Neovascular Age-Related Macular Degeneration
Conditions
Brief summary
The primary objective of the study was to explore the effect of REGN2176-3 on the Early Treatment Diabetic Retinopathy Scale (ETDRS) best-corrected visual acuity (BCVA) in participants with neovascular age-related macular degeneration (AMD), compared to intravitreal aflibercept injection (IAI) monotherapy. The secondary objectives of the study were the following: * To explore the effect of 2 dose levels of IVT REGN2176-3 on anatomical changes of CNV in participants with nAMD compared to IAI monotherapy (at week 12) * To evaluate if short-term treatment with REGN2176-3 followed by IAI monotherapy offered the same or additional benefit compared to continuous treatment with REGN2176-3. Also to determine if there was benefit in initiating IAI treatment prior to REGN2176-3 compared to continuous treatment with IAI. * To assess the safety and tolerability of IVT REGN2176-3 in participants with nAMD
Interventions
Sponsors
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Men or women ≥50 years of age 2. Active subfoveal CNV secondary to AMD as evidenced by FA in the study eye, as determined by the reading center, including juxtafoveal lesions that affect the fovea 3. BCVA ETDRS letter score of 73 to 24 (20/40 to 20/320) in the study eye at the screening visit 4. Provide signed informed consent Key
Exclusion criteria
1. Any prior treatment with anti-VEGF treatment in the study eye 2. Any prior treatment (ie, systemic or ocular treatment) with PDGF or PDGFR inhibitors 3. Dense fibrotic scar or atrophy in the study eye involving the center of the fovea 4. Presence of retinal pigment epithelial tears or rips involving the macula in the study eye 5. Prior vitrectomy in the study eye 6. Any history of macular hole of stage 2 and above in the study eye 7. Any intraocular or periocular surgery within 3 months of day 1 in the study eye, except lid surgery 8. History of corneal transplant in the study eye 9. Evidence of diabetic retinopathy or diabetic macular edema in either eye 10. Positive serum human chorionic gonadotropin/urine pregnancy test at the screening or baseline visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Best Corrected Visual Acuity (BCVA) of the Study Eye at Week 12 | Baseline, Week 12 | Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. BCVA score was measured using an eye chart and was reported as the number of letters read correctly at a testing distance of 4 meters using the ETDRS Scale (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. Change from baseline calculated by subtracting baseline value from observed post-baseline value at Week 12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Resolution of Intraretinal and Subretinal Fluid From Baseline at Week 12 Measured by Optical Coherence Tomography (OCT) | Week 12 | CST was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. |
| Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 12 Measured by Fluorescein Angiography (FA) | Baseline, Week 12 | The anatomical state of the retinal vasculature of the study eye and the fellow eye was evaluated by funduscopic examination, fundus photography and FA to evaluate the total lesion area, CNV area, classic CNV area, and fluorescein leakage. CNV area values measured in square millimeters, each disc area was equivalent to 2.54 mm\^2 on the retina; lower values represent better outcomes. |
| Change From Baseline in Total Lesion Size at Week 12 Measured by Fluorescein Angiography (FA) | Baseline, Week 12 | Total Lesion Size was assessed by Fluorescein Angiography. |
| Change From Baseline in Central Subfield Retinal Thickness (CST) at Week 12, as Measured by Optical Coherence Tomography (OCT) | Baseline, Week 12 | CST was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from baseline indicated improvement. Change from baseline calculated by subtracting baseline value from LOCF post-baseline value at Week 12. |
| Percent Change From Baseline in Subretinal Hyperreflectivity Material (SHM) at Week 12 Measured by Optical Coherence Tomography (OCT) | Baseline, Week 12 | SHM was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from baseline indicated improvement. |
| Change From Baseline in Central Retinal/Lesion Thickness at Week 12 Measured by Optical Coherence Tomography (OCT) | Baseline, Week 12 | CST was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from baseline indicated improvement. Change from baseline calculated by subtracting baseline value from LOCF post-baseline value at Week 12. |
| Percentage of Participants Who Gained At Least 15 Letters in BCVA From Baseline at Week 12, Measured by 4-meter Early Treatment Diabetic Retinopathy Scale (ETDRS) | Week 12 | Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. BCVA score was measured using an eye chart and was reported as the number of letters read correctly at a testing distance of 4 meters using the ETDRS Scale (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. This outcome assessed the percentage of participants who gained 15 or more letters of visual acuity at Week 12 compared with baseline. |
Countries
Japan, United States
Participant flow
Recruitment details
The study was conducted at 82 sites in US and 11 sites in Japan. A total of 804 participants were screened. Out of 804 participants, 505 were randomized and treated.
Pre-assignment details
Participants were initially randomized in a 1:2:2 ratio to receive REGN2176-3 (1 mg:2 mg) (REGN2176 1 mg:REGN3 2 mg) or REGN2176-3 (3 mg:2 mg) (REGN2176 3 mg:REGN3 2 mg) or 2 mg intravitreal aflibercept injection (IAI). One eye was under study (the fellow eye was assessed for safety only).
Participants by arm
| Arm | Count |
|---|---|
| Group 1: REGN2176-3 (1 mg:2 mg) Intravitreal injection of REGN2176-3 (REGN2176 1 mg and REGN3 2 mg) every 4 weeks for 12 weeks. At Week 12, Group 1 continued without a secondary randomization. After Week 12, dosing in Group 1 was monthly up to Week 28, then criteria based re-dosing from Week 28-52. | 103 |
| Group 2: REGN2176-3 (3 mg:2 mg) Intravitreal injection of REGN2176-3 (REGN2176 3 mg and REGN3 2 mg) every 4 weeks for 12 weeks. At Week 12, a secondary randomization occurred in Group 2 for those participants who completed the Week 12 assessments. After Week 12, dosing in Group 2 was monthly up to Week 28, then criteria based re-dosing from Week 28-52. | 200 |
| Group 3: Intravitreal Aflibercept Injection (IAI) 2 mg IAI every 4 weeks for 12 weeks. At Week 12, a secondary randomization occurred in Group 3 for those participants who completed the Week 12 assessments. After Week 12, dosing in Group 3 was monthly up to Week 28, then criteria based re-dosing from Week 28-52. | 202 |
| Total | 505 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Period 1 (Day 1 to Week 12) | Adverse Event | 0 | 2 | 0 | 0 | 0 |
| Period 1 (Day 1 to Week 12) | Death | 1 | 0 | 0 | 0 | 0 |
| Period 1 (Day 1 to Week 12) | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 |
| Period 1 (Day 1 to Week 12) | Physician Decision | 1 | 0 | 0 | 0 | 0 |
| Period 1 (Day 1 to Week 12) | Withdrawal by Subject | 0 | 2 | 1 | 0 | 0 |
| Period 2 (Day 1 to Week 52/End of Study) | Adverse Event | 3 | 7 | 6 | 2 | 2 |
| Period 2 (Day 1 to Week 52/End of Study) | Death | 1 | 0 | 0 | 0 | 0 |
| Period 2 (Day 1 to Week 52/End of Study) | Lost to Follow-up | 0 | 2 | 1 | 2 | 1 |
| Period 2 (Day 1 to Week 52/End of Study) | Other Un-specified | 0 | 1 | 0 | 1 | 0 |
| Period 2 (Day 1 to Week 52/End of Study) | Physician Decision | 26 | 28 | 26 | 21 | 24 |
| Period 2 (Day 1 to Week 52/End of Study) | Withdrawal by Subject | 3 | 4 | 4 | 1 | 0 |
Baseline characteristics
| Characteristic | Group 1: REGN2176-3 (1 mg:2 mg) | Total | Group 3: Intravitreal Aflibercept Injection (IAI) 2 mg | Group 2: REGN2176-3 (3 mg:2 mg) |
|---|---|---|---|---|
| Age, Continuous | 79.2 years STANDARD_DEVIATION 8.01 | 78.3 years STANDARD_DEVIATION 8.56 | 77.7 years STANDARD_DEVIATION 8.61 | 78.6 years STANDARD_DEVIATION 8.77 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 14 Participants | 6 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 102 Participants | 491 Participants | 196 Participants | 193 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 24 Participants | 10 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 98 Participants | 473 Participants | 186 Participants | 189 Participants |
| Region of Enrollment Japan | 5 Participants | 20 Participants | 8 Participants | 7 Participants |
| Region of Enrollment United States | 98 Participants | 485 Participants | 194 Participants | 193 Participants |
| Sex: Female, Male Female | 61 Participants | 317 Participants | 135 Participants | 121 Participants |
| Sex: Female, Male Male | 42 Participants | 188 Participants | 67 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 103 | 2 / 106 | 3 / 108 | 1 / 94 | 1 / 94 |
| other Total, other adverse events | 48 / 103 | 50 / 106 | 51 / 108 | 52 / 94 | 52 / 94 |
| serious Total, serious adverse events | 17 / 103 | 20 / 106 | 23 / 108 | 17 / 94 | 15 / 94 |
Outcome results
Primary
Change From Baseline in Best Corrected Visual Acuity (BCVA) of the Study Eye at Week 12
Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. BCVA score was measured using an eye chart and was reported as the number of letters read correctly at a testing distance of 4 meters using the ETDRS Scale (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. Change from baseline calculated by subtracting baseline value from observed post-baseline value at Week 12.
Time frame: Baseline, Week 12
Population: Full analysis set (FAS) that included all randomized participants who received any study treatment, had a baseline measurement of BCVA, and at least 1 post-baseline assessment of BCVA. Last observation carried forward (LOCF) method was used to impute missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: REGN2176-3 (1 mg:2 mg) | Change From Baseline in Best Corrected Visual Acuity (BCVA) of the Study Eye at Week 12 | 5.9 Letters | Standard Error 1.01 |
| Group 2: REGN2176-3 (3 mg:2 mg) | Change From Baseline in Best Corrected Visual Acuity (BCVA) of the Study Eye at Week 12 | 5.7 Letters | Standard Error 0.73 |
| Group 3: Intravitreal Aflibercept Injection (IAI) 2 mg | Change From Baseline in Best Corrected Visual Acuity (BCVA) of the Study Eye at Week 12 | 7.4 Letters | Standard Error 0.72 |
Comparison: To control for the family-wise type I error rate of 5%, for each of the 2 REGN2176-3 groups the 2-sided hypothesis comparing REGN2176-3 (1 mg: 2 mg) vs. Intravitreal Aflibercept Injection (IAI) 2 mg was tested at a significance level of α = 2.5%.p-value: 0.205295% CI: [-4.37, 1.22]ANCOVA
Comparison: To control for the family-wise type I error rate of 5%, for each of the 2 REGN2176-3 groups the 2-sided hypothesis comparing REGN2176-3 (1 mg: 2 mg) vs. Intravitreal Aflibercept Injection (IAI) 2 mg was tested at a significance level of α = 2.5%.p-value: 0.098295% CI: [-4, 0.61]ANCOVA
Secondary
Change From Baseline in Central Retinal/Lesion Thickness at Week 12 Measured by Optical Coherence Tomography (OCT)
CST was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from baseline indicated improvement. Change from baseline calculated by subtracting baseline value from LOCF post-baseline value at Week 12.
Time frame: Baseline, Week 12
Population: Analysis was performed on FAS. LOCF was used to impute missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: REGN2176-3 (1 mg:2 mg) | Change From Baseline in Central Retinal/Lesion Thickness at Week 12 Measured by Optical Coherence Tomography (OCT) | -150.7 Microns | Standard Error 7.4 |
| Group 2: REGN2176-3 (3 mg:2 mg) | Change From Baseline in Central Retinal/Lesion Thickness at Week 12 Measured by Optical Coherence Tomography (OCT) | -139.6 Microns | Standard Error 5.32 |
| Group 3: Intravitreal Aflibercept Injection (IAI) 2 mg | Change From Baseline in Central Retinal/Lesion Thickness at Week 12 Measured by Optical Coherence Tomography (OCT) | -160.4 Microns | Standard Error 5.29 |
Secondary
Change From Baseline in Central Subfield Retinal Thickness (CST) at Week 12, as Measured by Optical Coherence Tomography (OCT)
CST was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from baseline indicated improvement. Change from baseline calculated by subtracting baseline value from LOCF post-baseline value at Week 12.
Time frame: Baseline, Week 12
Population: Analysis was performed on FAS. LOCF method was used to impute missing data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: REGN2176-3 (1 mg:2 mg) | Change From Baseline in Central Subfield Retinal Thickness (CST) at Week 12, as Measured by Optical Coherence Tomography (OCT) | -131.1 Microns | Standard Error 6.88 |
| Group 2: REGN2176-3 (3 mg:2 mg) | Change From Baseline in Central Subfield Retinal Thickness (CST) at Week 12, as Measured by Optical Coherence Tomography (OCT) | -116.9 Microns | Standard Error 4.96 |
| Group 3: Intravitreal Aflibercept Injection (IAI) 2 mg | Change From Baseline in Central Subfield Retinal Thickness (CST) at Week 12, as Measured by Optical Coherence Tomography (OCT) | -134.4 Microns | Standard Error 4.92 |
Secondary
Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 12 Measured by Fluorescein Angiography (FA)
The anatomical state of the retinal vasculature of the study eye and the fellow eye was evaluated by funduscopic examination, fundus photography and FA to evaluate the total lesion area, CNV area, classic CNV area, and fluorescein leakage. CNV area values measured in square millimeters, each disc area was equivalent to 2.54 mm\^2 on the retina; lower values represent better outcomes.
Time frame: Baseline, Week 12
Population: Analysis was performed on FAS. LOCF was used to impute missing data. Here, number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: REGN2176-3 (1 mg:2 mg) | Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 12 Measured by Fluorescein Angiography (FA) | -3.4 Square Millimeter (mm^2) | Standard Error 0.44 |
| Group 2: REGN2176-3 (3 mg:2 mg) | Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 12 Measured by Fluorescein Angiography (FA) | -2.0 Square Millimeter (mm^2) | Standard Error 0.31 |
| Group 3: Intravitreal Aflibercept Injection (IAI) 2 mg | Change From Baseline in Choroidal Neovascularization (CNV) Area at Week 12 Measured by Fluorescein Angiography (FA) | -3.6 Square Millimeter (mm^2) | Standard Error 0.31 |
Secondary
Change From Baseline in Total Lesion Size at Week 12 Measured by Fluorescein Angiography (FA)
Total Lesion Size was assessed by Fluorescein Angiography.
Time frame: Baseline, Week 12
Population: Analysis was performed on FAS. LOCF was used to impute missing data. Here, number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: REGN2176-3 (1 mg:2 mg) | Change From Baseline in Total Lesion Size at Week 12 Measured by Fluorescein Angiography (FA) | -3.1 mm | Standard Error 0.43 |
| Group 2: REGN2176-3 (3 mg:2 mg) | Change From Baseline in Total Lesion Size at Week 12 Measured by Fluorescein Angiography (FA) | -2.1 mm | Standard Error 0.31 |
| Group 3: Intravitreal Aflibercept Injection (IAI) 2 mg | Change From Baseline in Total Lesion Size at Week 12 Measured by Fluorescein Angiography (FA) | -3.5 mm | Standard Error 0.31 |
Secondary
Percentage of Participants Who Gained At Least 15 Letters in BCVA From Baseline at Week 12, Measured by 4-meter Early Treatment Diabetic Retinopathy Scale (ETDRS)
Visual function of the study eye was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at 4 meters. BCVA score was measured using an eye chart and was reported as the number of letters read correctly at a testing distance of 4 meters using the ETDRS Scale (ranging from 0 to 100 letters) in the study eye. The lower the number of letters read correctly on the eye chart, the worse the vision (or visual acuity). An increase in the number of letters read correctly means that vision has improved. This outcome assessed the percentage of participants who gained 15 or more letters of visual acuity at Week 12 compared with baseline.
Time frame: Week 12
Population: Analysis was performed on FAS. LOCF was used to impute missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: REGN2176-3 (1 mg:2 mg) | Percentage of Participants Who Gained At Least 15 Letters in BCVA From Baseline at Week 12, Measured by 4-meter Early Treatment Diabetic Retinopathy Scale (ETDRS) | 11.7 Percentage of Participants |
| Group 2: REGN2176-3 (3 mg:2 mg) | Percentage of Participants Who Gained At Least 15 Letters in BCVA From Baseline at Week 12, Measured by 4-meter Early Treatment Diabetic Retinopathy Scale (ETDRS) | 18.5 Percentage of Participants |
| Group 3: Intravitreal Aflibercept Injection (IAI) 2 mg | Percentage of Participants Who Gained At Least 15 Letters in BCVA From Baseline at Week 12, Measured by 4-meter Early Treatment Diabetic Retinopathy Scale (ETDRS) | 21.8 Percentage of Participants |
Secondary
Percentage of Participants With Complete Resolution of Intraretinal and Subretinal Fluid From Baseline at Week 12 Measured by Optical Coherence Tomography (OCT)
CST was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation.
Time frame: Week 12
Population: Analysis was performed on FAS. LOCF method was used to impute missing data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: REGN2176-3 (1 mg:2 mg) | Percentage of Participants With Complete Resolution of Intraretinal and Subretinal Fluid From Baseline at Week 12 Measured by Optical Coherence Tomography (OCT) | 35.0 Percentage of Participants |
| Group 2: REGN2176-3 (3 mg:2 mg) | Percentage of Participants With Complete Resolution of Intraretinal and Subretinal Fluid From Baseline at Week 12 Measured by Optical Coherence Tomography (OCT) | 24.0 Percentage of Participants |
| Group 3: Intravitreal Aflibercept Injection (IAI) 2 mg | Percentage of Participants With Complete Resolution of Intraretinal and Subretinal Fluid From Baseline at Week 12 Measured by Optical Coherence Tomography (OCT) | 42.1 Percentage of Participants |
Secondary
Percent Change From Baseline in Subretinal Hyperreflectivity Material (SHM) at Week 12 Measured by Optical Coherence Tomography (OCT)
SHM was assessed using spectral domain optical coherence tomography (SD-OCT), a non-invasive diagnostic system providing high-resolution imaging sections of the retina. SD-OCT was performed in the study eye after pupil dilation. A negative change from baseline indicated improvement.
Time frame: Baseline, Week 12
Population: Analysis was performed on FAS. LOCF was used to impute missing data. Here, number of participants analyzed = participants with available data for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: REGN2176-3 (1 mg:2 mg) | Percent Change From Baseline in Subretinal Hyperreflectivity Material (SHM) at Week 12 Measured by Optical Coherence Tomography (OCT) | -50.0 Percent change | Standard Error 5.94 |
| Group 2: REGN2176-3 (3 mg:2 mg) | Percent Change From Baseline in Subretinal Hyperreflectivity Material (SHM) at Week 12 Measured by Optical Coherence Tomography (OCT) | -41.9 Percent change | Standard Error 4.17 |
| Group 3: Intravitreal Aflibercept Injection (IAI) 2 mg | Percent Change From Baseline in Subretinal Hyperreflectivity Material (SHM) at Week 12 Measured by Optical Coherence Tomography (OCT) | -48.8 Percent change | Standard Error 4.14 |