Adverse Events in Study Eye
timeFrame: Up to Week 48
measure: Incidence of AEs (Serious and Nonserious) Reported in Patients Treated With Brolucizumab - Non-Ocular Adverse Events
timeFrame: Up to Week 48
Other outcomes:
Locations:
city: Nice
country: France
facility: Novartis Investigative Site
state: Cedex1
city: Rennes Cedex 9
country: France
facility: Novartis Investigative Site
state: FRA
city: Saint Cyr sur Loire
country: France
facility: Novartis Investigative Site
state: Indre Et Loire
city: Lyon cedex 04
country: France
facility: Novartis Investigative Site
state: Rhone
city: Bobigny cedex
country: France
facility: Novartis Investigative Site
state: Seine Saint Denis
city: Aix en Provence
country: France
facility: Novartis Investigative Site
city: Angers
country: France
facility: Novartis Investigative Site
city: Avignon
country: France
facility: Novartis Investigative Site
city: Bordeaux
country: France
facility: Novartis Investigative Site
city: Boulogne sur Mer
country: France
facility: Novartis Investigative Site
city: Caen Cedex
country: France
facility: Novartis Investigative Site
city: Caen
country: France
facility: Novartis Investigative Site
city: Creteil
country: France
facility: Novartis Investigative Site
city: Dijon
country: France
facility: Novartis Investigative Site
city: Floirac
country: France
facility: Novartis Investigative Site
city: Grenoble
country: France
facility: Novartis Investigative Site
city: La Rochelle
country: France
facility: Novartis Investigative Site
city: Lagord
country: France
facility: Novartis Investigative Site
city: Le Chesnay
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Montargis
country: France
facility: Novartis Investigative Site
city: Montauban
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Mulhouse cedex
country: France
facility: Novartis Investigative Site
city: Nantes Cedex 1
country: France
facility: Novartis Investigative Site
city: Nantes
country: France
facility: Novartis Investigative Site
city: Paris cedex 10
country: France
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Perpignan
country: France
facility: Novartis Investigative Site
city: Plerin
country: France
facility: Novartis Investigative Site
city: Poitiers
country: France
facility: Novartis Investigative Site
city: Rouen
country: France
facility: Novartis Investigative Site
city: Royan
country: France
facility: Novartis Investigative Site
city: Rueil Malmaison
country: France
facility: Novartis Investigative Site
city: Saint Herblain
country: France
facility: Novartis Investigative Site
city: Saint Martin des Champs
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 9
country: France
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: