Diabetic Macular Edema
Conditions
Brief summary
A two part, multi-center study consisting of a Phase 1b open label, sequential dose escalation followed by a Phase 2a randomized, double-masked, dose expansion evaluating OPT-302 in combination with aflibercept in participants with persistent central-involved Diabetic Macular Edema.
Detailed description
Study OPT-302-1003 was designed as a 2-part, multicenter study consisting of a Phase 1b open-label, sequential dose escalation followed by a Phase 2a randomized, parallel-group, sham-controlled, double-masked, dose-expansion evaluating intravitreal OPT-302 in combination with aflibercept in participants with persistent central-involved diabetic macula edema.
Interventions
BIOLOGICALAflibercept
Intravitreal injection
BIOLOGICALOPT-302
Intravitreal Injection
Sham (mock) intravitreal injection
Sponsors
Opthea Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Ph 1b open label; Ph 2a quadruple masked
Intervention model description
Phase 1b - sequential dose followed by Phase 2a - parallel arm
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* History of diabetic macular edema (DME) ≤ 2 year * Persistent DME despite prior intravitreal anti-VEGF-A therapy with a sub-optimal response * Three or more prior anti-VEGF-A therapy intravitreal injections * EDTRS BCVA score ≤ 73 and ≥ 24 letters
Exclusion criteria
* Ocular disorders or ocular treatments which may interfere with assessment of visual acuity, assessment of toxicity, or fundus photography in the Study Eye * HbA1c ≥ 12% and/or recent signs of uncontrolled diabetes * Any clinically significant disorder or condition or disease (e.g. cardiovascular, renal conditions) that would make the participant unsuitable for the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Baseline to Week 12 | Safety and Tolerability will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events and CTC v4.0 (if available, otherwise protocol defined grading were used) |
| Phase 2a: Response Rate Defined as Proportion of Participants Receiving OPT-302 With Aflibercept Achieving at Least a 5-letter Gain in BCVA at Week 12 | Baseline to Week 12 | Change from baseline in Best Corrected Visual Acuity (BCVA) will be measured at Week 12 according to Early Treatment Diabetic Retinopathy Score (ETDRS) criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in BCVA | Baseline to Week 12 | Mean change in Best Corrected Visual Acuity (BCVA). BCVA will be measured according to Early Treatment Diabetic Retinopathy Score (ETDRS) criteria |
| Mean Change in CST | Baseline to Week 12 | Mean change in central subfield thickness (CST) on spectral domain coherence tomography (SD-OCT) |
Countries
Australia, Israel, Latvia, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ph 1b: 2.0 mg Aflibercept With 0.3 mg OPT-302 2.0 mg aflibercept intravitreal injection (0.05 mL) followed by 0.3 mg OPT-302 intravitreal injection (0.05 mL)
Aflibercept: Intravitreal injection
OPT-302: Intravitreal Injection | 3 |
| Ph 1b: 2.0 mg Aflibercept With 1.0 mg OPT-302 2.0 mg aflibercept intravitreal injection (0.05 mL) followed by 1.0 mg OPT-302 intravitreal injection (0.05 mL)
Aflibercept: Intravitreal injection
OPT-302: Intravitreal Injection | 3 |
| Ph 1b: 2.0 mg Aflibercept With 2.0 mg OPT-302 2.0 mg aflibercept intravitreal injection (0.05 mL) followed by 2.0 mg OPT-302 intravitreal injection (0.05 mL)
Aflibercept: Intravitreal injection
OPT-302: Intravitreal Injection | 3 |
| Ph 2a: 2.0 mg Aflibercept With 2.0 mg OPT-302 2.0 mg aflibercept intravitreal injection (0.05 mL) followed by 2.0 mg OPT-302 intravitreal injection (0.05 mL)
Aflibercept: Intravitreal injection
OPT-302: Intravitreal Injection | 96 |
| Ph 2a: 2.0 mg Aflibercept With Sham 2.0 mg aflibercept intravitreal injection (0.05 mL) followed by sham intravitreal injection
Aflibercept: Intravitreal injection
Sham intravitreal injection: Sham (mock) intravitreal injection | 48 |
| Total | 153 |
Baseline characteristics
| Characteristic | Ph 1b: 2.0 mg Aflibercept With 0.3 mg OPT-302 | Ph 2a: 2.0 mg Aflibercept With Sham | Total | Ph 2a: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Ph 1b: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Ph 1b: 2.0 mg Aflibercept With 1.0 mg OPT-302 |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 16 Participants | 57 Participants | 38 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 32 Participants | 96 Participants | 58 Participants | 3 Participants | 1 Participants |
| Age, Continuous Ph 1b | 59.0 years STANDARD_DEVIATION 6.24 | — | 61.1 years STANDARD_DEVIATION 8.39 | — | 55.7 years STANDARD_DEVIATION 7.02 | 68.7 years STANDARD_DEVIATION 7.51 |
| Age, Continuous Ph 2a | — | 61.2 years STANDARD_DEVIATION 9.4 | 61.6 years STANDARD_DEVIATION 9.93 | 61.8 years STANDARD_DEVIATION 10.07 | — | — |
| Baseline ETDRS Best Corrected Visual Acuity | 64.3 Letters read STANDARD_DEVIATION 7.02 | 63.9 Letters read STANDARD_DEVIATION 9.44 | 63.5 Letters read STANDARD_DEVIATION 8.68 | 63.3 Letters read STANDARD_DEVIATION 8.31 | 66.0 Letters read STANDARD_DEVIATION 8.89 | 64.7 Letters read STANDARD_DEVIATION 1.53 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 8 Participants | 17 Participants | 8 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 37 Participants | 132 Participants | 87 Participants | 3 Participants | 2 Participants |
| Region of Enrollment Australia | 0 participants | 4 participants | 9 participants | 5 participants | 0 participants | 0 participants |
| Region of Enrollment Israel | 0 participants | 10 participants | 34 participants | 24 participants | 0 participants | 0 participants |
| Region of Enrollment Latvia | 0 participants | 3 participants | 9 participants | 6 participants | 0 participants | 0 participants |
| Region of Enrollment United States | 3 participants | 31 participants | 92 participants | 61 participants | 3 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 18 Participants | 56 Participants | 36 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 2 Participants | 30 Participants | 97 Participants | 60 Participants | 3 Participants | 2 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 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 95 | 0 / 49 |
| other Total, other adverse events | 2 / 3 | 1 / 3 | 1 / 3 | 36 / 95 | 15 / 49 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 0 / 3 | 8 / 95 | 1 / 49 |
Outcome results
Primary
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
Safety and Tolerability will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events and CTC v4.0 (if available, otherwise protocol defined grading were used)
Time frame: Baseline to Week 12
Population: Safety Population; Ph2a: One participant assigned 2.0 mg OPT-302 with aflibercept did not receive OPT-302 therefore this participant was analyzed as part of the sham combination for the safety analysis only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ph 1b: 2.0 mg Aflibercept With 0.3 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Non-ocular Treatment Emergnt AEs to Wk 12 | 2 Participants |
| Ph 1b: 2.0 mg Aflibercept With 0.3 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Ocular Treatment Emergent AEs to Wk 12 | 2 Participants |
| Ph 1b: 2.0 mg Aflibercept With 0.3 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Non Ocular SAEs to Wk 12 | 1 Participants |
| Ph 1b: 2.0 mg Aflibercept With 0.3 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Ocular SAEs to Wk 12 | 0 Participants |
| Ph 1b: 2.0 mg Aflibercept With 0.3 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Treatment Emergent AE to Wk 12 | 3 Participants |
| Ph 1b: 2.0 mg Aflibercept With 1.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Non-ocular Treatment Emergnt AEs to Wk 12 | 2 Participants |
| Ph 1b: 2.0 mg Aflibercept With 1.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Treatment Emergent AE to Wk 12 | 2 Participants |
| Ph 1b: 2.0 mg Aflibercept With 1.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Ocular Treatment Emergent AEs to Wk 12 | 2 Participants |
| Ph 1b: 2.0 mg Aflibercept With 1.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Ocular SAEs to Wk 12 | 0 Participants |
| Ph 1b: 2.0 mg Aflibercept With 1.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Non Ocular SAEs to Wk 12 | 1 Participants |
| Ph 1b: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Non Ocular SAEs to Wk 12 | 0 Participants |
| Ph 1b: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Treatment Emergent AE to Wk 12 | 1 Participants |
| Ph 1b: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Non-ocular Treatment Emergnt AEs to Wk 12 | 0 Participants |
| Ph 1b: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Ocular SAEs to Wk 12 | 0 Participants |
| Ph 1b: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Ocular Treatment Emergent AEs to Wk 12 | 1 Participants |
| Ph 2a: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Ocular Treatment Emergent AEs to Wk 12 | 43 Participants |
| Ph 2a: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Treatment Emergent AE to Wk 12 | 59 Participants |
| Ph 2a: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Non-ocular Treatment Emergnt AEs to Wk 12 | 35 Participants |
| Ph 2a: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Non Ocular SAEs to Wk 12 | 8 Participants |
| Ph 2a: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Ocular SAEs to Wk 12 | 0 Participants |
| Ph 2a: 2.0 mg Aflibercept With Sham | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Ocular SAEs to Wk 12 | 0 Participants |
| Ph 2a: 2.0 mg Aflibercept With Sham | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Non Ocular SAEs to Wk 12 | 1 Participants |
| Ph 2a: 2.0 mg Aflibercept With Sham | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Non-ocular Treatment Emergnt AEs to Wk 12 | 17 Participants |
| Ph 2a: 2.0 mg Aflibercept With Sham | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Treatment Emergent AE to Wk 12 | 28 Participants |
| Ph 2a: 2.0 mg Aflibercept With Sham | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Ocular Treatment Emergent AEs to Wk 12 | 16 Participants |
Primary
Phase 2a: Response Rate Defined as Proportion of Participants Receiving OPT-302 With Aflibercept Achieving at Least a 5-letter Gain in BCVA at Week 12
Change from baseline in Best Corrected Visual Acuity (BCVA) will be measured at Week 12 according to Early Treatment Diabetic Retinopathy Score (ETDRS) criteria
Time frame: Baseline to Week 12
Population: Primary Analysis (pre-specified) OPT-302 combination therapy will be considered to have clinical activity if \>= 27 of 72 participants have a \>= 5 letters gain in BCVA from baseline to week 12. The combination therapy will be considered to have insufficient clinical activity if \<= 25 of 72 participants have a \>= 5 letters gain in BCVA from baseline to week 12.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ph 1b: 2.0 mg Aflibercept With 0.3 mg OPT-302 | Phase 2a: Response Rate Defined as Proportion of Participants Receiving OPT-302 With Aflibercept Achieving at Least a 5-letter Gain in BCVA at Week 12 | 38 Participants |
Secondary
Mean Change in BCVA
Mean change in Best Corrected Visual Acuity (BCVA). BCVA will be measured according to Early Treatment Diabetic Retinopathy Score (ETDRS) criteria
Time frame: Baseline to Week 12
Population: Per Protocol Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ph 1b: 2.0 mg Aflibercept With 0.3 mg OPT-302 | Mean Change in BCVA | 3.0 Letters | Standard Error 2.52 |
| Ph 1b: 2.0 mg Aflibercept With 1.0 mg OPT-302 | Mean Change in BCVA | 5.7 Letters | Standard Error 1.2 |
| Ph 1b: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Mean Change in BCVA | 14.3 Letters | Standard Error 5.46 |
| Ph 2a: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Mean Change in BCVA | 5.9 Letters | Standard Error 0.79 |
| Ph 2a: 2.0 mg Aflibercept With Sham | Mean Change in BCVA | 6.1 Letters | Standard Error 0.96 |
Secondary
Mean Change in CST
Mean change in central subfield thickness (CST) on spectral domain coherence tomography (SD-OCT)
Time frame: Baseline to Week 12
Population: Per Protocol Population; and where CST measurements at Week 12 were available to assess the endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ph 1b: 2.0 mg Aflibercept With 0.3 mg OPT-302 | Mean Change in CST | -116.0 µm | Standard Error 46.12 |
| Ph 1b: 2.0 mg Aflibercept With 1.0 mg OPT-302 | Mean Change in CST | -41.0 µm | Standard Error 28.88 |
| Ph 1b: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Mean Change in CST | -57.0 µm | Standard Error 12.86 |
| Ph 2a: 2.0 mg Aflibercept With 2.0 mg OPT-302 | Mean Change in CST | -52.2 µm | Standard Error 10.28 |
| Ph 2a: 2.0 mg Aflibercept With Sham | Mean Change in CST | -34.9 µm | Standard Error 12.01 |