Neovascular Age-related Macular Degeneration
Conditions
Keywords
nAMD, wet AMD, Wet Macular Degeneration, Macular Degeneration, Eye Diseases, Retinal Diseases, Retinal Degeneration
Brief summary
A 2-year phase 3, multicentre, randomised, parallel-group, sham-controlled, double-masked study. Primary efficacy will be determined at Week 52.
Interventions
BIOLOGICAL2.0 mg OPT-302
intravitreal injection
BIOLOGICAL2.0 aflibercept
intravitreal injection
PROCEDURESham
intravitreal injection
Sponsors
Opthea Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Active subfoveal CNV lesion or juxtafoveal CNV lesion with foveal involvement that is secondary to AMD in the Study Eye. * An ETDRS BCVA score between 60 and 25 (inclusive) letters in the Study Eye. Main
Exclusion criteria
* Any previous treatment for neovascular AMD. * Clinically significant ocular disorders (other than neovascular AMD), which may interfere with assessment of BCVA, assessment of safety, or fundus imaging. * Any current (or history of a) social, psychological, or medical condition that precludes enrolment into the study. * Additional inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Early Treatment Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) Letters | Baseline to Week 52 | To determine the efficacy of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 2.0 mg aflibercept, in participants with neovascular age-related macular degeneration (nAMD), in terms of change in ETDRS BCVA letter score in the study eye from Baseline to Week 52. The primary analysis presented used mixed model for repeated measures in the overall population. (A positive outcome measure means an improvement in ETDRS BCVA letter score from baseline; a negative outcome measure means a deterioration in ETDRS BCVA letter score from baseline) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Gaining 15 or More ETDRS BCVA Letters | Baseline to Week 52 | To determine the effects of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 2.0 mg aflibercept, in participants with neovascular age-related macular degeneration (nAMD), in terms of proportion of participants gaining 15 or more letters in ETDRS BCVA in the study eye from Baseline to Week 52. The secondary analysis presented used multiple imputation analysis assuming missing at random in the overall population. |
| Proportion of Participants Gaining 10 or More ETDRS BCVA Letters | Baseline to Week 52 | To determine the effects of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 2.0 mg aflibercept, in participants with neovascular age-related macular degeneration (nAMD), in terms of proportion of participants gaining 10 or more letters in ETDRS BCVA in the study eye from Baseline to Week 52. The secondary analysis presented used multiple imputation analysis assuming missing at random in the overall population. |
| Change in Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA) | Baseline to Week 52 | To determine the effects of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 2.0 mg aflibercept, in participants with neovascular age-related macular degeneration (nAMD), in terms of change in CNV area as measured by FA in the study eye from Baseline to Week 52. The secondary analysis presented used mixed model for repeated measures in the overall population. |
| Proportion of Participants With Absence of Both Sub-retinal Fluid and Intra-retinal Cysts by SD-OCT | at Week 52 | To determine the effects of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 2.0 mg aflibercept, in participants with neovascular age-related macular degeneration (nAMD), in terms of proportion of participants with absence of both sub-retinal fluid and intra-retinal cysts by SD-OCT in the study eye at Week 52. The secondary analysis presented used multiple imputation analysis assuming missing at random in the overall population. |
Countries
Argentina, Australia, Austria, Brazil, Bulgaria, Canada, Colombia, Croatia, Czechia, Denmark, Estonia, France, Germany, Greece, Hungary, India, Israel, Italy, Latvia, Lithuania, Netherlands, Philippines, Poland, Puerto Rico, Slovakia, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants 50 years or older with active subfoveal CNV lesion or juxtafoveal CNV lesion with foveal involvement that is secondary to AMD in the study eye with an ETDRS BCVA score between 60 and 25 (inclusive) letters in the study eye.
Pre-assignment details
Participants who met all inclusion criteria and none of the exclusion criteria were enrolled in the study. 2 subjects (in the 2.0 mg aflibercept with sham arm) were enrolled, but never treated.
Participants by arm
| Arm | Count |
|---|---|
| 2.0 mg Aflibercept With Standard Dosing 2.0 mg OPT-302 2.0 mg aflibercept intravitreal injection (0.05mL) followed by 2.0 mg OPT-302 intravitreal injection (0.05mL) administered into the study eye at 4-weekly intervals for three treatments, and then at 8-weekly intervals through Week 96, with OPT-302 administered alone at visits when aflibercept was not.
2.0 mg OPT-302: intravitreal injection
2.0 aflibercept: intravitreal injection | 333 |
| 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302 2.0 mg aflibercept intravitreal injection (0.05mL) followed by 2.0 mg OPT-302 intravitreal injection (0.05mL) administered into the study eye at 4-weekly intervals for 3 treatments, and then at 8-weekly intervals through Week 96, with sham intravitreal injection administered alone into the study eye at the alternating visits when aflibercept and OPT-302 were not administered.
2.0 mg OPT-302: intravitreal injection
2.0 aflibercept: intravitreal injection
Sham: intravitreal injection | 330 |
| 2.0 mg Aflibercept With Sham 2.0 mg aflibercept intravitreal injection (0.05mL) followed by sham intravitreal injection administered into the study eye at 4-weekly intervals for 3 treatments, and then at 8-weekly intervals through Week 96, with sham intravitreal injection administered alone at visits when aflibercept was not.
2.0 aflibercept: intravitreal injection
Sham: intravitreal injection | 330 |
| Total | 993 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 25 | 8 | 11 |
| Overall Study | Death | 9 | 12 | 6 |
| Overall Study | Discontinued Study Treatment at or prior to Week 52 | 0 | 1 | 0 |
| Overall Study | Lack of Efficacy | 2 | 0 | 0 |
| Overall Study | Lost to Follow-up | 1 | 6 | 7 |
| Overall Study | Physician Decision | 1 | 3 | 4 |
| Overall Study | Randomized in Error | 0 | 0 | 2 |
| Overall Study | Sponsor Decision | 0 | 0 | 1 |
| Overall Study | Study Terminated by Sponsor | 103 | 104 | 114 |
| Overall Study | Withdrawal by Subject | 20 | 23 | 18 |
Baseline characteristics
| Characteristic | 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302 | 2.0 mg Aflibercept With Sham | 2.0 mg Aflibercept With Standard Dosing 2.0 mg OPT-302 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 298 Participants | 296 Participants | 294 Participants | 888 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants | 34 Participants | 39 Participants | 105 Participants |
| Age, Continuous | 74.9 years STANDARD_DEVIATION 7.97 | 75.2 years STANDARD_DEVIATION 8.28 | 74.3 years STANDARD_DEVIATION 7.8 | 74.8 years STANDARD_DEVIATION 8.02 |
| Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA) | 6.47 mm^2 STANDARD_DEVIATION 3.137 | 6.54 mm^2 STANDARD_DEVIATION 3.185 | 6.16 mm^2 STANDARD_DEVIATION 3.277 | 6.39 mm^2 STANDARD_DEVIATION 3.199 |
| Early Treatment Retinopathy Study (ETDRS) Best-Corrected Visual Acuity (BCVA) Letters | 52.3 letters read STANDARD_DEVIATION 9.63 | 52.4 letters read STANDARD_DEVIATION 9.65 | 52.8 letters read STANDARD_DEVIATION 9.04 | 52.5 letters read STANDARD_DEVIATION 9.44 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 6 Participants | 4 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 81 Participants | 77 Participants | 83 Participants | 241 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 247 Participants | 247 Participants | 246 Participants | 740 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 9 Participants | 6 Participants | 3 Participants | 18 Participants |
| Race (NIH/OMB) Asian | 25 Participants | 29 Participants | 29 Participants | 83 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 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 | 9 Participants | 14 Participants | 12 Participants | 35 Participants |
| Race (NIH/OMB) White | 287 Participants | 281 Participants | 288 Participants | 856 Participants |
| Sex: Female, Male Female | 183 Participants | 184 Participants | 190 Participants | 557 Participants |
| Sex: Female, Male Male | 147 Participants | 146 Participants | 143 Participants | 436 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 9 / 333 | 12 / 330 | 6 / 330 |
| other Total, other adverse events | 288 / 333 | 290 / 330 | 282 / 330 |
| serious Total, serious adverse events | 71 / 333 | 61 / 330 | 68 / 330 |
Outcome results
Primary
Mean Change in Early Treatment Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) Letters
To determine the efficacy of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 2.0 mg aflibercept, in participants with neovascular age-related macular degeneration (nAMD), in terms of change in ETDRS BCVA letter score in the study eye from Baseline to Week 52. The primary analysis presented used mixed model for repeated measures in the overall population. (A positive outcome measure means an improvement in ETDRS BCVA letter score from baseline; a negative outcome measure means a deterioration in ETDRS BCVA letter score from baseline)
Time frame: Baseline to Week 52
Population: Modified Intent-to-Treat (mITT) analysis set - comprised all randomised participants with at least one dose of study medication. Participants were analysed according to the study medication to which they were randomised for all efficacy analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 2.0 mg Aflibercept With Standard Dosing 2.0 mg OPT-302 | Mean Change in Early Treatment Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) Letters | 13.48 Letters read | Standard Error 0.729 |
| 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302 | Mean Change in Early Treatment Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) Letters | 12.82 Letters read | Standard Error 0.728 |
| 2.0 mg Aflibercept With Sham | Mean Change in Early Treatment Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) Letters | 13.66 Letters read | Standard Error 0.728 |
p-value: 0.86140995% CI: [-2.2, 1.84]MMRM
p-value: 0.41626495% CI: [-2.86, 1.18]MMRM
Secondary
Change in Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA)
To determine the effects of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 2.0 mg aflibercept, in participants with neovascular age-related macular degeneration (nAMD), in terms of change in CNV area as measured by FA in the study eye from Baseline to Week 52. The secondary analysis presented used mixed model for repeated measures in the overall population.
Time frame: Baseline to Week 52
Population: Modified Intent-to-Treat (mITT) analysis set - comprised all randomised participants with at least one dose of study medication. Participants were analysed according to the study medication to which they were randomised for all efficacy analyses.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 2.0 mg Aflibercept With Standard Dosing 2.0 mg OPT-302 | Change in Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA) | -4.91 mm^2 | Standard Error 0.165 |
| 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302 | Change in Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA) | -4.92 mm^2 | Standard Error 0.166 |
| 2.0 mg Aflibercept With Sham | Change in Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA) | -4.61 mm^2 | Standard Error 0.166 |
p-value: 0.19982895% CI: [-0.76, 0.16]MMRM
p-value: 0.18872595% CI: [-0.77, 0.15]MMRM
Secondary
Proportion of Participants Gaining 10 or More ETDRS BCVA Letters
To determine the effects of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 2.0 mg aflibercept, in participants with neovascular age-related macular degeneration (nAMD), in terms of proportion of participants gaining 10 or more letters in ETDRS BCVA in the study eye from Baseline to Week 52. The secondary analysis presented used multiple imputation analysis assuming missing at random in the overall population.
Time frame: Baseline to Week 52
Population: Modified Intent-to-Treat (mITT) analysis set - comprised all randomised participants with at least one dose of study medication. Participants were analysed according to the study medication to which they were randomised for all efficacy analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2.0 mg Aflibercept With Standard Dosing 2.0 mg OPT-302 | Proportion of Participants Gaining 10 or More ETDRS BCVA Letters | 204 Participants |
| 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302 | Proportion of Participants Gaining 10 or More ETDRS BCVA Letters | 197 Participants |
| 2.0 mg Aflibercept With Sham | Proportion of Participants Gaining 10 or More ETDRS BCVA Letters | 204 Participants |
p-value: 0.65510495% CI: [-8.9, 5.6]Mantel Haenszel
p-value: 0.82125795% CI: [-8.2, 6.5]Mantel Haenszel
Secondary
Proportion of Participants Gaining 15 or More ETDRS BCVA Letters
To determine the effects of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 2.0 mg aflibercept, in participants with neovascular age-related macular degeneration (nAMD), in terms of proportion of participants gaining 15 or more letters in ETDRS BCVA in the study eye from Baseline to Week 52. The secondary analysis presented used multiple imputation analysis assuming missing at random in the overall population.
Time frame: Baseline to Week 52
Population: Modified Intent-to-Treat (mITT) analysis set - comprised all randomised participants with at least one dose of study medication. Participants were analysed according to the study medication to which they were randomised for all efficacy analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2.0 mg Aflibercept With Standard Dosing 2.0 mg OPT-302 | Proportion of Participants Gaining 15 or More ETDRS BCVA Letters | 167 Participants |
| 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302 | Proportion of Participants Gaining 15 or More ETDRS BCVA Letters | 156 Participants |
| 2.0 mg Aflibercept With Sham | Proportion of Participants Gaining 15 or More ETDRS BCVA Letters | 162 Participants |
p-value: 0.98134895% CI: [-7.5, 7.7]Mantel Haenszel
p-value: 0.85695% CI: [-8.5, 7]Mantel Haenszel
Secondary
Proportion of Participants With Absence of Both Sub-retinal Fluid and Intra-retinal Cysts by SD-OCT
To determine the effects of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 2.0 mg aflibercept, in participants with neovascular age-related macular degeneration (nAMD), in terms of proportion of participants with absence of both sub-retinal fluid and intra-retinal cysts by SD-OCT in the study eye at Week 52. The secondary analysis presented used multiple imputation analysis assuming missing at random in the overall population.
Time frame: at Week 52
Population: Modified Intent-to-Treat (mITT) analysis set - comprised all randomised participants with at least one dose of study medication. Participants were analysed according to the study medication to which they were randomised for all efficacy analyses.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 2.0 mg Aflibercept With Standard Dosing 2.0 mg OPT-302 | Proportion of Participants With Absence of Both Sub-retinal Fluid and Intra-retinal Cysts by SD-OCT | 30 Participants |
| 2.0 mg Aflibercept With Extended Dosing 2.0 mg OPT-302 | Proportion of Participants With Absence of Both Sub-retinal Fluid and Intra-retinal Cysts by SD-OCT | 32 Participants |
| 2.0 mg Aflibercept With Sham | Proportion of Participants With Absence of Both Sub-retinal Fluid and Intra-retinal Cysts by SD-OCT | 29 Participants |
p-value: 0.8478195% CI: [-5.6, 4.6]Mantel Haenszel
p-value: 0.71869995% CI: [-4.2, 6.1]Mantel Haenszel