Neovascular Age-related Macular Degeneration
Conditions
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
BIOLOGICAL0.5 mg ranibizumab
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 Diabetic 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 0.5 mg ranibizumab, 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 |
|---|---|---|
| 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 0.5 mg ranibizumab, 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. |
| Participants Gaining 10 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 0.5 mg ranibizumab, 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. |
| 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 0.5 mg ranibizumab, 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. |
| 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 0.5 mg ranibizumab, 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. |
Countries
Argentina, Australia, Brazil, Bulgaria, Canada, Colombia, Czechia, Denmark, France, Germany, Greece, Hungary, India, Israel, Italy, Latvia, Malaysia, Poland, South Korea, Spain, Thailand, Ukraine, 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. 1 subject (in the 0.5 mg ranibizumab with standard dosing 2.0 mg OPT-302 arm) was enrolled, but never treated.
Participants by arm
| Arm | Count |
|---|---|
| 0.5 mg Ranibizumab With Standard Dosing 2.0 mg OPT-302 0.5 mg ranibizumab intravitreal injection (0.05mL) followed by 2.0 mg OPT-302 intravitreal injection (0.05mL) administered into the study eye at 4-weekly intervals through Week 96.
2.0 mg OPT-302: intravitreal injection
0.5 mg ranibizumab: intravitreal injection | 328 |
| 0.5 mg Ranibizumab With Extended Dosing 2.0 mg OPT-302 0.5 mg ranibizumab 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 ranibizumab intravitreal injection followed by sham intravitreal injection administered into the study eye at the alternating visits when OPT-302 was not administered.
2.0 mg OPT-302: intravitreal injection
0.5 mg ranibizumab: intravitreal injection
Sham: intravitreal injection | 326 |
| 0.5 mg Ranibizumab With Sham 0.5 mg ranibizumab intravitreal injection (0.05mL) followed by sham intravitreal injection administered into the study eye at 4-weekly intervals through Week 96.
0.5 mg ranibizumab: intravitreal injection
Sham: intravitreal injection | 331 |
| Total | 985 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 13 | 10 | 5 |
| Overall Study | Death | 5 | 13 | 8 |
| Overall Study | Lack of Efficacy | 1 | 2 | 3 |
| Overall Study | Lost to Follow-up | 7 | 2 | 7 |
| Overall Study | Physician Decision | 4 | 1 | 2 |
| Overall Study | Randomized in Error | 1 | 0 | 0 |
| Overall Study | Study Terminated by Sponsor | 105 | 105 | 110 |
| Overall Study | Withdrawal by Subject | 26 | 25 | 25 |
Baseline characteristics
| Characteristic | 0.5 mg Ranibizumab With Extended Dosing 2.0 mg OPT-302 | 0.5 mg Ranibizumab With Sham | 0.5 mg Ranibizumab 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 | 288 Participants | 296 Participants | 297 Participants | 881 Participants |
| Age, Categorical Between 18 and 65 years | 38 Participants | 35 Participants | 31 Participants | 104 Participants |
| Age, Continuous | 75.8 years STANDARD_DEVIATION 8.62 | 75.1 years STANDARD_DEVIATION 8.52 | 75.3 years STANDARD_DEVIATION 8.28 | 75.4 years STANDARD_DEVIATION 8.47 |
| Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA) | 6.576 mm^2 STANDARD_DEVIATION 3.2278 | 6.286 mm^2 STANDARD_DEVIATION 3.177 | 6.256 mm^2 STANDARD_DEVIATION 2.8634 | 6.373 mm^2 STANDARD_DEVIATION 3.0894 |
| Early Treatment Retinopathy Study (ETDRS) Best-Corrected Visual Acuity (BCVA) Letters | 52.1 letters read STANDARD_DEVIATION 8.83 | 52.5 letters read STANDARD_DEVIATION 9.13 | 52.1 letters read STANDARD_DEVIATION 9.45 | 52.23 letters read STANDARD_DEVIATION 9.14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 5 Participants | 10 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 121 Participants | 123 Participants | 117 Participants | 361 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 195 Participants | 203 Participants | 201 Participants | 599 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 42 Participants | 48 Participants | 44 Participants | 134 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 2 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 | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 10 Participants | 6 Participants | 6 Participants | 22 Participants |
| Race (NIH/OMB) White | 273 Participants | 274 Participants | 277 Participants | 824 Participants |
| Sex: Female, Male Female | 169 Participants | 179 Participants | 184 Participants | 532 Participants |
| Sex: Female, Male Male | 157 Participants | 152 Participants | 144 Participants | 453 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 5 / 328 | 13 / 327 | 8 / 330 |
| other Total, other adverse events | 290 / 328 | 261 / 327 | 265 / 330 |
| serious Total, serious adverse events | 65 / 328 | 60 / 327 | 52 / 330 |
Outcome results
Primary
Mean Change in Early Treatment Diabetic 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 0.5 mg ranibizumab, 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 |
|---|---|---|---|
| 0.5 mg Ranibizumab With Standard Dosing 2.0 mg OPT-302 | Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) Letters | 13.20 Letters read | Standard Error 0.728 |
| 0.5 mg Ranibizumab With Extended Dosing 2.0 mg OPT-302 | Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) Letters | 12.41 Letters read | Standard Error 0.731 |
| 0.5 mg Ranibizumab With Sham | Mean Change in Early Treatment Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) Letters | 14.30 Letters read | Standard Error 0.719 |
p-value: 0.28442195% CI: [-3.1, 0.91]MMRM
p-value: 0.06667895% CI: [-3.9, 0.13]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 0.5 mg ranibizumab, 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.
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 (MEAN) | Dispersion |
|---|---|---|---|
| 0.5 mg Ranibizumab With Standard Dosing 2.0 mg OPT-302 | Change in Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA) | -3.359 mm^2 | Standard Error 0.3483 |
| 0.5 mg Ranibizumab With Extended Dosing 2.0 mg OPT-302 | Change in Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA) | -3.901 mm^2 | Standard Error 0.3972 |
| 0.5 mg Ranibizumab With Sham | Change in Choroidal Neovascularisation (CNV) Area by Fluorescein Angiography (FA) | -3.238 mm^2 | Standard Error 0.3588 |
Secondary
Participants Gaining 10 More ETDRS BCVA Letters
To determine the effects of intravitreal 2.0 mg OPT-302 when administered in combination with intravitreal 0.5 mg ranibizumab, 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.
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) |
|---|---|---|
| 0.5 mg Ranibizumab With Standard Dosing 2.0 mg OPT-302 | Participants Gaining 10 More ETDRS BCVA Letters | 198 Participants |
| 0.5 mg Ranibizumab With Extended Dosing 2.0 mg OPT-302 | Participants Gaining 10 More ETDRS BCVA Letters | 182 Participants |
| 0.5 mg Ranibizumab With Sham | Participants Gaining 10 More ETDRS BCVA Letters | 202 Participants |
Secondary
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 0.5 mg ranibizumab, 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.
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) |
|---|---|---|
| 0.5 mg Ranibizumab With Standard Dosing 2.0 mg OPT-302 | Participants Gaining 15 or More ETDRS BCVA Letters | 159 Participants |
| 0.5 mg Ranibizumab With Extended Dosing 2.0 mg OPT-302 | Participants Gaining 15 or More ETDRS BCVA Letters | 135 Participants |
| 0.5 mg Ranibizumab With Sham | Participants Gaining 15 or More ETDRS BCVA Letters | 164 Participants |
Secondary
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 0.5 mg ranibizumab, 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.
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) |
|---|---|---|
| 0.5 mg Ranibizumab With Standard Dosing 2.0 mg OPT-302 | Participants With Absence of Both Sub-retinal Fluid and Intra-retinal Cysts by SD-OCT | 33 Participants |
| 0.5 mg Ranibizumab With Extended Dosing 2.0 mg OPT-302 | Participants With Absence of Both Sub-retinal Fluid and Intra-retinal Cysts by SD-OCT | 22 Participants |
| 0.5 mg Ranibizumab With Sham | Participants With Absence of Both Sub-retinal Fluid and Intra-retinal Cysts by SD-OCT | 22 Participants |