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

Age-Related Macular Degeneration Clinical Trial

— MERLIN  

Official title:

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03710564
• Other study ID #: CRTH258AUS04
• Status: Terminated
• Phase: Phase 3
• Start date: October 30, 2018
• Est. completion date: July 1, 2021

Study information

• Verified date: January 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 535
• Est. completion date: July 1, 2021
• Est. primary completion date: December 21, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Age-Related Macular Degeneration
• Macular Degeneration

Intervention

Biological:
• Brolucizumab
6 mg/0.05mL solution for intravitreal injection
• Aflibercept
2 mg/0.05mL solution for intravitreal injection

Locations

Country	Name	City	State
Puerto Rico	Novartis Investigative Site	Arecibo
United States	Novartis Investigative Site	'Aiea	Hawaii
United States	Novartis Investigative Site	Abilene	Texas
United States	Novartis Investigative Site	Austin	Texas
United States	Novartis Investigative Site	Austin	Texas
United States	Novartis Investigative Site	Austin	Texas
United States	Novartis Investigative Site	Beverly Hills	California
United States	Novartis Investigative Site	Bloomfield	New Jersey
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Charlotte	North Carolina
United States	Novartis Investigative Site	Cleveland	Ohio
United States	Novartis Investigative Site	Colorado Springs	Colorado
United States	Novartis Investigative Site	Deerfield Beach	Florida
United States	Novartis Investigative Site	Eugene	Oregon
United States	Novartis Investigative Site	Fairfax	Virginia
United States	Novartis Investigative Site	Fairfield	Ohio
United States	Novartis Investigative Site	Fort Lauderdale	Florida
United States	Novartis Investigative Site	Fort Myers	Florida
United States	Novartis Investigative Site	Fort Worth	Texas
United States	Novartis Investigative Site	Fort Worth	Texas
United States	Novartis Investigative Site	Germantown	Tennessee
United States	Novartis Investigative Site	Golden	Colorado
United States	Novartis Investigative Site	Harlingen	Texas
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Huntington Beach	California
United States	Novartis Investigative Site	Kingston	Pennsylvania
United States	Novartis Investigative Site	Las Vegas	Nevada
United States	Novartis Investigative Site	Lenexa	Kansas
United States	Novartis Investigative Site	Marietta	Georgia
United States	Novartis Investigative Site	Miami	Florida
United States	Novartis Investigative Site	Mount Dora	Florida
United States	Novartis Investigative Site	Mountain View	California
United States	Novartis Investigative Site	New Orleans	Louisiana
United States	Novartis Investigative Site	Oakland	California
United States	Novartis Investigative Site	Oxnard	California
United States	Novartis Investigative Site	Palo Alto	California
United States	Novartis Investigative Site	Pensacola	Florida
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Phoenix	Arizona
United States	Novartis Investigative Site	Phoenix	Arizona
United States	Novartis Investigative Site	Phoenix	Arizona
United States	Novartis Investigative Site	Redlands	California
United States	Novartis Investigative Site	Reno	Nevada
United States	Novartis Investigative Site	Royal Oak	Michigan
United States	Novartis Investigative Site	Sacramento	California
United States	Novartis Investigative Site	Saint Louis	Missouri
United States	Novartis Investigative Site	Saint Petersburg	Florida
United States	Novartis Investigative Site	San Antonio	Texas
United States	Novartis Investigative Site	San Francisco	California
United States	Novartis Investigative Site	Santa Barbara	California
United States	Novartis Investigative Site	Spokane	Washington
United States	Novartis Investigative Site	Springfield	Massachusetts
United States	Novartis Investigative Site	Stuart	Florida
United States	Novartis Investigative Site	Syracuse	New York
United States	Novartis Investigative Site	Toms River	New Jersey
United States	Novartis Investigative Site	Tyler	Texas
United States	Novartis Investigative Site	Waldorf	Maryland
United States	Novartis Investigative Site	West Des Moines	Iowa
United States	Novartis Investigative Site	West Monroe	Louisiana
United States	Novartis Investigative Site	Wheaton	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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

External Links

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