Choroidal Neovascularization, Macular Degeneration
Conditions
Keywords
Age-related macular degeneration; AMD, choroidal neovascularization, verteporfin, ranibizumab
Brief summary
This study evaluated the effect of combination therapy with verteporfin photodynamic therapy and ranibizumab on visual acuity and anatomic outcomes 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 (Standard Fluence rate) or 25 J/cm\^2 (Reduced Fluence rate) to the study eye, begun 15 minutes after the start of the infusion.
DRUGRanibizumab
Ranibizumab 0.5 mg administered as an intravitreal injection.
DRUGVerteporfin Placebo
To maintain masking, as a placebo for verteporfin photodynamic therapy, 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.
DRUGRanibizumab Placebo
To maintain masking, patients in the combination groups received sham intravitreal injections whenever retreatment with active Ranibizumab was not warranted based on the retreatment algorithm.
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 choroidal neovascularization (CNV) due to age-related macular degeneration (AMD)
Exclusion criteria
* Choroidal 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 |
|---|---|---|
| Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye 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 Patients With a Treatment-free Interval of at Least 3 Months Following the Month 2 Visit | Month 2 up 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 |
|---|---|---|
| Change From Baseline in Total Area of Leakage of the Study Eye at Month 12 | Baseline and Month 12 | Total area of leakage of the study eye was assessed at the Central Reading Center (CRC) using Fluorescein angiography (FA). |
| Percentage of Patients With Fluorescein Leakage in the Study Eye at Month 12 | Month 12 | The percentage of patients with leakage of the study eye was assessed at the Central Reading Center (CRC) using Fluorescein angiography (FA). |
| Change From Baseline in Central Retinal Thickness at Month 12 | Baseline and Month 12 | Optical coherence tomography was performed in the study eyes and the evaluations of the images were performed by the central reading center. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Verteporfin SF + Ranibizumab Patients received three consecutive monthly ranibizumab injections on Day 1 and at Months 1 and 2, and thereafter as needed at intervals of at least 30 days based on retreatment criteria. These patients also received verteporfin photodynamic therapy (PDT) with standard fluence (SF) rate 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 choroidal neovascularization (CNV) leakage assessed by fluorescein angiography (FA). Patients received sham intravitreal injections for the first 12 months if retreatment with ranibizumab was not warranted based on the retreatment criteria. | 104 |
| Verteporfin RF + Ranibizumab Patients received three consecutive monthly ranibizumab injections on Day 1 and at Months 1 and 2, and thereafter as needed at intervals of at least 30 days based on retreatment criteria. These patients also received verteporfin PDT with reduced fluence (RF) rate 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 choroidal neovascularization (CNV) leakage assessed by fluorescein angiography (FA). Patients received sham intravitreal injections for the first 12 months if retreatment with ranibizumab was not warranted based on the retreatment criteria. | 105 |
| Ranibizumab Monotherapy Patients received monthly ranibizumab injections for 12 months and thereafter as needed 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. 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 choroidal neovascularization (CNV) leakage assessed by fluorescein angiography (FA). | 112 |
| Total | 321 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 3 | 4 |
| Overall Study | Death | 3 | 1 | 3 |
| Overall Study | Lost to Follow-up | 0 | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 6 | 3 |
Baseline characteristics
| Characteristic | Verteporfin SF + Ranibizumab | Verteporfin RF + Ranibizumab | Ranibizumab Monotherapy | Total |
|---|---|---|---|---|
| Age Continuous | 77.5 years STANDARD_DEVIATION 8.42 | 77.4 years STANDARD_DEVIATION 8.48 | 77.2 years STANDARD_DEVIATION 7.97 | 77.3 years STANDARD_DEVIATION 8.26 |
| Sex: Female, Male Female | 64 Participants | 53 Participants | 75 Participants | 192 Participants |
| Sex: Female, Male Male | 40 Participants | 52 Participants | 37 Participants | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 85 / 104 | 81 / 106 | 87 / 111 |
| serious Total, serious adverse events | 32 / 104 | 29 / 106 | 41 / 111 |
Outcome results
Primary
Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye 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: The Full analysis set (FAS) consisting of all randomized patients that received at least one application of study drug and had at least one post-baseline assessment for BCVA in the study eye. Last observation carried forward (LOCF) was utilized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Verteporfin SF + Ranibizumab | Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye at Month 12 | Month 12 | 59.0 Letters | Standard Deviation 17.47 |
| Verteporfin SF + Ranibizumab | Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye at Month 12 | Baseline | 53.7 Letters | Standard Deviation 13.52 |
| Verteporfin SF + Ranibizumab | Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye at Month 12 | Change from baseline | 5.3 Letters | Standard Deviation 15.66 |
| Verteporfin RF + Ranibizumab | Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye at Month 12 | Month 12 | 59.0 Letters | Standard Deviation 18.03 |
| Verteporfin RF + Ranibizumab | Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye at Month 12 | Baseline | 54.6 Letters | Standard Deviation 12.78 |
| Verteporfin RF + Ranibizumab | Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye at Month 12 | Change from baseline | 4.4 Letters | Standard Deviation 15.47 |
| Ranibizumab Monotherapy | Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye at Month 12 | Baseline | 54.8 Letters | Standard Deviation 13.55 |
| Ranibizumab Monotherapy | Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye at Month 12 | Change from baseline | 8.1 Letters | Standard Deviation 15.09 |
| Ranibizumab Monotherapy | Mean Change From Baseline in Best-corrected Visual Acuity (BCVA) of the Study Eye at Month 12 | Month 12 | 63.0 Letters | Standard Deviation 18.88 |
Primary
Percent of Patients 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 up to Month 11
Population: Full analysis set (FAS) - Only the combination groups were analyzed. The percent of subjects with a ranibizumab treatment-free interval of at least 3 months duration following the Month 2 ranibizumab treatment was calculated using the subjects still in the study at Month 5.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Verteporfin SF + Ranibizumab | Percent of Patients With a Treatment-free Interval of at Least 3 Months Following the Month 2 Visit | 92.6 Percent of participants |
| Verteporfin RF + Ranibizumab | Percent of Patients With a Treatment-free Interval of at Least 3 Months Following the Month 2 Visit | 83.5 Percent of participants |
Secondary
Change From Baseline in Central Retinal Thickness at Month 12
Optical coherence tomography was performed in the study eyes and the evaluations of the images were performed by the central reading center.
Time frame: Baseline and Month 12
Population: Full analysis set (FAS), observed data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Verteporfin SF + Ranibizumab | Change From Baseline in Central Retinal Thickness at Month 12 | Change from Baseline | -151.733 micrometer | Standard Deviation 135.62 |
| Verteporfin SF + Ranibizumab | Change From Baseline in Central Retinal Thickness at Month 12 | Month 12 | 292.921 micrometer | Standard Deviation 79.2733 |
| Verteporfin SF + Ranibizumab | Change From Baseline in Central Retinal Thickness at Month 12 | Baseline | 444.654 micrometer | Standard Deviation 137.7119 |
| Verteporfin RF + Ranibizumab | Change From Baseline in Central Retinal Thickness at Month 12 | Change from Baseline | -140.919 micrometer | Standard Deviation 128.0741 |
| Verteporfin RF + Ranibizumab | Change From Baseline in Central Retinal Thickness at Month 12 | Baseline | 446.638 micrometer | Standard Deviation 129.5482 |
| Verteporfin RF + Ranibizumab | Change From Baseline in Central Retinal Thickness at Month 12 | Month 12 | 305.719 micrometer | Standard Deviation 80.4508 |
| Ranibizumab Monotherapy | Change From Baseline in Central Retinal Thickness at Month 12 | Change from Baseline | -172.238 micrometer | Standard Deviation 166.6691 |
| Ranibizumab Monotherapy | Change From Baseline in Central Retinal Thickness at Month 12 | Baseline | 456.824 micrometer | Standard Deviation 153.427 |
| Ranibizumab Monotherapy | Change From Baseline in Central Retinal Thickness at Month 12 | Month 12 | 284.586 micrometer | Standard Deviation 75.4892 |
Secondary
Change From Baseline in Total Area of Leakage of the Study Eye at Month 12
Total area of leakage of the study eye was assessed at the Central Reading Center (CRC) using Fluorescein angiography (FA).
Time frame: Baseline and Month 12
Population: Full analysis set (FAS), observed data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Verteporfin SF + Ranibizumab | Change From Baseline in Total Area of Leakage of the Study Eye at Month 12 | Month 12 | 3.472 mm^2 | Standard Deviation 4.234 |
| Verteporfin SF + Ranibizumab | Change From Baseline in Total Area of Leakage of the Study Eye at Month 12 | Baseline | 6.654 mm^2 | Standard Deviation 4.0956 |
| Verteporfin SF + Ranibizumab | Change From Baseline in Total Area of Leakage of the Study Eye at Month 12 | Change from Baseline | -3.182 mm^2 | Standard Deviation 4.9729 |
| Verteporfin RF + Ranibizumab | Change From Baseline in Total Area of Leakage of the Study Eye at Month 12 | Month 12 | 3.024 mm^2 | Standard Deviation 4.0188 |
| Verteporfin RF + Ranibizumab | Change From Baseline in Total Area of Leakage of the Study Eye at Month 12 | Baseline | 6.211 mm^2 | Standard Deviation 5.0618 |
| Verteporfin RF + Ranibizumab | Change From Baseline in Total Area of Leakage of the Study Eye at Month 12 | Change from Baseline | -3.187 mm^2 | Standard Deviation 5.9744 |
| Ranibizumab Monotherapy | Change From Baseline in Total Area of Leakage of the Study Eye at Month 12 | Baseline | 6.931 mm^2 | Standard Deviation 4.6473 |
| Ranibizumab Monotherapy | Change From Baseline in Total Area of Leakage of the Study Eye at Month 12 | Change from Baseline | -3.753 mm^2 | Standard Deviation 5.8005 |
| Ranibizumab Monotherapy | Change From Baseline in Total Area of Leakage of the Study Eye at Month 12 | Month 12 | 3.177 mm^2 | Standard Deviation 4.993 |
Secondary
Percentage of Patients With Fluorescein Leakage in the Study Eye at Month 12
The percentage 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: Full analysis set (FAS), observed data.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Verteporfin SF + Ranibizumab | Percentage of Patients With Fluorescein Leakage in the Study Eye at Month 12 | 58.2 Percentage of participants | 0 |
| Verteporfin RF + Ranibizumab | Percentage of Patients With Fluorescein Leakage in the Study Eye at Month 12 | 54.5 Percentage of participants | 0 |
| Ranibizumab Monotherapy | Percentage of Patients With Fluorescein Leakage in the Study Eye at Month 12 | 41.8 Percentage of participants | 0 |