Choroidal Neovascularization, Macular Degeneration
Conditions
Keywords
Age-related macular degeneration, AMD, Choroidal neovascularization, Verteporfin, Ranibizumab
Brief summary
This study will evaluate the effect of combination therapy with verteporfin photodynamic therapy and ranibizumab on visual acuity compared to ranibizumab monotherapy and the durability of response observed in patients with choroidal neovascularization secondary to age-related macular degeneration
Interventions
After a 10-minute intravenous infusion of verteporfin at a dose of 6 mg/m\^2 body surface area, verteporfin was activated by light application of 50 J/cm\^2 to the study eye, begun 15 minutes after the start of the infusion.
DRUGRanibizumab
Ranibizumab 0.5 mg (0.05 mL of 10 mg/mL solution for injection) administered as an intravitreal injection
DRUGPlacebo
As a placebo for verteporfin photodynamic therapy (for masking purposes), patients were administered a 10-minute intravenous infusion of 5% dextrose solution, followed by light application of 50 J/cm\^2 to the study eye, begun 15 minutes after the start of infusion.
Sponsors
Novartis
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
* Subjects of either gender age 50 years or older * Subfoveal choriodal neovascularization (CNV) due to age-related macular degeneration (AMD)
Exclusion criteria
* Choriodal neovascularization due to causes other than AMD * Prior treatment for neovascular AMD in the study eye Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Best-corrected Visual Acuity (BCVA) at Month 12. | Baseline and Month 12 | BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An ETDRS visual acuity score of 85 is approximately 20/20. An increase in the VA score indicates improvement in visual acuity. |
| Percent of Participants With a Treatment-free Interval of at Least 3 Months Following the Month 2 Visit | Month 2 to Month 11 | The number of patients with a ranibizumab treatment-free interval, ie, no active ranibizumab treatments for at least 3 months duration (at least 2 consecutive monthly visits), anytime following the Month 2 ranibizumab treatment. Only active ranibizumab treatments were considered. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Fluorescein Leakage in the Study Eye at Month 12 | Month 12 | The proportion of patients with leakage of the study eye was assessed at the Central Reading Center (CRC) using Fluorescein angiography (FA). |
| Mean Change in Total Area of Leakage (Observed) of the Study Eye at Month 12 | Baseline and Month 12 | Fluorescein angiography (FA) was used to assess the mean change of leakage of the study eye at the Central Reading Center (CRC). A negative change from baseline indicates improvement, ie, less leakage. |
| Mean Change in Central Retinal Thickness of the Study Eye at Month 12 | Baseline and Month 12 | Optical coherence tomography (OCT) was used to assess the mean change in retinal thickness of the study eye at the Central Reading Center (CRC). A negative change from baseline indicates improvement, ie, less thickness. |
Countries
Austria, Belgium, Denmark, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, Switzerland, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Verteporfin + Ranibizumab Patients received three consecutive monthly ranibizumab injections starting on Day 1, and then as needed at intervals of at least 30 days based on retreatment criteria. These patients also received verteporfin PDT on Day 1 and then as needed from Month 3 at intervals of at least 90 days based on the retreatment criteria. From month 3 onward, retreatments were determined based on study-specific retreatment criteria that included retinal thickness by Optical Coherence Tomography (OCT), sub-retinal hemorrhage evaluated by ophthalmoscopic examination, visual acuity assessed using Early treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart and CNV leakage assessed by fluorescein angiography (FA). | 122 |
| Ranibizumab Patients received three consecutive monthly ranibizumab injections starting on Day 1 and then as needed from Month 3 based on the retreatment criteria. These patients were also administered verteporfin placebo infusion with sham PDT on Day 1 and then as needed from Month 3 at intervals of at least 90 days based on the retreatment criteria. From month 3 onward, retreatments were determined based on study-specific retreatment criteria that included retinal thickness by Optical Coherence Tomography (OCT), sub-retinal hemorrhage evaluated by ophthalmoscopic examination, visual acuity assessed using Early treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart and CNV leakage assessed by fluorescein angiography (FA). | 133 |
| Total | 255 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 80 | 86 |
| Overall Study | Adverse Event | 5 | 3 |
| Overall Study | Death | 2 | 2 |
| Overall Study | Lost to Follow-up | 3 | 4 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Subject no longer requires study drug | 1 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 5 |
Baseline characteristics
| Characteristic | Ranibizumab | Verteporfin + Ranibizumab | Total |
|---|---|---|---|
| Age Continuous | 75.5 years STANDARD_DEVIATION 7.44 | 76.8 years STANDARD_DEVIATION 7.65 | 76.1 years STANDARD_DEVIATION 7.55 |
| Sex: Female, Male Female | 74 Participants | 78 Participants | 152 Participants |
| Sex: Female, Male Male | 59 Participants | 44 Participants | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 64 / 122 | 63 / 133 |
| serious Total, serious adverse events | 25 / 122 | 28 / 133 |
Outcome results
Primary
Change From Baseline in Best-corrected Visual Acuity (BCVA) at Month 12.
BCVA score was based on the number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart assessed at a starting distance of 4 meters. An ETDRS visual acuity score of 85 is approximately 20/20. An increase in the VA score indicates improvement in visual acuity.
Time frame: Baseline and Month 12
Population: Performed on the Full analysis set (FAS) using the Last Observation Carried Forward (LOCF) approach for imputing missing data. FAS consisted of all patients as randomized that received at least one application of study drug and had at least one post-baseline assessment for best corrected visual acuity in the study eye.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Verteporfin + Ranibizumab | Change From Baseline in Best-corrected Visual Acuity (BCVA) at Month 12. | Baseline | 54.6 Letters | Standard Deviation 13.5 |
| Verteporfin + Ranibizumab | Change From Baseline in Best-corrected Visual Acuity (BCVA) at Month 12. | Month 12 | 57.1 Letters | Standard Deviation 18.3 |
| Verteporfin + Ranibizumab | Change From Baseline in Best-corrected Visual Acuity (BCVA) at Month 12. | Change from Baseline | 2.5 Letters | Standard Deviation 14.82 |
| Ranibizumab | Change From Baseline in Best-corrected Visual Acuity (BCVA) at Month 12. | Baseline | 55.1 Letters | Standard Deviation 12.3 |
| Ranibizumab | Change From Baseline in Best-corrected Visual Acuity (BCVA) at Month 12. | Month 12 | 59.4 Letters | Standard Deviation 18.8 |
| Ranibizumab | Change From Baseline in Best-corrected Visual Acuity (BCVA) at Month 12. | Change from Baseline | 4.4 Letters | Standard Deviation 15.92 |
Primary
Percent of Participants With a Treatment-free Interval of at Least 3 Months Following the Month 2 Visit
The number of patients with a ranibizumab treatment-free interval, ie, no active ranibizumab treatments for at least 3 months duration (at least 2 consecutive monthly visits), anytime following the Month 2 ranibizumab treatment. Only active ranibizumab treatments were considered.
Time frame: Month 2 to Month 11
Population: Full analysis set. Includes number of participants in the treatment group with at least one visit assessment of re-treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Verteporfin + Ranibizumab | Percent of Participants With a Treatment-free Interval of at Least 3 Months Following the Month 2 Visit | 95.8 Percentage of Participants |
| Ranibizumab | Percent of Participants With a Treatment-free Interval of at Least 3 Months Following the Month 2 Visit | 92.2 Percentage of Participants |
Secondary
Mean Change in Central Retinal Thickness of the Study Eye at Month 12
Optical coherence tomography (OCT) was used to assess the mean change in retinal thickness of the study eye at the Central Reading Center (CRC). A negative change from baseline indicates improvement, ie, less thickness.
Time frame: Baseline and Month 12
Population: Full analysis set, LOCF
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Verteporfin + Ranibizumab | Mean Change in Central Retinal Thickness of the Study Eye at Month 12 | Baseline | 335.2 μm | Standard Deviation 94.7 |
| Verteporfin + Ranibizumab | Mean Change in Central Retinal Thickness of the Study Eye at Month 12 | Month 12 | 219.9 μm | Standard Deviation 61.1 |
| Verteporfin + Ranibizumab | Mean Change in Central Retinal Thickness of the Study Eye at Month 12 | Change from Baseline | -115.3 μm | Standard Deviation 98.7 |
| Ranibizumab | Mean Change in Central Retinal Thickness of the Study Eye at Month 12 | Baseline | 339.8 μm | Standard Deviation 125.6 |
| Ranibizumab | Mean Change in Central Retinal Thickness of the Study Eye at Month 12 | Month 12 | 232.0 μm | Standard Deviation 54.5 |
| Ranibizumab | Mean Change in Central Retinal Thickness of the Study Eye at Month 12 | Change from Baseline | -107.7 μm | Standard Deviation 124.6 |
Secondary
Mean Change in Total Area of Leakage (Observed) of the Study Eye at Month 12
Fluorescein angiography (FA) was used to assess the mean change of leakage of the study eye at the Central Reading Center (CRC). A negative change from baseline indicates improvement, ie, less leakage.
Time frame: Baseline and Month 12
Population: Full analysis set based on observed data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Verteporfin + Ranibizumab | Mean Change in Total Area of Leakage (Observed) of the Study Eye at Month 12 | Baseline | 7.4 mm^2 | Standard Deviation 4.63 |
| Verteporfin + Ranibizumab | Mean Change in Total Area of Leakage (Observed) of the Study Eye at Month 12 | Month 12 | 2.2 mm^2 | Standard Deviation 4.88 |
| Verteporfin + Ranibizumab | Mean Change in Total Area of Leakage (Observed) of the Study Eye at Month 12 | Change from Baseline | -5.3 mm^2 | Standard Deviation 5.32 |
| Ranibizumab | Mean Change in Total Area of Leakage (Observed) of the Study Eye at Month 12 | Baseline | 8.1 mm^2 | Standard Deviation 5.82 |
| Ranibizumab | Mean Change in Total Area of Leakage (Observed) of the Study Eye at Month 12 | Month 12 | 2.0 mm^2 | Standard Deviation 4.68 |
| Ranibizumab | Mean Change in Total Area of Leakage (Observed) of the Study Eye at Month 12 | Change from Baseline | -6.1 mm^2 | Standard Deviation 6.44 |
Secondary
Percentage of Patients With Fluorescein Leakage in the Study Eye at Month 12
The proportion of patients with leakage of the study eye was assessed at the Central Reading Center (CRC) using Fluorescein angiography (FA).
Time frame: Month 12
Population: The Full Analysis Set (FAS) based on observed data.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Verteporfin + Ranibizumab | Percentage of Patients With Fluorescein Leakage in the Study Eye at Month 12 | 28.9 Percentage of participants |
| Ranibizumab | Percentage of Patients With Fluorescein Leakage in the Study Eye at Month 12 | 25.2 Percentage of participants |