Safety and Efficacy of Ranibizumab in Japanese Patients With Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration

Study Overview
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Brief Summary
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Open-label Multicenter, Phase I/II Study comprising three phases (single dose, multiple dose and extension phase), Assessing the Safety and Efficacy of Ranibizumab (RFB002) in Japanese Patients With Subfoveal Choroidal Neovascularization (CNV) Secondary to Age-related Macular Degeneration (AMD).

Detailed Description
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The safety and tolerability of single intravitreal injections of ranibizumab was evaluated in patients enrolled in the single dose phase (Group A). Patients who successfully completed the single dose phase (i.e. did not experience a grade-3 targeted adverse event) could enter the multiple dose phase and receive ranibizumab injections for an additional 11 months. Simultaneously, the multiple dose phase was initiated in two parallel dose groups of additional patients (Group B), who received ranibizumab injections for 12 months. After patients in Group A and Group B had completed the multiple dose phase, all patients who provided written consent and were considered eligible based on the inclusion and exclusion criteria of the extension phase had the opportunity to continue on study treatment with the individualized flexible treatment regimen guided by monthly acuity scores and other ophthalmic examinations until approval of ranibizumab in Japan.

Official Title
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Open-label Multicenter, Phase I/II Study Assessing the Safety and Efficacy of Ranibizumab (RFB002) in Japanese Patients With Subfoveal Choroidal Neovascularization (CNV) Secondary to Age-related Macular Degeneration (AMD)

Conditions
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Subfoveal Choroidal Neovascularization(CNV) Secondary to Age-related Macular Degeneration (AMD)

Intervention / Treatment
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* Drug: Ranibizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female patients 50 years of age or greater Patients with primary or recurrent subfoveal CNV secondary to AMD Patients who have a BCVA score between 73 and 24 letters in the study eye using ETDRS-like grading charts (approximately 20/40 to 20/320) Exclusion Criteria 1. No prior treatment in the study eye with verteporfin, external-beam radiation therapy, subfoveal focal laser photocoagulation, vitrectomy, or transpupillary thermotherapy Extension Phase Inclusion criteria: Personally provided written informed consent to participate in the extension phase. Patients with subfoveal CNV secondary to AMD who had completed the multiple dose phase in either of the ranibizumab groups (Group A or B). Patients could participate in the extension phase even if they failed to do so on the day of the exit visit in the multiple dose phase (Group A and B), regardless of the time elapsed until the participation in the extension phase. Exclusion criteria: Received anti-angiogenic drugs (bevacizumab, pegaptanib, ranibizumab, anecortave acetate, corticosteroids or protein kinase C inhibitors, etc.) or Participated in any clinical study of an investigational drug other than this one during the period between the exit visit of the multiple dose phase and the start in the extension phase, if they failed to be enrolled into the extension on the day of the exit visit. Patients were to be excluded even when the fellow eye was treated with any of these drugs.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: Ranibizumab 0.3 mg<br>In the single dose phase, all patients randomized in Group A received a single intravitreal injection of 0.3 mg of ranibizumab into the study eye. Those patients who successfully completed this phase entered the multiple dose phase, where they received an intravitreal injection of 0.3 mg of ranibizumab once a month for an additional 11 months. Subsequently patients enrolling in the extension phase received an intravitreal injection of 0.3 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.70 years. | Drug: Ranibizumab<br>* Ranibizumab was administered by intravitreal injection in the study eye. Intravitreal injection was performed by the investigator following slitlamp examination.<br>* Other names: Lucentis;|
| Experimental: Group A: Ranibizumab 0.5 mg<br>In the single dose phase, all patients randomized in Group A received a single intravitreal injection of 0.5 mg of ranibizumab into the study eye. Those patients who successfully completed this phase entered the multiple dose phase, where they received an intravitreal injection of 0.5 mg of ranibizumab once a month for an additional 11 months. Subsequently Group A patients enrolling in the extension phase received an intravitreal injection of 0.5 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.93 years. | Drug: Ranibizumab<br>* Ranibizumab was administered by intravitreal injection in the study eye. Intravitreal injection was performed by the investigator following slitlamp examination.<br>* Other names: Lucentis;|
| Experimental: Group B: Ranibizumab 0.3 mg<br>Group B patients received a total of 12 monthly intravitreal injections of 0.3 mg of ranibizumab into the study eye in the multiple dose phase of the study. Group B patients who enrolled in the extension phase received an intravitreal injection of 0.3 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.45 years. | Drug: Ranibizumab<br>* Ranibizumab was administered by intravitreal injection in the study eye. Intravitreal injection was performed by the investigator following slitlamp examination.<br>* Other names: Lucentis;|
| Experimental: Group B: Ranibizumab 0.5 mg<br>Group B patients received a total of 12 monthly intravitreal injections of 0.5 mg of ranibizumab into the study eye in the multiple dose phase of the study. Group B patients who enrolled in the extension phase received an intravitreal injection of 0.5 mg of ranibizumab according to an individualized flexible interval regimen guided by monthly best corrected visual acuity scores and other ophthalmic examinations. In the extension phase patients received the same dose level as they received in the multiple dose phase of the study, for an average of 1.36 years. | Drug: Ranibizumab<br>* Ranibizumab was administered by intravitreal injection in the study eye. Intravitreal injection was performed by the investigator following slitlamp examination.<br>* Other names: Lucentis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Best Corrected Visual Acuity Score of the Study Eye at Month 6 in Group B | The efficacy assessment was based on Group B patients. Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 2 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a starting test distance of 2 meters. The BCVA score is the number of letters read correctly by the patient, hence an increase in score indicates improvement in acuity. | Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Best Corrected Visual Acuity Score of the Study Eye at Month 12 in Group B | The efficacy assessment was based on Group B patients. BCVA was assessed during all study visits using best correction determined from protocol refraction and ETDRS-like visual acuity testing charts at a starting test distance of 2 meters. The BCVA score is the number of letters read correctly by the patient, hence an increase in score indicates improvement in acuity. | Baseline and Month 12 | 
| Categorical Analysis of Best Corrected Visual Acuity of the Study Eye at Month 6 and Month 12 in Group B | BCVA measurements were taken in a sitting position using best correction determined from protocol refraction and ETDRS-like visual acuity testing charts at a starting test distance of 2 meters. | Baseline, Month 6 and Month 12 | 
| Extension Phase: Mean Change From Month 12 (Start of Extension Phase) in Best Corrected Visual Acuity Score of the Study Eye at Last Visit of Extension Phase in Group B. | Best Corrected Visual Acuity (BCVA) was assessed during all study visits using best correction determined from protocol refraction at a starting test distance of 2 meters. VA measurements were taken in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a starting test distance of 2 meters. The BCVA score is the number of letters read correctly by the patient, hence an increase in score indicates improvement in acuity. | Month 12 (start of extension phase) and last visit of extension phase. Duration in the extension phase varied depending on the study entry. The mean duration of treatment was 1.45 years in the 0.3 mg group and 1.36 years in the 0.5 mg dose group. | 
| Extension Phase: Categorical Analysis of Best Corrected Visual Acuity of the Study Eye at Last Visit of Extension Phase in Group B | BCVA measurements were taken in a sitting position using best correction determined from protocol refraction and ETDRS-like visual acuity testing charts at a starting test distance of 2 meters. The following categories were evaluated: Participants with a BCVA score loss of fewer than 15 letters from baseline at Last Visit Participants with a BCVA score loss of 30 or more letters from baseline at Last Visit Participants with a BCVA score gain of 15 or more letters from baseline at Last Visit Participants with a BCVA score of less than 34 letters at Last Visit | Baseline and last visit of extension phase - Duration in the extension phase varied depending on the study entry. The mean duration of treatment was 1.45 years in the 0.3 mg group and 1.36 years in the 0.5 mg dose group. | 
| Mean Change From Baseline in Total Area of Choroidal Neovascularization of the Study Eye in Group B | Choroidal Neovascularization was assessed by fluorescein angiography in conjunction with color fundus photography. Analysis was performed by the central reading center. The area of Choroidal Neovascularization is expressed as Macular Photocoagulation Study standard Disc Areas (DA; equivalent to 2.54 mm^2 on the retina). | Baseline, Months 3, 6, 9 and 12 | 
| Mean Change From Baseline in Total Area of Leakage From CNV Plus Staining of Retinal Pigment Epithelium of the Study Eye in Group B | Area of leakage from CNV plus staining of retinal pigment epithelium was assessed by fluorescein angiography in conjunction with color fundus photography. Analysis was performed by the central reading center. The total area is expressed as Macular Photocoagulation Study standard Disc Areas (DA; equivalent to 2.54 mm^2 on the retina). | Baseline, Months 3, 6, 9 and 12 | 
| Percentage of Participants in Group B With Absence of Leakage in the Study Eye at Month 3, 6, 9 and 12. | Area of leakage was assessed by fluorescein angiography in conjunction with color fundus photography. Analysis was performed at the central reading center. | Months 3, 6, 9 and 12 | 
| Mean Change From Baseline in Foveal Retinal Thickness of the Study Eye in Group B | Foveal retinal thickness was assessed by Optical Coherence Tomography (OCT) at a subset of the study sites and was analyzed by the central reading center. | Baseline, Months 3, 6, 9 and 12 | 
| Mean Change From Baseline in Total Retinal Volume of the Study Eye in Group B | Total retinal volume was assessed by Optical Coherence tomography (OCT) at a subset of the study sites and was analyzed by the central reading center. | Baseline, Months 3, 6, 9 and 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Subfoveal CNV, AMD, ranibizumab