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Ranibizumab

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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.

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.

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.

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.

Ranibizumab was administered by intravitreal injection in the study eye. Intravitreal injection was performed by the investigator following slitlamp examination.

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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).

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.

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

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)

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.

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.

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.

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.

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

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).

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).

Area of leakage was assessed by fluorescein angiography in conjunction with color fundus photography. Analysis was performed at the central reading center.

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.

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.

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"Core" means Single and Multiple Dose Phases. Group A patients received a single intravitreal injection of 0.3 mg of ranibizumab into the study eye, followed by 11 additional intravitreal injections of 0.3 mg of ranibizumab once a month. Group B patients received a total of 12 monthly intravitreal injections of 0.3 mg of ranibizumab into the study eye.

Core Group A+B: Ranibizumab 0.3 mg

"Core" means Single and Multiple Dose Phases. Group A patients received a single intravitreal injection of 0.5 mg of ranibizumab into the study eye, followed by 11 additional intravitreal injections of 0.5 mg of ranibizumab once a month. Group B patients received a total of 12 monthly intravitreal injections of 0.5 mg of ranibizumab into the study eye.

Core Group A+B: Ranibizumab 0.5 mg

In the extension phase, enrolled patients received an intravitreal injection of 0.3 mg 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.

Extension Group A+B: Ranibizumab 0.3 mg

In the extension phase, all patients received an intravitreal injection of 0.5 mg 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.

Extension Group A+B: Ranibizumab 0.5 mg

Group A: Ranibizumab 0.3 mg

Group A: Ranibizumab 0.5 mg

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 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.

Group B: Ranibizumab 0.3 mg

Group B: Ranibizumab 0.5 mg

Total

50 to <65 years

65 to <75 years

75 to <85 years

>= 85 years

Age demographics for those subjects enrolled in the single and multiple dose phases of the study.

Age, Customized

Age demographics for those subjects enrolled in the extension phase of the study.

Gender demographics for those subjects enrolled in the single and multiple dose phases of the study.

Sex: Female, Male

Female

Male

Gender demographics for those subjects enrolled in the extension phase of the study.

Gender

Study Director

Baseline

Month 6

Change from Baseline

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 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.

Intent-to treat (ITT) population for Group B patients consisted of all patients randomized in Group B that received at least one dose of study drug and had at least one post-baseline assessment of the primary efficacy variable. The Last Observation Carried Forward (LOCF) was used to impute missing data at month 6 in the ITT analysis.

Mean Change From Baseline in the Best Corrected Visual Acuity Score of the Study Eye at Month 6 in Group B

Month 12

Intent-to treat (ITT) population for Group B patients consisted of all patients randomized in Group B that received at least one dose of study drug and had at least one post-baseline assessment of the efficacy variable. The Last Observation carried Forward (LOCF) was used to impute missing data at month 12 in the ITT analysis.

Mean Change From Baseline in the Best Corrected Visual Acuity Score of the Study Eye at Month 12 in Group B

Loss of < 15 letters from Baseline at month 6

Loss of < 15 letters from Baseline at month 12

Gain of ≥15 letters from Baseline at month 6

Gain of ≥15 letters from Baseline at month 12

Loss of ≥30 letters from Baseline at month 6

Loss of ≥30 letters from Baseline at month 12

Visual acuity < 34 letters at Month 6

Visual acuity < 34 letters at Month 12

Categorical Analysis of Best Corrected Visual Acuity of the Study Eye at Month 6 and Month 12 in Group B

Last visit

Change from Month 12

The analysis population included all enrolled patients in the extension phase. For the analysis of the results of the extension phase, all data are presented as observed. Patients must have values both at Month 12 and Last Visit to be included.

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.

Loss of < 15 letters from Baseline

Gain of ≥15 letters from Baseline

Loss of ≥30 letters from Baseline

Visual acuity < 34 letters

Includes patients enrolled in the extension phase, observed data.

Extension Phase: Categorical Analysis of Best Corrected Visual Acuity of the Study Eye at Last Visit of Extension Phase in Group B

Baseline [N=35, 41]

Mean change from Baseline at Month 3 [N=34, 40]

Mean change from Baseline at Month 6 [N=34, 40]

Mean change from Baseline at Month 9 [N=34, 40]

Mean change from Baseline at Month 12 [N=34, 40]

Intent-to treat (ITT) population for Group B patients consisted of all patients randomized in Group B that received at least one dose of study drug and had at least one post-baseline assessment. The Last Observation Carried Forward (LOCF) was used to impute missing data.

Mean Change From Baseline in Total Area of Choroidal Neovascularization of the Study Eye in Group B

Mean Change From Baseline in Total Area of Leakage From CNV Plus Staining of Retinal Pigment Epithelium of the Study Eye in Group B

Month 3

Month 9

Intent-to treat (ITT) population for Group B patients consisted of all patients randomized in Group B that received at least one dose of study drug and for whom data was available. The Last Observation Carried Forward (LOCF) was used to impute missing data.

Percentage of Participants in Group B With Absence of Leakage in the Study Eye at Month 3, 6, 9 and 12.

Baseline [N=28, 30]

Mean change from Baseline at Month 3 [N=27, 29]

Mean change from Baseline at Month 6 [N=26, 28]

Mean change from Baseline at Month 9 [N=26, 27]

Mean change from Baseline at Month 12 [N=26, 26]

The analysis includes Group B Intent-to treat (ITT) population, observed data. OCT was performed in a total of 58 patients at selected sites.

Mean Change From Baseline in Foveal Retinal Thickness of the Study Eye in Group B

Baseline [N=11, 11]

Mean change from Baseline at Month 3 [N=7, 7]

Mean change from Baseline at Month 6 [N=6, 6]

Mean change from Baseline at Month 9 [N=4, 5]

Mean change from Baseline at Month 12 [N=6, 6]

OCT was performed in a total of 58 patients at selected sites. Group B Intent-to treat (ITT) population, observed data only are included. The assessed sample size was small for total retinal volume data because the central reading center judged "Can not grade" due to retinal pigment epithelium disruption associated with CNV secondary to AMD.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Safety and Efficacy of Ranibizumab in Japanese Patients With Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration	NCT00284089	Subfoveal Choro...	Ranibizumab	50 Years -	Novartis
Safety and Efficacy of Ranibizumab in Japanese Patients With Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration	NCT00284089	Subfoveal Choro...	Ranibizumab	50 Years -	Novartis

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