Age Related Macular Degeneration, Choroidal Neovascularization
Conditions
Keywords
AMD, ranibizumab
Brief summary
Ranibizumab is a humanised recombinant monoclonal antibody fragment targeted against human vascular endothelial growth factor A. This study will assess the safety and efficacy of ranibizumab administered on an as-needed dosing regimen in patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).
Interventions
DRUGRanibizumab
Sponsors
Novartis
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients who participated in this study included those who had completed participation in the study CRFB002A2301 (ANCHOR; NCT00061594), newly diagnosed patients, as well as previously diagnosed patients who had had recent disease progression. Inclusion Criteria: * Male or female patients \> 50 years of age * Diagnosis of active primary or recurrent CNV secondary to AMD, including those with predominantly classic, minimally classic or occult lesions with no classic component * The total area of CNV (including both classic and occult components) encompassed within the lesion must be \>= 50% of the total lesion area * The total lesion area must be \<= 12 disc areas * Patients who have a BCVA (best corrected visual acuity) score between 73 and 24 letters, inclusive, in the study eye using ETDRS-like (Early Treatment of Diabetic Retinopathy Study) grading charts (approximately 20/40 to 20/320)
Exclusion criteria
* Patients who have a BCVA of \< 34 letters in both eyes (legally blind is defined as bilateral vision below 20/200 or less than 34 letters) * Laser photocoagulation, treatment with intravitreal steroids, verteporfin photo dynamic therapy or pegaptanib sodium in the study eye within 30 days preceding Day 1 * Previous participation in a clinical trial (for either eye) involving anti-angiogenic drugs (pegaptanib, ranibizumab, anecortave acetate, protein kinase C inhibitors, etc.) Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Ocular Adverse Events (AEs) in the Study Eye | Baseline through end of study (12 month treatment period) | Percentage of patients with ocular adverse events in the study eye over the one year (12 month) treatment period. |
| Percentage of Patients With Targeted Grade 3 Adverse Events (AEs) in the Study Eye | Baseline through end of study (12 month treatment period) | Grade 3 targeted AEs included: * 4+ ocular inflammation or 2-3+ ocular inflammation failing to decrease to ≤ 1+ within 30 days * ≥ 30 letter decrease in BCVA that developed within 14 days of ranibizumab injection * sustained (\>15 minutes) loss of light perception due to elevated intraocular pressure (IOP) or a \>20 mm Hg change in IOP persisting longer than 14 days * new retinal tear or detachment involving the macula * new vitreous hemorrhage \>2+ severity not resolving within 14 days * new or increase of previous retinal hemorrhage \>1 disc area in size and involving the fovea |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 3 | Baseline and Month 3 | Central retinal thickness was assessed using optical coherence tomography (OCT). OCT imaging was performed by trained personnel at each site using the Zeiss Stratus OCT™ 3 with version A6.1 (or more recent) software. Analysis of the OCT images was performed by the investigator. A negative number indicates improvement (reduced thickness). |
| Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 12 | Baseline and Month 12 | Central retinal thickness was assessed using optical coherence tomography (OCT). OCT imaging was performed by trained personnel at each site using the Zeiss Stratus OCT™ 3 with version A6.1 (or more recent) software. Analysis of the OCT images was performed by the investigator. A negative number indicates improvement (reduced thickness). |
| Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 3 | Baseline and Month 3 | BCVA was assessed using best correction determined from protocol refraction. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at an initial testing distance of 4 meters. BCVA is measured by the number of letters a patient could correctly read on an eye chart; hence an increased score indicates improvement in acuity. |
| Total Number of Treatments | Baseline (Month 0) to Month 11 | Total number of treatments administered during the entire treatment period (Month 0 to 11). |
| Time to the First Retreatment After Month 2 | Month 2 to Month 11 | Time to first re-treatment is calculated as time difference in months starting from Month 2 until the month of first re-treatment. Criteria for re-treatment: * a \>5 letter decrease in BCVA (determined using EDRS charts) based upon the highest visual acuity score from any prior scheduled study visit (Months 0, 1, 2 or 3) * a \>100 µm increase in central retinal thickness (determined using OCT) from the thinnest measurement from any prior scheduled study visit (Months 0, 1, 2 or 3) |
| Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 12 | Baseline and Month 12 | BCVA was assessed using best correction determined from protocol refraction. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at an initial testing distance of 4 meters. BCVA is measured by the number of letters a patient could correctly read on an eye chart; hence an increased score indicates improvement in acuity. |
Countries
Switzerland
Participant flow
Recruitment details
The study population consisted of two groups, one group being naïve to ranibizumab (Non-ANCHOR patients) and the other group were those patients who previously were treated with ranibizumab in the ANCHOR study (NCT00061594; ANCHOR patients).
Participants by arm
| Arm | Count |
|---|---|
| Ranibizumab Non-ANCHOR Patients received up to 12 intravitreal injections (Month 0 through Month 11). The dose of 0.3 mg ranibizumab was administered monthly for three consecutive months. From Month 3 through Month 11, either 0.3 mg ranibizumab or, after implementation of an amendment to the protocol, 0.5 mg ranibizumab were injected as individually needed based on retreatment criteria described in the protocol. Ranibizumab was administered no sooner than 14 days after the previous treatment. | 513 |
| Ranibizumab ANCHOR Patients received up to 12 intravitreal injections (Month 0 through Month 11). From Month 0 through Month 11, either 0.3 mg ranibizumab or, after implementation of an amendment to the protocol, 0.5 mg ranibizumab was injected if the patient met retreatment criteria described in the protocol. Ranibizumab was administered no sooner than 14 days after the previous treatment. | 18 |
| Total | 531 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Problems | 1 | 0 |
| Overall Study | Adverse Event | 30 | 1 |
| Overall Study | Death | 6 | 0 |
| Overall Study | Lack of Efficacy | 4 | 0 |
| Overall Study | Lost to Follow-up | 4 | 3 |
| Overall Study | Protocol Violation | 3 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 0 |
Baseline characteristics
| Characteristic | Ranibizumab Non-ANCHOR | Ranibizumab ANCHOR | Total |
|---|---|---|---|
| Age, Customized 50 to < 65 years | 49 participants | 0 participants | 49 participants |
| Age, Customized < 50 years | 1 participants | 0 participants | 1 participants |
| Age, Customized 65 to < 75 years | 173 participants | 5 participants | 178 participants |
| Age, Customized 75 to < 85 years | 230 participants | 12 participants | 242 participants |
| Age, Customized ≥ 85 years | 60 participants | 1 participants | 61 participants |
| Sex: Female, Male Female | 294 Participants | 9 Participants | 303 Participants |
| Sex: Female, Male Male | 219 Participants | 9 Participants | 228 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 199 / 513 | 8 / 18 |
| serious Total, serious adverse events | 80 / 513 | 4 / 18 |
Outcome results
Primary
Percentage of Patients With Ocular Adverse Events (AEs) in the Study Eye
Percentage of patients with ocular adverse events in the study eye over the one year (12 month) treatment period.
Time frame: Baseline through end of study (12 month treatment period)
Population: For Non-ANCHOR treatment group, the analysis population was the Safety population: All patients who had received at least one application of study drug and had at least one post-baseline safety assessment. For the ANCHOR treatment group, the analysis population was all enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranibizumab Non-ANCHOR | Percentage of Patients With Ocular Adverse Events (AEs) in the Study Eye | 48.5 Percentage of Participants |
| Ranibizumab ANCHOR | Percentage of Patients With Ocular Adverse Events (AEs) in the Study Eye | 38.9 Percentage of Participants |
Primary
Percentage of Patients With Targeted Grade 3 Adverse Events (AEs) in the Study Eye
Grade 3 targeted AEs included: * 4+ ocular inflammation or 2-3+ ocular inflammation failing to decrease to ≤ 1+ within 30 days * ≥ 30 letter decrease in BCVA that developed within 14 days of ranibizumab injection * sustained (\>15 minutes) loss of light perception due to elevated intraocular pressure (IOP) or a \>20 mm Hg change in IOP persisting longer than 14 days * new retinal tear or detachment involving the macula * new vitreous hemorrhage \>2+ severity not resolving within 14 days * new or increase of previous retinal hemorrhage \>1 disc area in size and involving the fovea
Time frame: Baseline through end of study (12 month treatment period)
Population: For Non-ANCHOR treatment group, the analysis population was the Safety population: All patients who had received at least one application of study drug and had at least one post-baseline safety assessment. For the ANCHOR treatment group, the analysis population was all enrolled patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ranibizumab Non-ANCHOR | Percentage of Patients With Targeted Grade 3 Adverse Events (AEs) in the Study Eye | 2.9 Percentage of Participants |
| Ranibizumab ANCHOR | Percentage of Patients With Targeted Grade 3 Adverse Events (AEs) in the Study Eye | 0.0 Percentage of Participants |
Secondary
Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 12
BCVA was assessed using best correction determined from protocol refraction. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at an initial testing distance of 4 meters. BCVA is measured by the number of letters a patient could correctly read on an eye chart; hence an increased score indicates improvement in acuity.
Time frame: Baseline and Month 12
Population: Non-ANCHOR patients: Analysis of Intent-to-Treat (ITT) population (all patients who received study drug at least once and had at least one post-baseline efficacy assessment) using last observation carried forward (LOCF). ANCHOR patients: Analysis of All Enrolled population (all enrolled patients) using LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab Non-ANCHOR | Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 12 | Baseline | 56.2 Letters on the ETDRS-like testing charts | Standard Deviation 12.11 |
| Ranibizumab Non-ANCHOR | Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 12 | Change to Month 12 | 3.6 Letters on the ETDRS-like testing charts | Standard Deviation 13.89 |
| Ranibizumab ANCHOR | Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 12 | Baseline | 47.2 Letters on the ETDRS-like testing charts | Standard Deviation 22.1 |
| Ranibizumab ANCHOR | Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 12 | Change to Month 12 | 1.6 Letters on the ETDRS-like testing charts | Standard Deviation 8.66 |
Secondary
Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 3
BCVA was assessed using best correction determined from protocol refraction. BCVA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at an initial testing distance of 4 meters. BCVA is measured by the number of letters a patient could correctly read on an eye chart; hence an increased score indicates improvement in acuity.
Time frame: Baseline and Month 3
Population: Non-ANCHOR patients: Analysis of Intent-to-Treat (ITT) population (all patients who received study drug at least once and had at least one post-baseline efficacy assessment) using last observation carried forward (LOCF). ANCHOR patients: Analysis of All Enrolled population (all enrolled patients) using LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab Non-ANCHOR | Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 3 | Baseline | 56.2 Letters on the ETDRS-like testing charts | Standard Deviation 12.11 |
| Ranibizumab Non-ANCHOR | Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 3 | Change to Month 3 | 5.8 Letters on the ETDRS-like testing charts | Standard Deviation 11.12 |
| Ranibizumab ANCHOR | Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 3 | Baseline | 47.2 Letters on the ETDRS-like testing charts | Standard Deviation 22.1 |
| Ranibizumab ANCHOR | Mean Change in Best Corrected Visual Acuity (BCVA) of the Study Eye From Baseline to Month 3 | Change to Month 3 | 1.9 Letters on the ETDRS-like testing charts | Standard Deviation 9.26 |
Secondary
Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 12
Central retinal thickness was assessed using optical coherence tomography (OCT). OCT imaging was performed by trained personnel at each site using the Zeiss Stratus OCT™ 3 with version A6.1 (or more recent) software. Analysis of the OCT images was performed by the investigator. A negative number indicates improvement (reduced thickness).
Time frame: Baseline and Month 12
Population: Non-ANCHOR patients: Analysis of Intent-to-Treat (ITT) population (all patients who received study drug at least once and had at least one post-baseline efficacy assessment) using last observation carried forward (LOCF). ANCHOR patients: Analysis of All Enrolled population (all enrolled patients) using LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab Non-ANCHOR | Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 12 | Baseline | 339.6 Micrometers | Standard Deviation 109.38 |
| Ranibizumab Non-ANCHOR | Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 12 | Change to Month 12 | -91.5 Micrometers | Standard Deviation 115.47 |
| Ranibizumab ANCHOR | Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 12 | Change to Month 12 | 39.3 Micrometers | Standard Deviation 84.61 |
| Ranibizumab ANCHOR | Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 12 | Baseline | 214.1 Micrometers | Standard Deviation 64.92 |
Secondary
Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 3
Central retinal thickness was assessed using optical coherence tomography (OCT). OCT imaging was performed by trained personnel at each site using the Zeiss Stratus OCT™ 3 with version A6.1 (or more recent) software. Analysis of the OCT images was performed by the investigator. A negative number indicates improvement (reduced thickness).
Time frame: Baseline and Month 3
Population: Non-ANCHOR patients: Analysis of Intent-to-Treat (ITT) population (all patients who received study drug at least once and had at least one post-baseline efficacy assessment) using last observation carried forward (LOCF). ANCHOR patients: Analysis of All Enrolled population (all enrolled patients) using LOCF.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ranibizumab Non-ANCHOR | Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 3 | Baseline | 339.6 Micrometers | Standard Deviation 109.38 |
| Ranibizumab Non-ANCHOR | Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 3 | Change to Month 3 | -101.1 Micrometers | Standard Deviation 115.69 |
| Ranibizumab ANCHOR | Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 3 | Baseline | 214.1 Micrometers | Standard Deviation 64.92 |
| Ranibizumab ANCHOR | Mean Change in Central Retinal Thickness of the Study Eye From Baseline to Month 3 | Change to Month 3 | 36.3 Micrometers | Standard Deviation 72.96 |
Secondary
Time to the First Retreatment After Month 2
Time to first re-treatment is calculated as time difference in months starting from Month 2 until the month of first re-treatment. Criteria for re-treatment: * a \>5 letter decrease in BCVA (determined using EDRS charts) based upon the highest visual acuity score from any prior scheduled study visit (Months 0, 1, 2 or 3) * a \>100 µm increase in central retinal thickness (determined using OCT) from the thinnest measurement from any prior scheduled study visit (Months 0, 1, 2 or 3)
Time frame: Month 2 to Month 11
Population: Intent-to-Treat (ITT) population patients: All patients who received study drug at least once and had at least one post-baseline efficacy assessment. The ANCHOR patients were not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ranibizumab Non-ANCHOR | Time to the First Retreatment After Month 2 | 2 Months |
Secondary
Total Number of Treatments
Total number of treatments administered during the entire treatment period (Month 0 to 11).
Time frame: Baseline (Month 0) to Month 11
Population: For Non-ANCHOR treatment group, the analysis population was the Safety population: All patients who had received at least one application of study drug and had at least one post-baseline safety assessment. For the ANCHOR treatment group, the analysis population was all enrolled patients.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ranibizumab Non-ANCHOR | Total Number of Treatments | 5.6 Treatments | Standard Deviation 2.37 |
| Ranibizumab ANCHOR | Total Number of Treatments | 1.1 Treatments | Standard Deviation 2.29 |