Wet Age-Related Macular Degeneration
Conditions
Brief summary
The purpose of the study was to compare the effect of intravitreal injections of ranibizumab and aflibercept on systemic VEGF protein levels in treatment naïve wet neovascular Age-related Macular Degeneration (wAMD) patients in a detailed time course.
Detailed description
A planned study visit schedule was established at the time of baseline visit (day 1) for all patients. Study assessments for patients were performed at screening visit, baseline (day 1), day 2, day 8 (± 1 day to allow for flexibility in scheduling) and as of day 15 through to day 169 at biweekly visits.
Interventions
Administered as an intravitreal injection
DRUGAflibercept 2 mg
Administered as an intravitreal injection
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Visual impairment predominantly due to neovascular AMD. * Active, newly diagnosed, untreated, angiographically documented, CNV lesion (i.e. leakage on fluorescein angiography plus intraretinal, subretinal or sub-RPE fluid on OCT) secondary to neovascular AMD in line with SmPC of ranibizumab and aflibercept
Exclusion criteria
* Stroke or myocardial infarction less than 3 months prior to screening. * Presence of uncontrolled systolic blood pressure or diastolic blood pressure * Type 1 or Type 2 diabetes mellitus * Use of any systemic anti-VEGF drugs * Use of systemic or inhaled corticosteroids for at least 30 consecutive days within 3 months prior to screening. * Women who are pregnant or breast feeding or who are menstruating and capable of becoming pregnant\* and not practicing a medically approved method of contraception For either eye: * Any active periocular or ocular infection or inflammation * Uncontrolled glaucoma * Neovascularization of the iris or neovascular glaucoma * History of treatment with any anti-angiogenic drugs For study eye: * Atrophy or fibrosis involving the center of the fovea at the time of screening or baseline. * Cataract (if causing significant visual impairment), planned cataract surgery during the study period, vitrectomy, aphakia, glaucoma surgery, severe vitreous hemorrhage, rhegmatogenous retinal detachment, proliferative retinopathy or choroidal neovascularization of any other cause than wAMD * Irreversible structural damage within 0.5 disc diameter of the center of the macula * Any intraocular procedure (including cataract surgery, Yttrium-Aluminum-Garnet capsulotomy) within 3 months prior to baseline or anticipated within the next 6 months following baseline. * Use of intravitreal or topical ocular corticosteroids administered for at least 30 consecutive days within 3 months prior to screening. For fellow eye \- Retinal or choroidal neovascularization or macula edema of any cause Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Standardized Area Under the Curve (AUC) for VEGF A Levels by SIMOA (Quanterix's Single Molecule Array) Method for the Comparative Phase | Baseline up to Week 12 visit (Days 1, 2, 8, 15, 29, 43, 57, 71, 85) | The AUC was calculated using the trapezoidal rule, where all available measurement between Day 1 and Week 12 were used. The AUC was standardized by dividing the calculated value by the number of days from first to last measurement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Systemic VEGF-A Protein Levels From Study Week 12 to 24 | From study week 12 to 24 (Days 85, 99, 113, 127, 141, 155, 169) | Systemic VEGF-A protein levels in patients switching from monthly 2 mg aflibercept injections to monthly 0.5 mg ranibizumab compared to patients treated with monthly 0.5 mg ranibizumab from baseline (standardized area under the curve) |
| Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | From study week 12 to 24 | Adjustment of systemic VEGF-A levels of patients switching from aflibercept to ranibizumab to levels comparable to baseline or to levels comparable as in patients treated from baseline with ranibizumab |
Countries
Germany
Participant flow
Recruitment details
The study included adult patients with active, newly diagnosed, and untreated wAMD. A total of 40 patients were treated at 6 study sites across Germany. Patients were treated in an outpatient setting.
Pre-assignment details
At Screening, the eligibility criteria were performed. .
Participants by arm
| Arm | Count |
|---|---|
| Ranibizumab 6 monthly intravitreal injections of 0.5 mg ranibizumab | 19 |
| Aflibercept and Ranibizumab 3 monthly intravitreal injections of 2 mg aflibercept followed by 3 monthly intravitreal injections of 0.5 mg ranibizumab | 21 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Ranibizumab | Aflibercept and Ranibizumab | Total |
|---|---|---|---|
| Age, Continuous | 74.3 Years STANDARD_DEVIATION 5.5 | 75.4 Years STANDARD_DEVIATION 8.94 | 74.9 Years STANDARD_DEVIATION 7.43 |
| Race/Ethnicity, Customized Caucasian | 19 Participants | 21 Participants | 40 Participants |
| Sex/Gender, Customized Female | 11 Participants | 10 Participants | 21 Participants |
| Sex/Gender, Customized Male | 8 Participants | 11 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 19 | 0 / 21 | 0 / 21 |
| other Total, other adverse events | 14 / 19 | 9 / 19 | 17 / 21 | 17 / 21 |
| serious Total, serious adverse events | 3 / 19 | 0 / 19 | 1 / 21 | 3 / 21 |
Outcome results
Primary
Standardized Area Under the Curve (AUC) for VEGF A Levels by SIMOA (Quanterix's Single Molecule Array) Method for the Comparative Phase
The AUC was calculated using the trapezoidal rule, where all available measurement between Day 1 and Week 12 were used. The AUC was standardized by dividing the calculated value by the number of days from first to last measurement.
Time frame: Baseline up to Week 12 visit (Days 1, 2, 8, 15, 29, 43, 57, 71, 85)
Population: Per-Protocol Set (PPS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab | Standardized Area Under the Curve (AUC) for VEGF A Levels by SIMOA (Quanterix's Single Molecule Array) Method for the Comparative Phase | 18.78 pg/mL | Standard Deviation 8.46 |
| Aflibercept and Ranibizumab | Standardized Area Under the Curve (AUC) for VEGF A Levels by SIMOA (Quanterix's Single Molecule Array) Method for the Comparative Phase | 33.95 pg/mL | Standard Deviation 7.659 |
p-value: <0.000195% CI: [-19.64, -10.32]ANCOVA
Secondary
Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline)
Adjustment of systemic VEGF-A levels of patients switching from aflibercept to ranibizumab to levels comparable to baseline or to levels comparable as in patients treated from baseline with ranibizumab
Time frame: From study week 12 to 24
Population: Per-Protocol Set (PPS) Number of participants analyzed at each time point represents patients with a value for both baseline and the specific post-baseline visit
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 12 | -1.37 pg/ml | Standard Deviation 5.369 |
| Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 16 | -0.01 pg/ml | Standard Deviation 4.675 |
| Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 20 | 1.62 pg/ml | Standard Deviation 6.46 |
| Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 18 | 1.99 pg/ml | Standard Deviation 5.582 |
| Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 22 | 0.66 pg/ml | Standard Deviation 8.109 |
| Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 14 | -1.00 pg/ml | Standard Deviation 6.128 |
| Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 24 | -1.18 pg/ml | Standard Deviation 3.664 |
| Aflibercept and Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 14 | 21.93 pg/ml | Standard Deviation 15.638 |
| Aflibercept and Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 20 | 4.84 pg/ml | Standard Deviation 11.065 |
| Aflibercept and Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 24 | 0.96 pg/ml | Standard Deviation 9.553 |
| Aflibercept and Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 12 | 23.73 pg/ml | Standard Deviation 13.7 |
| Aflibercept and Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 18 | 11.61 pg/ml | Standard Deviation 10.844 |
| Aflibercept and Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 16 | 19.26 pg/ml | Standard Deviation 16.432 |
| Aflibercept and Ranibizumab | Systemic VEGF-A Levels From Study Week 12 to 24 (Change From Baseline) | Change from Baseline at Week 22 | 2.45 pg/ml | Standard Deviation 8.543 |
Secondary
Systemic VEGF-A Protein Levels From Study Week 12 to 24
Systemic VEGF-A protein levels in patients switching from monthly 2 mg aflibercept injections to monthly 0.5 mg ranibizumab compared to patients treated with monthly 0.5 mg ranibizumab from baseline (standardized area under the curve)
Time frame: From study week 12 to 24 (Days 85, 99, 113, 127, 141, 155, 169)
Population: Per-Protocol Set (PPS)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab | Systemic VEGF-A Protein Levels From Study Week 12 to 24 | 17.93 pg/mL | Standard Deviation 5.316 |
| Aflibercept and Ranibizumab | Systemic VEGF-A Protein Levels From Study Week 12 to 24 | 29.07 pg/mL | Standard Deviation 7.863 |
p-value: <0.000195% CI: [-15.98, -6.94]ANCOVA