Study of Safety and Efficacy of Brolucizumab 6 mg Dosed Every 4 Weeks Compared to Aflibercept 2 mg Dosed Every 4 Weeks in Patients With Retinal Fluid Despite Frequent Anti-VEGF Injections (MERLIN)

A Multicenter, Randomized, Double-masked Phase 3a Study to Assess Safety and Efficacy of Brolucizumab 6 mg q4 Weeks Compared to Aflibercept 2 mg q4 Weeks in Patients With Neovascular Age-related Macular Degeneration (nAMD) With Persistent Retinal Fluid (MERLIN)

This clinical study was designed to compare the safety and efficacy of brolucizumab 6 mg dosed every 4 weeks to aflibercept 2 mg dosed every 4 weeks in those neovascular age-related macular degeneration (nAMD) patients with retinal fluid despite frequent anti-Vascular Endothelial Growth Factor (VEGF) injections.

Study Overview

• Status: Terminated
• Conditions: Age-Related Macular Degeneration
• Intervention / Treatment: Biological: Brolucizumab; Biological: Aflibercept

Detailed Description

This was a Phase III, multi-center, randomized, double-masked, parallel group study with 2 masked arms in which participants were randomized 2:1 to receive brolucizumab or aflibercept. All participants had study visits every 4 weeks through week 104.

The study consisted of three study periods:

Screening Period: The screening period lasted up to 2 weeks prior to administration of the first dose of study treatment, dependent upon confirmation of the patient meeting eligibility criteria.

Double-Masked Treatment Period: Participants meeting eligibility criteria entered the treatment period and were randomized in a 2:1 ratio into one of the following 2 masked treatment arms at the Baseline visit: Brolucizumab 6 mg injected every 4 weeks or Aflibercept 2 mg injected every 4 weeks. Treatment period lasted up to week 100.

Safety Follow up Period: Participants were followed up for safety during 4 weeks after the last dose of study treatment. Including the Screening Period, the total study duration for a participant was up to 106 weeks.

Some participants were eligible to continue into an extension study in order to receive treatment with brolucizumab (a) after completing the 104 -week double-masked treatment period, (b) upon meeting all inclusion/exclusion criteria for the extension study, and (c) based on Investigator's judgment that the participant was expected to benefit from treatment with brolucizumab.

• Study Type: Interventional
• Enrollment (Actual): 535
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • Arecibo, Puerto Rico, 00612
    • Novartis Investigative Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85020
      • Novartis Investigative Site
    • Phoenix, Arizona, United States, 85016
      • Novartis Investigative Site
    • Phoenix, Arizona, United States, 85053
      • Novartis Investigative Site
  • California
    • Beverly Hills, California, United States, 90211
      • Novartis Investigative Site
    • Huntington Beach, California, United States, 92647
      • Novartis Investigative Site
    • Mountain View, California, United States, 94040
      • Novartis Investigative Site
    • Oakland, California, United States, 94609
      • Novartis Investigative Site
    • Oxnard, California, United States, 93036
      • Novartis Investigative Site
    • Palo Alto, California, United States, 94303
      • Novartis Investigative Site
    • Redlands, California, United States, 92374
      • Novartis Investigative Site
    • Sacramento, California, United States, 95841
      • Novartis Investigative Site
    • San Francisco, California, United States, 94107
      • Novartis Investigative Site
    • Santa Barbara, California, United States, 93103
      • Novartis Investigative Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • Novartis Investigative Site
    • Golden, Colorado, United States, 80401
      • Novartis Investigative Site
  • Florida
    • Deerfield Beach, Florida, United States, 33064
      • Novartis Investigative Site
    • Fort Lauderdale, Florida, United States, 33308
      • Novartis Investigative Site
    • Fort Myers, Florida, United States, 33912-7125
      • Novartis Investigative Site
    • Miami, Florida, United States, 33136
      • Novartis Investigative Site
    • Mount Dora, Florida, United States, 32757
      • Novartis Investigative Site
    • Pensacola, Florida, United States, 32503
      • Novartis Investigative Site
    • Saint Petersburg, Florida, United States, 33711
      • Novartis Investigative Site
    • Stuart, Florida, United States, 34994
      • Novartis Investigative Site
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Novartis Investigative Site
  • Hawaii
    • 'Aiea, Hawaii, United States, 96701
      • Novartis Investigative Site
  • Illinois
    • Wheaton, Illinois, United States, 60187
      • Novartis Investigative Site
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Novartis Investigative Site
  • Kansas
    • Lenexa, Kansas, United States, 66215
      • Novartis Investigative Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70115-8139
      • Novartis Investigative Site
    • West Monroe, Louisiana, United States, 71291
      • Novartis Investigative Site
  • Maryland
    • Waldorf, Maryland, United States, 20602
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Novartis Investigative Site
    • Boston, Massachusetts, United States, 02114
      • Novartis Investigative Site
    • Springfield, Massachusetts, United States, 01107
      • Novartis Investigative Site
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • Novartis Investigative Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Novartis Investigative Site
  • Nevada
    • Las Vegas, Nevada, United States, 89144
      • Novartis Investigative Site
    • Reno, Nevada, United States, 89502
      • Novartis Investigative Site
  • New Jersey
    • Bloomfield, New Jersey, United States, 07003
      • Novartis Investigative Site
    • Toms River, New Jersey, United States, 08755
      • Novartis Investigative Site
  • New York
    • Syracuse, New York, United States, 13224
      • Novartis Investigative Site
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • Novartis Investigative Site
  • Ohio
    • Cleveland, Ohio, United States, 44122
      • Novartis Investigative Site
    • Fairfield, Ohio, United States, 45014
      • Novartis Investigative Site
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Novartis Investigative Site
  • Pennsylvania
    • Kingston, Pennsylvania, United States, 95403
      • Novartis Investigative Site
    • Philadelphia, Pennsylvania, United States, 19107
      • Novartis Investigative Site
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Novartis Investigative Site
  • Texas
    • Abilene, Texas, United States, 79606
      • Novartis Investigative Site
    • Austin, Texas, United States, 78705
      • Novartis Investigative Site
    • Austin, Texas, United States, 78731
      • Novartis Investigative Site
    • Austin, Texas, United States, 78793
      • Novartis Investigative Site
    • Fort Worth, Texas, United States, 76104
      • Novartis Investigative Site
    • Fort Worth, Texas, United States, 76102
      • Novartis Investigative Site
    • Harlingen, Texas, United States, 78550
      • Novartis Investigative Site
    • Houston, Texas, United States, 77030
      • Novartis Investigative Site
    • San Antonio, Texas, United States, 78240
      • Novartis Investigative Site
    • Tyler, Texas, United States, 75701
      • Novartis Investigative Site
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Novartis Investigative Site
  • Washington
    • Spokane, Washington, United States, 99204
      • 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:

• Signed informed consent
• Diagnosis of wet age-related macular degeneration (AMD)
• Currently receiving anti-VEGF injections

Exclusion Criteria:

• Active infection or inflammation in either eye
• Significant fibrosis in the study eye
• Recent ocular surgery
• Uncontrolled glaucoma
• Use of medications as specified in the protocol
• Pregnant, nursing
• Of child-bearing potential unless using highly effective method of contraception

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Brolucizumab; Brolucizumab 6 mg dosed every 4 weeks was administered via intravitreal injection for 100 weeks.	Biological: Brolucizumab; 6 mg/0.05mL solution for intravitreal injection; Other Names: RTH258
Active Comparator: Aflibercept; Aflibercept 2 mg dosed every 4 weeks was administered via intravitreal injection for 100 weeks.	Biological: Aflibercept; 2 mg/0.05mL solution for intravitreal injection; Other Names: EYLEA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Best-Corrected Visual Acuity (BCVA) at Week 52	BCVA was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. BCVA min and max possible scores are 0-100 respectively and a higher score represents better functioning. A positive change from baseline represents better functioning. Baseline BCVA was defined as the last measurement on or prior to the baseline visit. BCVA assessments after start of alternative anti-VEGF treatment in the study eye were censored and imputed by the last value prior to start of alternative treatment. Last observation carried forward (LOCF) was used for the imputation of missing values.	Baseline, week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stable Visual Acuity (VA) or Improvement in VA at Week 52 and Week 104	Visual Acuity (VA) was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. VA min and max possible scores are 0-100 respectively and a higher score represents better functioning. The number of participants with no change or gain in VA compared to baseline was reported. VA stabilization or improvement is defined as a change from baseline no worse than 5 letters loss in VA compared to Baseline. Baseline VA was defined as the last measurement on or prior to the baseline visit. VA assessments after start of alternative anti-VEGF treatment in the study eye were censored and imputed by the last value prior to start of alternative treatment.	Baseline, weeks 52 and 104
Loss in Best-Corrected Visual Acuity (BCVA) of 5 Letters or More	BCVA was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. BCVA min and max possible scores are 0-100 respectively and a higher score represents better functioning. The number of subjects with loss in BCVA of 5 letters or more from baseline was reported for each post-baseline visit. Baseline BCVA was defined as the last measurement on or prior to the baseline visit. BCVA assessments after start of alternative anti-VEGF treatment in the study eye were censored and imputed by the last value prior to start of alternative treatment.	Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Loss in Best-Corrected Visual Acuity (BCVA) of 10 Letters or More	BCVA was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. BCVA min and max possible scores are 0-100 respectively and a higher score represents better functioning. The number of subjects with loss in BCVA of 10 letters or more from baseline was reported for each post-baseline visit. Baseline BCVA was defined as the last measurement on or prior to the baseline visit. BCVA assessments after start of alternative anti-VEGF treatment in the study eye were censored and imputed by the last value prior to start of alternative treatment.	Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Loss in Best-Corrected Visual Acuity (BCVA) of 15 Letters or More	BCVA was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. BCVA min and max possible scores are 0-100 respectively and a higher score represents better functioning. The number of subjects with loss in BCVA of 15 letters or more from baseline was reported for each post-baseline visit. Baseline BCVA was defined as the last measurement on or prior to the baseline visit. BCVA assessments after start of alternative anti-VEGF treatment in the study eye were censored and imputed by the last value prior to start of alternative treatment.	Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Gain in Best-Corrected Visual Acuity (BCVA) of 5 Letters or More	BCVA was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. BCVA min and max possible scores are 0-100 respectively and a higher score represents better functioning. The number of subjects with gain in BCVA of 5 letters or more from baseline was reported for each post-baseline visit. Baseline BCVA was defined as the last measurement on or prior to the baseline visit. BCVA assessments after start of alternative anti-VEGF treatment in the study eye were censored and imputed by the last value prior to start of alternative treatment.	Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Gain in Best-Corrected Visual Acuity (BCVA) of 10 Letters or More	BCVA was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. BCVA min and max possible scores are 0-100 respectively and a higher score represents better functioning. The number of subjects with gain in BCVA of 10 letters or more from baseline was reported for each post-baseline visit. Baseline BCVA was defined as the last measurement on or prior to the baseline visit. BCVA assessments after start of alternative anti-VEGF treatment in the study eye were censored and imputed by the last value prior to start of alternative treatment.	Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Gain in Best-Corrected Visual Acuity (BCVA) of 15 Letters or More	BCVA was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. BCVA min and max possible scores are 0-100 respectively and a higher score represents better functioning. The number of subjects with gain in BCVA of 15 letters or more from baseline was reported for each post-baseline visit. Baseline BCVA was defined as the last measurement on or prior to the baseline visit. BCVA assessments after start of alternative anti-VEGF treatment in the study eye were censored and imputed by the last value prior to start of alternative treatment.	Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Change in Central Subfield Thickness (CST) From Baseline	CST was assessed using Spectral Domain Optical Coherence Tomography (SD-OCT) images. A negative change from baseline is a favorable outcome. CST assessments after start of alternative anti-VEGF treatment in the study eye were censored and imputed by the last value prior to start of alternative treatment. These results were based on analysis using the Last observation carried forward (LOCF) approach for replacement/imputation of censored/missing values and observed data.	Baseline, weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Number of Participants With Intraretinal Fluid (IRF)	IRF was assessed using Spectral Domain Optical Coherence Tomography (SD-OCT) images. The number of participants with presence of IRF was reported for each post-baseline visit. These results were based on analysis using the Last observation carried forward (LOCF) approach for replacement/imputation of censored/missing values and observed data.	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Number of Participants With Subretinal Fluid (SRF)	SRF was assessed using Spectral Domain Optical Coherence Tomography (SD-OCT) images. The number of participants with presence of SRF was reported for each post-baseline visit. These results were based on analysis using the Last observation carried forward (LOCF) approach for replacement/imputation of censored/missing values and observed data.	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Number of Participants With Sub-Retinal Pigment Epithelium (Sub-RPE) Fluid	Sub-RPE fluid was assessed using Spectral Domain Optical Coherence Tomography (SD-OCT) images. The number of participants with presence of sub-RPE fluid in participants with sub-RPE fluid at baseline was reported for each post-baseline visit. These results were based on analysis using the Last observation carried forward (LOCF) approach for replacement/imputation of censored/missing values and observed data.	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Number of Participants With Fluid-free Status (no IRF, SRF or Sub-RPE Fluid)	Intraretinal fluid (IRF), Subretinal fluid (SRF) and Sub-Retinal Pigment Epithelium fluid (sub-RPE) were assessed using Spectral Domain Optical Coherence Tomography (SD-OCT) images. The number of participants with fluid-free status (simultaneous absence of IRF, SRF, and sub-RPE) was reported for each post-baseline visit. These results were based on analysis using the Last observation carried forward (LOCF) approach for replacement/imputation of censored/missing values and observed data.	Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100 and 104
Time to First Dry Retina (no IRF or SRF)	Intraretinal fluid (IRF) and Subretinal fluid (SRF) were assessed using Spectral Domain Optical Coherence Tomography (SD-OCT) images. A dry retina is defined as no IRF or SRF at the respective visit. Kaplan-Meier method was used for estimate of percentiles with 95% CI based on methodology of Brookmeyer and Crowley. Data was censored at the last time when IRF/SRF assessments for fluid-free retina were available for participants who discontinued on/or prior to the time of the start of alternative anti-VEGF treatment. IRF and SRF assessments on unscheduled visits were considered.	Baseline, Up to Week 104 (assessments every 4 weeks)
Time to Sustained Dry Retina (no IRF or SRF at ≥ 2 Consecutive Visits)	Intraretinal fluid (IRF) and Subretinal fluid (SRF) were assessed using Spectral Domain Optical Coherence Tomography (SD-OCT) images. A sustained dry retina is defined as no IRF or SRF at 2 or more consecutive visits. Kaplan-Meier method was used for estimate of percentiles with 95% CI based on methodology of Brookmeyer and Crowley. Data was censored at the last time when IRF/SRF assessments for fluid-free retina were available for participants who discontinued on/or prior to the time of the start of alternative anti-VEGF treatment. IRF and SRF assessments on unscheduled visits were considered.	Baseline, Up to Week 104 (assessments every 4 weeks)
Number of Participants With Anti-drug Antibody (ADA) Negative Status	A blood sample was collected for anti-drug antibody assessment. ADA negative status = ADA negative result at the corresponding study visit. The baseline sample was collected prior to first dose of study treatment and the post-baseline assessments were taken at the scheduled timepoints. A negative Titer was used to assess the ADA status for the brolucizumab arm.	Baseline, weeks 4, 12, 24, 36, 52, 76 and 104
Free Brolucizumab Serum Concentration	A blood sample was collected for Free Brolucizumab serum concentration assessment. This outcome measure was pre-specified for the brolucizumab arm only. The baseline sample was collected prior to first dose of study treatment and the post-baseline assessments. Values below the limit of quantification (BLQ) (<0.5 ng/mL) were replaced by one half of the LLOQ (0.25 ng/mL) in the calculation of the summary statistics. For the Mean score at each visit, if the calculated value was less than 0.5, then "NA" was displayed instead; meaning that the score is below the limit of quantitation (<0.5 ng/mL).	pre-dose a baseline, weeks 4, 12, 24, 36, 52, 76 and 104

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2018
• Primary Completion (Actual): December 21, 2020
• Study Completion (Actual): July 1, 2021

Study Registration Dates

• First Submitted: October 16, 2018
• First Submitted That Met QC Criteria: October 16, 2018
• First Posted (Actual): October 18, 2018

Study Record Updates

• Last Update Posted (Estimate): January 30, 2023
• Last Update Submitted That Met QC Criteria: January 27, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: intravitreal injection; anti-VEGF; BEOVU; neovascular age-related macular degeneration; aflibercept; IVT; brolucizumab; nAMD; EYLEA; double-masked; MERLIN
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept
• Other Study ID Numbers: CRTH258AUS04

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