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)

• ClinicalTrials.gov Identifier: NCT03710564
• Recruitment Status: Terminated
• First Posted: October 18, 2018
• Results First Posted: July 22, 2022
• Last Update Posted: January 30, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: October 16, 2018
• First Posted Date: October 18, 2018
• Results First Submitted Date: June 28, 2022
• Results First Posted Date: July 22, 2022
• Last Update Posted Date: January 30, 2023
• Actual Study Start Date: October 30, 2018
• Actual Primary Completion Date: December 21, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 28, 2022)

Change From Baseline in Best-Corrected Visual Acuity (BCVA) at Week 52 [ Time Frame: Baseline, 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.

Original Primary Outcome Measures (submitted: October 16, 2018)

Change from baseline in Best-Corrected Visual Acuity (BCVA) at Week 52 [ Time Frame: Baseline (Week 0), Week 52 ]

BCVA will be assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. Baseline BCVA is defined as the last measurement on or prior to the baseline visit.

Current Secondary Outcome Measures (submitted: June 28, 2022)

• Stable Visual Acuity (VA) or Improvement in VA at Week 52 and Week 104 [ Time Frame: Baseline, weeks 52 and 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.
• Loss in Best-Corrected Visual Acuity (BCVA) of 5 Letters or More [ Time Frame: 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 ]
  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.
• Loss in Best-Corrected Visual Acuity (BCVA) of 10 Letters or More [ Time Frame: 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 ]
  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.
• Loss in Best-Corrected Visual Acuity (BCVA) of 15 Letters or More [ Time Frame: 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 ]
  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.
• Gain in Best-Corrected Visual Acuity (BCVA) of 5 Letters or More [ Time Frame: 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 ]
  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.
• Gain in Best-Corrected Visual Acuity (BCVA) of 10 Letters or More [ Time Frame: 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 ]
  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.
• Gain in Best-Corrected Visual Acuity (BCVA) of 15 Letters or More [ Time Frame: 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 ]
  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.
• Change in Central Subfield Thickness (CST) From Baseline [ Time Frame: 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 ]
  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.
• Number of Participants With Intraretinal Fluid (IRF) [ Time Frame: 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 ]
  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.
• Number of Participants With Subretinal Fluid (SRF) [ Time Frame: 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 ]
  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.
• Number of Participants With Sub-Retinal Pigment Epithelium (Sub-RPE) Fluid [ Time Frame: 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 ]
  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.
• Number of Participants With Fluid-free Status (no IRF, SRF or Sub-RPE Fluid) [ Time Frame: 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 ]
  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.
• Time to First Dry Retina (no IRF or SRF) [ Time Frame: Baseline, Up to Week 104 (assessments every 4 weeks) ]
  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.
• Time to Sustained Dry Retina (no IRF or SRF at ≥ 2 Consecutive Visits) [ Time Frame: Baseline, Up to Week 104 (assessments every 4 weeks) ]
  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.
• Number of Participants With Anti-drug Antibody (ADA) Negative Status [ Time Frame: Baseline, weeks 4, 12, 24, 36, 52, 76 and 104 ]
  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.
• Free Brolucizumab Serum Concentration [ Time Frame: pre-dose a baseline, weeks 4, 12, 24, 36, 52, 76 and 104 ]
  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).

Original Secondary Outcome Measures (submitted: October 16, 2018)

• Stable VA or improvement in VA at Week 52 [ Time Frame: Baseline, Week 52 ]
  BCVA will be assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing protocol at an initial testing distance of 4 meters. The number of subjects with no change or gain in BCVA compared to baseline will be reported.
• Loss in BCVA of 5/10/15 letters or more from baseline to each post-baseline visit [ Time Frame: Baseline, Up to Week 52 ]
  BCVA will be assessed using the ETDRS visual acuity testing protocol at an initial testing distance of 4 meters. The number of subjects with loss in BCVA of 5/10/15 letters or more from baseline will be reported for each post-baseline visit.
• Gain in BCVA of 5/10/15 letters or more from baseline to each post-baseline visit [ Time Frame: Baseline, Up to Week 52 ]
  BCVA will be assessed using the ETDRS visual acuity testing protocol at an initial testing distance of 4 meters. The number of subjects with gain in BCVA of 5/10/15 letters or more from baseline will be reported for each post-baseline visit.
• Change in Central Subfield Thickness (CST) from baseline to each post-baseline visit [ Time Frame: Baseline, Up to Week 52 ]
  CST will be assessed using Spectral Domain Optical Coherence Tomography (SD-OCT) images.
• Intraretinal fluid (IRF) at each post-baseline visit [ Time Frame: Up to Week 52 ]
  IRF will be assessed using SD-OCT images. The number of subjects with IRF (present, absent) will be reported for each post-baseline visit.
• Subretinal fluid (SRF) at each post-baseline visit [ Time Frame: Up to Week 52 ]
  SRF will be assessed using SD-OCT images. The number of subjects with SRF (present, absent) will be reported for each post-baseline visit.
• Sub-Retinal Pigment Epithelium (sub-RPE) fluid in patients with sub-RPE fluid at baseline [ Time Frame: Baseline, Up to Week 52 ]
  Sub-RPE fluid will be assessed using SD-OCT images. The number of subjects with sub-RPE fluid in subjects with sub-RPE fluid at baseline (present, absent) will be reported for each post-baseline visit.
• Fluid-free status (no IRF, SRF or sub-RPE fluid) at each post-baseline treatment visit [ Time Frame: Up to Week 52 ]
  IRF, SRF, and sub-RPE fluid will assessed using SD-OCT images. The number of subjects with fluid-free status (no IRF, SRF, or sub-RPE) will be reported for each post-baseline visit.
• Time to first dry retina (no IRF or SRF) finding [ Time Frame: Time to event (Baseline, Up to Week 52) ]
  IRF and SRF will be assessed using SD-OCT images. A dry retina is defined as no IRF or SRF at the visit.
• Time to first sustained dry retina (no IRF or SRF at ≥ 2 consecutive visits) finding [ Time Frame: Time to event (Baseline, Up to Week 52) ]
  IRF and SRF will be assessed using SD-OCT images. A sustained dry retina is defined as no IRF or SRF at 2 or more consecutive visits.
• Change in anti-drug antibody (ADA) levels from baseline [ Time Frame: Baseline, Up to Week 52 ]
  A blood sample will be collected. The baseline sample will be collected prior to first dose of study treatment. This outcome measure is pre-specified for the brolucizumab arm only.
• Change in systemic brolucizumab levels from baseline [ Time Frame: Baseline, Up to Week 52 ]
  A blood sample will be collected. The baseline sample will be collected prior to first dose of study treatment. This outcome measure is pre-specified for the brolucizumab arm only.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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)
• Brief 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.

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
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

multicenter, randomized, double-masked

Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment

• Condition: Age-Related Macular Degeneration

Intervention

• Biological: Brolucizumab
  6 mg/0.05mL solution for intravitreal injection
  Other Name: RTH258
• Biological: Aflibercept
  2 mg/0.05mL solution for intravitreal injection
  Other Name: EYLEA

Study Arms

• Experimental: Brolucizumab
  Brolucizumab 6 mg dosed every 4 weeks was administered via intravitreal injection for 100 weeks.
  Intervention: Biological: Brolucizumab
• Active Comparator: Aflibercept
  Aflibercept 2 mg dosed every 4 weeks was administered via intravitreal injection for 100 weeks.
  Intervention: Biological: Aflibercept

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: June 28, 2022): 535
• Original Estimated Enrollment (submitted: October 16, 2018): 500
• Actual Study Completion Date: July 1, 2021
• Actual Primary Completion Date: December 21, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Puerto Rico, United States

Administrative Information

• NCT Number: NCT03710564
• Other Study ID Numbers: CRTH258AUS04
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

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

• URL: https://www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: January 2023