Study of Safety and Efficacy of Brolucizumab 6 mg Drug Product Intended for Commercialization in Patients With nAMD

A 24-week, Double-masked, Multicenter, Two-arm Extension Study to Collect Safety and Efficacy Data on Brolucizumab 6 mg Drug Product Intended for Commercialization in Patients With Neovascular Age-related Macular Degeneration Who Have Completed the CRTH258A2301 Study

The purpose of this extension study was to assess the safety and efficacy of the new formulation of brolucizumab 6 mg ophthalmic solution when given to the same patients who received brolucizumab in the core trial CRTH258A2301 (also known as CRTH258-C002). The medical condition treated in the core and extension trials was neo-vascular age-related macular degeneration (nAMD).

Study Overview

• Status: Completed
• Conditions: Neovascular Age-related Macular Degeneration
• Intervention / Treatment: Drug: Brolucizumab 6 mg; Drug: Aflibercept 2 mg

Detailed Description

Subjects in the United States who had completed the 96 week core trial, CRTH258A2301 (also referred as CRTH258-C002), were eligible to participate in the extension trial provided the core trial Visit 26 at week 96, was less than or equal to 12 weeks from the Baseline Visit in the extension trial, CRTH258A2301E1.

Subjects who were treated with aflibercept during the core trial and met the eligibility requirements of this extension trial continued to receive aflibercept in this extension trial in order to maintain the masking during the extension trial. No hypothesis testing or descriptive analyses were planned.

Subjects who were treated in the core trial with brolucizumab 3mg or brolucizumab 6 mg, and met the eligibility requirements of this extension trial, received the new formulation of brolucizumab 6 mg solution in the extension trial.

Enrolled subjects were to receive three intravitreal (IVT) ophthalmic injections. The study eye was the same eye that received the treatment in the core study. The extension trial consisted of 7 study visits at 4 week intervals over a period of 24 weeks.

Assessment of the efficacy and safety of brolucizumab 6 mg was based on a within-patient comparison with the last 6 months of corresponding core-study efficacy and safety data serving as the reference. Neither the patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data was presented descriptively for only brolucizumab in line with the study objective. No formal hypothesis testing was planned.

• Study Type: Interventional
• Enrollment (Actual): 151
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • Arecibo, Puerto Rico, 00612
    • Novartis Investigative Site
  • San Juan, Puerto Rico, 00907
    • Novartis Investigative Site
• United States
  • Arizona
    • Peoria, Arizona, United States, 85381
      • Novartis Investigative Site
    • Phoenix, Arizona, United States, 85014
      • Novartis Investigative Site
  • California
    • Arcadia, California, United States, 91006
      • Novartis Investigative Site
    • Huntington Beach, California, United States, 92647
      • Novartis Investigative Site
    • La Jolla, California, United States, 92093
      • Novartis Investigative Site
    • Loma Linda, California, United States, 92354
      • Novartis Investigative Site
    • Mountain View, California, United States, 94040
      • Novartis Investigative Site
    • Oakland, California, United States, 94609
      • Novartis Investigative Site
    • Redlands, California, United States, 92374
      • Novartis Investigative Site
    • Sacramento, California, United States, 95841
      • Novartis Investigative Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • Novartis Investigative Site
    • Golden, Colorado, United States, 80401
      • Novartis Investigative Site
  • Connecticut
    • Bridgeport, Connecticut, United States, 06606
      • Novartis Investigative Site
    • New London, Connecticut, United States, 06320
      • Novartis Investigative Site
  • Florida
    • Altamonte Springs, Florida, United States, 32701
      • Novartis Investigative Site
    • Deerfield Beach, Florida, United States, 33064
      • Novartis Investigative Site
    • Fort Myers, Florida, United States, 33912-7125
      • Novartis Investigative Site
    • Ocala, Florida, United States, 34474
      • Novartis Investigative Site
    • Palm Beach Gardens, Florida, United States, 33410
      • Novartis Investigative Site
    • Pensacola, Florida, United States, 32503
      • Novartis Investigative Site
    • Sarasota, Florida, United States, 34239
      • Novartis Investigative Site
    • Tallahassee, Florida, United States, 32308
      • Novartis Investigative Site
    • Vero Beach, Florida, United States, 32960
      • Novartis Investigative Site
    • Winter Haven, Florida, United States, 33880
      • Novartis Investigative Site
  • Idaho
    • Boise, Idaho, United States, 83713
      • Novartis Investigative Site
  • Illinois
    • Bloomington, Illinois, United States, 61704
      • Novartis Investigative Site
  • Indiana
    • Indianapolis, Indiana, United States, 46280
      • Novartis Investigative Site
  • Kansas
    • Leawood, Kansas, United States, 66211
      • Novartis Investigative Site
    • Shawnee Mission, Kansas, United States, 66204
      • Novartis Investigative Site
  • Maine
    • Portland, Maine, United States, 04102
      • Novartis Investigative Site
  • Maryland
    • Baltimore, Maryland, United States, 21237-4350
      • Novartis Investigative Site
    • Waldorf, Maryland, United States, 20602
      • Novartis Investigative Site
  • Nevada
    • Las Vegas, Nevada, United States, 89144
      • Novartis Investigative Site
    • Reno, Nevada, United States, 89502
      • Novartis Investigative Site
  • New Jersey
    • Toms River, New Jersey, United States, 08755
      • Novartis Investigative Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Novartis Investigative Site
  • New York
    • Rochester, New York, United States, 14642
      • Novartis Investigative Site
    • Rochester, New York, United States, 14620
      • Novartis Investigative Site
    • Shirley, New York, United States, 11967
      • Novartis Investigative Site
    • Syracuse, New York, United States, 13224
      • Novartis Investigative Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Novartis Investigative Site
    • Southern Pines, North Carolina, United States, 28387
      • Novartis Investigative Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Novartis Investigative Site
    • Cleveland, Ohio, United States, 44122
      • Novartis Investigative Site
    • Dublin, Ohio, United States, 43016
      • Novartis Investigative Site
    • Fairfield, Ohio, United States, 45014
      • Novartis Investigative Site
  • Pennsylvania
    • Camp Hill, Pennsylvania, United States, 17011
      • Novartis Investigative Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Novartis Investigative Site
  • Texas
    • Abilene, Texas, United States, 79606
      • Novartis Investigative Site
    • Austin, Texas, United States, 78731
      • Novartis Investigative Site
    • Fort Worth, Texas, United States, 76104
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
    • Houston, Texas, United States, 77025
      • Novartis Investigative Site
    • Plano, Texas, United States, 75093
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78240
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78215
      • Novartis Investigative Site
  • Virginia
    • Richmond, Virginia, United States, 23235
      • Novartis Investigative Site
    • Warrenton, Virginia, United States, 20186
      • Novartis Investigative Site
  • Washington
    • Silverdale, Washington, United States, 98383
      • Novartis Investigative Site
    • Spokane, Washington, United States, 99204
      • Novartis Investigative Site
    • University Place, Washington, United States, 98467
      • Novartis Investigative Site
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Novartis Investigative Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Sign written informed consent
• Completed the core study, CRTH258A2301, also known as CRTH258-C002 as defined by assessments at Visit 26/Week 96 within ≤12 weeks of the baseline.

Exclusion Criteria:

• Patient discontinued the treatment or the core study prematurely at any time
• Patient received standard of care treatment for nAMD after completion of the core study
• Pregnant or nursing women and women of child-bearing potential
• Stroke or MI (myocardial infarction) within 3 months of the baseline extension visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Brolucizumab; Brolucizumab 6 mg solution for IVT injection, single injection at Day 1 (baseline), Week 8, and Week 16 or Week 20	Drug: Brolucizumab 6 mg; Administered as opthalmic solution for an intravitreal injection to the study eye; Other Names: RTH258
Other: Aflibercept; Aflibercept 2 mg solution for IVT injection, single injection at Day 1 (baseline), Week 8 and Week 16 to maintain the masking of the extension trial only.	Drug: Aflibercept 2 mg; Administered as an opthalmic solution for intravitreal injection to the study eye; Other Names: EYELEA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Ocular and Non-Ocular Treatment Emergent Adverse Events	Number of participants with ocular and non-ocular treatment emergent events with the new formulation brolucizumab 6 mg in this extension trial up to week 24 vs. the corresponding last 6 months of brolucizumab treatment in the Core trial >= 2%. Safety assessment of the new formulation brolucizumab 6 mg was based on a within-patient comparison with the last 6 months of corresponding Core safety data. Missing brolucizumab data were imputed using last observation carried forward (LOCF).	Up to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Loss in BCVA of 15 Letters or More From Extension Baseline at Each Post-baseline Visit	Best-corrected visual acuity for the study eye was tested at all study visits in a sitting position using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. Outcome measure was prespecified for brolucizumab arm only. Neither patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data presented descriptively for only brolucizumab in line with study objective. No formal hypothesis testing was planned. Missing brolucizumab data were imputed using last observation carried forward (LOCF).	Extension Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24
Change in BCVA From Extension Baseline at Each Post-baseline Visit	Best-corrected visual acuity for the study eye was tested at all study visits in a sitting position using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. Outcome measure was prespecified for brolucizumab arm only. Neither the patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data was presented descriptively for only brolucizumab in line with the study objective. No formal hypothesis testing was planned. Missing brolucizumab data were imputed using last observation carried forward (LOCF).	Extension baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24
Patients With Positive q12w Treatment Status at Week 20	The estimate for the proportion of patients with a positive q12w treatment status at Week 24 was derived from Kaplan Meier time-to-event analyses for the event 'first q8w-need'. The outcome of the Kaplan-Meier analysis was estimated probability for maintaining on q12w up to the Disease Activity Assessment (DAA) at exWeek 20. Outcome measure was prespecified for brolucizumab arm only. Neither the patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data was presented descriptively for only brolucizumab in line with the study objective. No formal hypothesis testing was planned. Missing brolucizumab data were imputed using last observation carried forward (LOCF).	Week 20
Change in Central Sub-Field Thickness (CSFT) From Extension Baseline at Each Post-baseline Visit	Measurement of the central subfield thickness of the retina was assessed using Optical Coherence Tomography (OCT) at each visit for the study eye. Outcome measure was prespecified for brolucizumab arm only. Neither the patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data was presented descriptively for only brolucizumab in line with the study objective. No formal hypothesis testing was planned. Missing brolucizumab data were imputed using last observation carried forward (LOCF).	Extension Baseline, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24
Percentage of Subjects With Positive Anti-drug Antibody (ADA) Status for Brolucuzumab 6 mg in Extension	Positive integrated anti-drug antibodies (ADA) status is defined as induced ADA status with ADA negative at pre-dose and a post-dose titer value of greater than or equal to 30 at any time point or boosted ADA status with ADA positive at pre-dose and a post-dose titer value increase by more than 3-fold (1 dilution) at any time point. Outcome measure was prespecified for brolucizumab arm only. Neither the patient selection process nor expected sample sizes supported a valid comparison between aflibercept and brolucizumab. The aflibercept arm was included only to maintain the masking in the extension trial. Data was presented descriptively for only brolucizumab in line with the study objective. No formal hypothesis testing was planned. Missing brolucizumab data were imputed using last observation carried forward (LOCF).	Extension Baseline, Week 8, Week 16, Week 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicatrials.com

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2018
• Primary Completion (Actual): September 6, 2018
• Study Completion (Actual): September 6, 2018

Study Registration Dates

• First Submitted: December 11, 2017
• First Submitted That Met QC Criteria: December 21, 2017
• First Posted (Actual): December 29, 2017

Study Record Updates

• Last Update Posted (Actual): January 5, 2021
• Last Update Submitted That Met QC Criteria: December 9, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: intravitreal injection; neovascular age-related macular degeneration; aflibercept; brolucizumab; double-masked, extension study
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Wet Macular Degeneration; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept
• Other Study ID Numbers: CRTH258A2301E1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No