A Study to Assess the Effects of Brolucizumab in Adult Patients With Neovascular Age Related Macular Degeneration

Neovascular Age Related Macular Degeneration Clinical Trial

— OCTOPUS  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04239027
• Other study ID #: CRTH258AFR01
• Secondary ID: 2019-003338-17
• Status: Completed
• Phase: Phase 3
• Start date: January 26, 2021
• Est. completion date: February 2, 2023

Study information

• Verified date: June 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 210
• Est. completion date: February 2, 2023
• Est. primary completion date: May 23, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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.)

Related Conditions & MeSH terms

• Macular Degeneration
• Neovascular Age Related Macular Degeneration
• Wet Macular Degeneration

Intervention

Drug:
• RTH258/Brolucizumab
Brolucizumab is a new generation of anti-VEGF (vascular endothelial growth factor). All patients were treated with brolucizumab 6mg: 3 loading injections (at Screening/Baseline, Week 4 and Week 8), followed by maintenance treatment every 8 weeks (Q8W) or every 12 weeks (Q12W) depending on disease activity from Week 16/Week20 to Week 40/Week 44. Brolucizumab was administered by an intravitreal (IVT) injection to the study. eye.

Locations

Country	Name	City	State
France	Novartis Investigative Site	Aix en Provence
France	Novartis Investigative Site	Angers
France	Novartis Investigative Site	Avignon
France	Novartis Investigative Site	Bobigny cedex	Seine Saint Denis
France	Novartis Investigative Site	Bordeaux
France	Novartis Investigative Site	Boulogne sur Mer
France	Novartis Investigative Site	Caen
France	Novartis Investigative Site	Caen Cedex
France	Novartis Investigative Site	Creteil
France	Novartis Investigative Site	Dijon
France	Novartis Investigative Site	Floirac
France	Novartis Investigative Site	Grenoble
France	Novartis Investigative Site	La Rochelle
France	Novartis Investigative Site	Lagord
France	Novartis Investigative Site	Le Chesnay
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Lyon cedex 04	Rhone
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Montargis
France	Novartis Investigative Site	Montauban
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Mulhouse cedex
France	Novartis Investigative Site	Nantes
France	Novartis Investigative Site	Nantes Cedex 1
France	Novartis Investigative Site	Nice	Cedex1
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris cedex 10
France	Novartis Investigative Site	Perpignan
France	Novartis Investigative Site	Plerin
France	Novartis Investigative Site	Poitiers
France	Novartis Investigative Site	Rennes Cedex 9	FRA
France	Novartis Investigative Site	Rouen
France	Novartis Investigative Site	Royan
France	Novartis Investigative Site	Rueil Malmaison
France	Novartis Investigative Site	Saint Cyr sur Loire	Indre Et Loire
France	Novartis Investigative Site	Saint Herblain
France	Novartis Investigative Site	Saint Martin des Champs
France	Novartis Investigative Site	Strasbourg
France	Novartis Investigative Site	Toulouse Cedex 9

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage Change in Choroidal Neovascularization (CNV) Lesion Area Measured by Optical Coherence Tomography-Angiograph (OCT-A) From Baseline to Week 12	OCT-A is a dye-less angiographic procedure based on split-spectrum-decorrelation-amplitude angiography.; It enables the capture of scattered intra-vessel particles (mainly erythrocyte cells) at all levels of the retinal and inner-choroidal vasculature, thus providing 3-D imaging of the retinal circulation.; The literature suggests that OCT-A is a good marker for assessing anti-VEGF therapeutic response, especially lesion size.; Inter-Quartile Range = q1 - q3.	Baseline, Week 12
Secondary	Percentage Change in Choroidal Neovascularization (CNV) Lesion Area Measured by Optical Coherence Tomography-Angiograph (OCT-A) From Baseline to Week 48	OCT-A is a dye-less angiographic procedure based on split-spectrum-decorrelation-amplitude angiography.; It enables the capture of scattered intra-vessel particles (mainly erythrocyte cells) at all levels of the retinal and inner-choroidal vasculature, thus providing 3-D imaging of the retinal circulation.; The literature suggests that OCT-A is a good marker for assessing anti-VEGF therapeutic response, especially lesion size.	Baseline, Weeks 4, 8, 48
Secondary	Change in Choroidal Neovascularization (CNV) Lesion Area Measured by Optical Coherence Tomography-Angiograph (OCT-A) From Baseline to Week 48	OCT-A is a dye-less angiographic procedure based on split-spectrum-decorrelation-amplitude angiography.; It enables the capture of scattered intra-vessel particles (mainly erythrocyte cells) at all levels of the retinal and inner-choroidal vasculature, thus providing 3-D imaging of the retinal circulation.; The literature suggests that OCT-A is a good marker for assessing anti-VEGF therapeutic response, especially lesion size.	Baseline, Weeks 4, 8, 12, 48
Secondary	Presence of Choroidal Neovascularization (CNV) Lesion Area Measured by Optical Coherence Tomography-Angiograph (OCT-A) From Baseline to Week 48	OCT-A is a dye-less angiographic procedure based on split-spectrum-decorrelation-amplitude angiography.; It enables the capture of scattered intra-vessel particles (mainly erythrocyte cells) at all levels of the retinal and inner-choroidal vasculature, thus providing 3-D imaging of the retinal circulation.; The literature suggests that OCT-A is a good marker for assessing anti-VEGF therapeutic response, especially lesion size.	Baseline, Week 48
Secondary	Change in Best Corrected Visual Acuity (BCVA) From Baseline up to Week 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. 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.	Baseline, Weeks 4, 8, 12, 48
Secondary	Percentage of Patients Who Are Maintained on an Exclusive Treatment Interval Every 12 Weeks (q12w) Following the Loading Phase to Week 48	To estimate the proportion of patients treated at q12w frequency with brolucizumab.	Weeks 20, 32, 44, 48
Secondary	The Probability of the First q12w Interval for Determining Successful q12w Maintenance	To estimate the predictive value of the first q12w cycle for maintenance of q12w treatment with brolucizumab via the Kaplan-Meier method.	Weeks 0,4,5,8,9,15,16,17,18,20,21,22,24,32,33,34,35,40,41,43,44,48
Secondary	Time From Last Intravitreal (IVT) Injection in the Initiation Phase to First Visit With no Disease Activity - Probability of no Disease Activity	To evaluate the time from last IVT injection in the initiation phase to first visit with no disease activity.; The 95% CI are estimated by using the Greenwood formula Kaplan-Meier (KM) method.	Week 8 until Week 41
Secondary	Change From Baseline up to Week 48 in SD-OCT Assessed by Qualitative and Quantitative Criteria: Central Sub-Field Retinal Thickness (CSFT)	Central sub-field thickness (CSFT) was measured by Spectral Domain Optical Coherence Tomography (SD-OCT). The CSFT evaluated in this study represents the average retinal thickness of the circular area within 1 mm diameter around the foveal center. SD-OCT images were obtained and assessed in the study eye by SD-OCT machines. (i.e. no time-domain nor swept-source OCT).	Baseline, Weeks 4, 8, 12, 48
Secondary	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	To evaluate the effect of brolucizumab on anatomical parameters as assessed by Spectral Domain Optical Coherence Tomography (SD-OCT) and Fluorescein Angiography (FA).; RPE = Retinal Pigmented Epithelium IRF = Intraretinal Fluid SRF = Subretinal Fluid Sub-RPE = Sub Retinal Pigmented Epithelium	Baseline, Weeks 4, 8, 12, 48
Secondary	Incidence of Adverse Events (AEs) (Serious and Nonserious) Reported in Patients Treated With Brolucizumab.	An 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.	Up to Week 48
Secondary	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	An 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.	Up to Week 48
Secondary	Incidence of AEs (Serious and Nonserious) Reported in Patients Treated With Brolucizumab - Non-Ocular Adverse Events	An 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.	Up to Week 48