OLIMPIC: A Study of the Criteria Establishing the Need for Re-treatment With Ranibizumab Upon Relapse in Patients With Visual Impairment Due to Choroidal Neovascularization Secondary to Pathologic Myopia.

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02034006
• Collaborator: (none)
• Enrollment: 200
• Locations: 31
• Arm: 1
• Actual Duration (Months): 25.2
• Patients Per Site: 6.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The primary objective of the study was to investigate current criteria driving re-treatment in patients affected by Choroidal Neovascularization (CNV) secondary to Pathologic Myopia (PM) and experiencing a relapse of the disease after the first administration of ranibizumab.

Condition or Disease	Intervention/Treatment	Phase
Choroidal Neovascularization Secondary to Pathologic Myopia	Drug: Ranibizumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 200 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 12-month, Open-label, Interventional, Multicentre Study to Investigate the Current Criteria Driving Re-treatment With Ranibizumab Upon Relapse in Patients With Visual Impairment Due to Choroidal Neovascularization Secondary to Pathologic Myopia
• Actual Study Start Date: Jun 10, 2014
• Actual Primary Completion Date: Jul 15, 2016
• Actual Study Completion Date: Jul 15, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Ranibizumab Patients treated with a single ranibizumab 0.5 mg/0.05ml intravitreal injection

Drug: Ranibizumab; All patients received a single initial intravitreal injection of ranibizumab 0.5 mg/0.05 ml as per Committee for Human Medicinal Products (CHMP)approval. Further injections might have been required when monitoring reveals disease activity. Disease activity, defined as reduced visual acuity and/or signs of lesion activity, was evaluated based on clinical examination (BCVA, fundus), and/or optical coherence tomography (OCT), and/or fluorescein angiography (FAG). Bilateral treatment was allowed provided at least 14 days of intercurrence.; Other Names: RFB002

Outcome Measures

Primary Outcome Measures

1. Number of Patients Treated and Re-treated Based on Presence/Absence of Active Leakage [Screening, Month 2, Month 6]

   Presence of active leakage on fluorescein angiography (FAG) was assessed at screening (14 to 3 days before baseline visit), month 2 and month 6. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of active leakage (Yes/No). For retreated patients, the presence/absence of active leakage was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable

2. Number of Patients Treated and Re-treated Based on Presence/Absence of Macular Edema [Screening, Month 2, Month 6, Month 12]

   Presence of macular edema from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of macular edema (Yes/No). For retreated patients, the presence/absence of macular edema was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable

3. Number of Patients Treated and Re-treated Based on Presence/Absence of Cysts [Screening, Month 2, Month 6, Month 12]

   Presence of cysts from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of cysts (Yes/No). For retreated patients, the presence/absence of cysts was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable

4. Number of Patients Treated and Re-treated Based on Presence/Absence of Intra-retinal Fluid [Screening, Month 2, Month 6, Month 12]

   Presence of Intra-retinal fluid from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of Intra-retinal fluid (Yes/No). For retreated patients, the presence/absence of Intra-retinal fluid was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable

5. Change in Central Subfield Thickness (CSFT) [Screening, Month 2, Month 6, Month 12]

   Central subfield thickness (CSFT) from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of change in CSFT versus previous visit. For retreated patients, the change in CSFT was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.

6. Change in Central Subfield Volume (CSV) [Screening, Month 2, Month 6, Month 12]

   Central subfield volume (CSV) from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of change in CSV versus previous visit. For retreated patients, the change in CSV was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.

7. Number of Patients Treated and Re-treated Based on Presence/Absence of Sub-retinal Fluid [Screening, Month 2, Month 6, Month 12]

   Presence of sub-retinal fluid from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. The regression model for sub-retinal fluid was not valid because "Yes" was reported in almost all subjects causing a quasi-complete separation of data points. *NE = Not evaluable

8. Number of Patients Treated and Re-treated Based on Presence/Absence of Clinically Significant Abnormalities [Baseline, Month 1, Month 2, Month 3, Month 6, Month 12]

   Presence of clinically significant abnormalities was assessed at baseline, month 1, month 2, month 3, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of clinically significant abnormalities (Yes/No). For retreated patients, the presence/absence of clinically significant abnormalities was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.

9. Number of Patients Treated and Re-treated Based on Improvement in Best Corrective Visual Acuity (BCVA) < 5 Letters [Baseline, Month 1, Month 2, Month 3, Month 6, Month 12]

   Improvement in BCVA < 5 letters (Yes/No) was assessed at month1, month 2, month 3, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of improvement in BCVA < 5 letters (Yes/No) which was reported as Gain >= 5 letters versus Gain < 5 letters. For retreated patients, Gain >= 5 letters and Gain < 5 letters were considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.

10. Number of Patients Treated and Re-treated Based on Improvement in Best Corrective Visual Acuity (BCVA) < 10 Letters [Baseline, Month 1, Month 2, Month 3, Month 6, Month 12]

    Improvement in BCVA < 10 letters (Yes/No) was assessed at month1, month 2, month 3, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of improvement in BCVA < 10 letters (Yes/No) which was reported as Gain >= 10 letters versus Gain < 10 letters. For retreated patients, Gain >= 10 letters and Gain < 10 letters were considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.

11. Number of Patients in Different Categories of Changes From Baseline in BCVA [Baseline, Month 1, Month 2, Month 3, Month 6, Month 12]

    Changes from baseline in BCVA are described for the ETDRS parameter considering the following categories at each assessment: "no change" if the change was equal to 0 letter, "worsening" if change < 0 letter , "improvement" if change > 0 letter. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of change from baseline in BCVA (improved/worsened/stable) which was reported as Improved versus no change and worsened versus no change. For retreated patients, this variable was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.

Secondary Outcome Measures

1. Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 6 and Month 12 on Study Eye [Baseline, Month 6, Month 12]

   Change from baseline in BCVA (Best Corrected Visual Acuity) was Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score. Patients with a BCVA ETDRS letter score of 78 to 24 in the study eye were included; A higher score represents better functioning of the study eye. A positive change from baseline shows improvement.

2. Mean Number of Ranibizumab Injection [Baseline to Month 12]

   Mean number of ranibizumab injection is reported as number of injections per patient.

3. Time to Re-treatment [Baseline to Month 12]

   Time to re-treatment, defined as time in months from the data of first dose of ranibizumab to the date of re-treatment, was evaluated.

4. Number of Patients Having Ocular and/or Systemic Adverse Event (AE) [Baseline to Month 12]

   Number of patients with any systemic AE, with serious systemic AE, with an ocular AE, with an ocular serious AE are reported

5. Change in Patient Quality of Life From Baseline to Month 2 and Month 12 [Baseline, Month 2, Month 12]

   Patient quality of life was assessed by Impact of Vision Impairment (IVI) questionnaire. IVI is a 32-item instrument, either self- or interviewer-administered, developed to measure the impact of vision impairment on daily activities in five domains. The 32 items were divided into 5 domains as follows: Leisure and work (items 1 to 5), Social and consumer interaction (items 6 to 10 and items 23-24), Household and personal care (items 11 to 14 and items 20-21), Mobility (items 15 to 19 and item 22), Emotional reaction to vision loss (items 25 to 32). Responses to the IVI items were rated on a five-category Likert scale: not at all, 0; hardly at all, 1; a little, 2; a fair amount, 3; a lot, 4; and can't do because of eyesight, 5. Total score was an arithmetic average of the items rated between 0 (the best score) and 5 (the worst score). A negative change indicates improvement. Data was computed on items with non missing response

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA:

• Written informed consent given before any study related procedure is performed

• Diagnosis of active CNV secondary to PM confirmed by complete ocular examination in the affected eye(s) using the following criteria:

• Presence of high myopia greater than -6D of spherical equivalence

• Presence of posterior changes compatible with pathologic myopia (any signs of attenuation of retinal pigment epithelium (RPE) and choroids, mottling of the RPE, tilted disc, geographic atrophy of RPE, Fuchs spots, posterior staphyloma, submacular hemorrhage, lacquer cracks) detected by fundus ophthalmoscopy and fundus photography

• Presence of active leakage from CNV observed through fluorescein angiography (FAG)

• Presence of intra or subretinal fluid demonstrated by Optical Coherence Tomography (OCT)

• BCVA > 24 letters and < 78 letters tested at 4 meters staring distance using ETDRS-like visual acuity chart

• Visual loss must be only due to the presence of any eligible types of CNV related to PM based on clinical ocular findings, FAG and OCT. (Also patients that have for example 20/60 as their best visual acuity due to PM in their history and have additional vision loss due to CNV lesion can be included)

EXCLUSION CRITERIA:

• Patients with inability to comply with study related procedures

• Pregnant or nursing (lactating) women and women of childbearing potential UNLESS using effective contraception during treatment

• Presence of confirmed systolic blood pressure > 150 mmHg or diastolic > 90 mmHg at the time of enrollment

• History of stroke

• Any type of advanced, severe or unstable medical condition or its treatment that could significantly bias the assessment of clinical status and interfere with primary and/or secondary outcome evaluations or put the patient at risk

• Presence of active infectious disease or intra-ocular inflammation in either eye at the time of enrollment

• Ocular disorders in the study eye that may confound interpretation of study results, compromise visual acuity or require medical or surgical intervention during the 12-month study period (including retinal detachment, cataract and pre-retinal membrane of the macula)

• History of pan-retinal or focal/grid laser photocoagulation with involvement of the macular area in the study eye at any time

• History of intraocular treatment with any anti-vascular endothelial growth factor (VEGF), verteporfin photodynamic therapy (vPDT) and any intra-ocular surgery or corticosteroid administration within one month before study entrance

• Known hypersensitivity to ranibizumab or any component of the ranibizumab formulation

• Simultaneous participation in a study that includes administration of any investigational drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Ancona	AN	Italy	60126
2	Novartis Investigative Site	Bari	BA	Italy	70124
3	Novartis Investigative Site	Bologna	BO	Italy	40138
4	Novartis Investigative Site	Desenzano del Garda	BS	Italy	25015
5	Novartis Investigative Site	Bolzano	BZ	Italy	39100
6	Novartis Investigative Site	Cagliari	CA	Italy	09124
7	Novartis Investigative Site	Catania	CT	Italy	95123
8	Novartis Investigative Site	Catanzaro	CZ	Italy	88100
9	Novartis Investigative Site	Firenze	FI	Italy	50134
10	Novartis Investigative Site	Rapallo	GE	Italy	16035
11	Novartis Investigative Site	Terracina	LT	Italy	04019
12	Novartis Investigative Site	Milano	MI	Italy	20100
13	Novartis Investigative Site	Milano	MI	Italy	20122
14	Novartis Investigative Site	Milano	MI	Italy	20132
15	Novartis Investigative Site	Palermo	PA	Italy	90127
16	Novartis Investigative Site	Padova	PD	Italy	35100
17	Novartis Investigative Site	Padova	PD	Italy	35128
18	Novartis Investigative Site	Perugia	PG	Italy	06100
19	Novartis Investigative Site	Pisa	PI	Italy	56124
20	Novartis Investigative Site	Parma	PR	Italy	43100
21	Novartis Investigative Site	Roma	RM	Italy	00133
22	Novartis Investigative Site	Roma	RM	Italy	00161
23	Novartis Investigative Site	Roma	RM	Italy	00198
24	Novartis Investigative Site	Siena	SI	Italy	53100
25	Novartis Investigative Site	Torino	TO	Italy	10122
26	Novartis Investigative Site	Conegliano	TV	Italy	31015
27	Novartis Investigative Site	Udine	UD	Italy	33100
28	Novartis Investigative Site	Varese	VA	Italy	21100
29	Novartis Investigative Site	Negrar	VR	Italy	37024
30	Novartis Investigative Site	Napoli		Italy	80131
31	Novartis Investigative Site	Napoli		Italy	80138

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02034006
• Other Study ID Numbers: CRFB002FIT01; 2013-003334-33
• First Posted: Jan 13, 2014
• Last Update Posted: Feb 18, 2019
• Last Verified: Oct 1, 2018

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: pathological myopia; choroidal neovascularization; ranibizumab; mono-bilateral; poor visual acuity; retinal disease; eye disease; Angiogenesis Inhibitors; Angiogenesis Modulating Agents
• Additional relevant MeSH terms: Neoplasm Metastasis; Vision Disorders; Vision, Low; Myopia; Choroidal Neovascularization; Neovascularization, Pathologic; Ranibizumab

Study Results

Participant Flow

Pre-assignment Detail	Two hundred fifteen (215) subjects were screened in this study (i.e. provided written informed consent). Two hundred (200) subjects underwent baseline visit and received at least one injection of ranibizumab.

Arm/Group Title	Ranibizumab
Arm/Group Description	All subjects who received at least one dose of ranibizumab
Period Title: Overall Study
STARTED	200
Once Treated Patients	70
Re-treated Patients	130
COMPLETED	186
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once	Total
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Total of all reporting groups
Overall Participants	70	130	200
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.27 (13.03)	62.12 (12.52)	61.82 (12.67)
Sex: Female, Male (Count of Participants)
Female	53 75.7%	94 72.3%	147 73.5%
Male	17 24.3%	36 27.7%	53 26.5%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Treated and Re-treated Based on Presence/Absence of Active Leakage
Description	Presence of active leakage on fluorescein angiography (FAG) was assessed at screening (14 to 3 days before baseline visit), month 2 and month 6. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of active leakage (Yes/No). For retreated patients, the presence/absence of active leakage was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable
Time Frame	Screening, Month 2, Month 6

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab and underwent fluorescein angiography at that time point.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Screening: Active leakage, No	3	0
Screening: Active leakage, Yes	61	121
Screening: Active leakage, NE	0	2
Screening: Active leakage, Missing	0	1
Month 2: Active leakage, No	58	61
Month 2: Active leakage, Yes	3	56
Month 2: Active leakage, NE	0	2
Month 6: Active leakage, No	55	73
Month 6: Active leakage, Yes	4	40
Month 6: Active leakage, NE	1	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab: Treated Once, Ranibizumab: Re-treated Once
	Comments	Presence vs. absence of active leakage.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	72.37
	Confidence Interval	(2-Sided) 95%; 23.44 to 223.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Change in Best Corrected Visual Acuity (BCVA) From Baseline to Month 6 and Month 12 on Study Eye
Description	Change from baseline in BCVA (Best Corrected Visual Acuity) was Measured by Early Treatment Diabetic Retinopathy Study (ETDRS) Letter Score. Patients with a BCVA ETDRS letter score of 78 to 24 in the study eye were included; A higher score represents better functioning of the study eye. A positive change from baseline shows improvement.
Time Frame	Baseline, Month 6, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab. The study eyes of the patients belonging to the FAS were analyzed.

Arm/Group Title	Ranibizumab
Arm/Group Description	Patients treated with a single ranibizumab 0.5 mg/0.05ml intravitreal injection. Further injections might be required when monitoring reveals disease activity.
Measure Participants	200
Measure study eyes	200
Change at 6 month	7.51 (11.68)
Change at 12 month	8.42 (12.81)

3. Secondary Outcome

Title	Mean Number of Ranibizumab Injection
Description	Mean number of ranibizumab injection is reported as number of injections per patient.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all subjects who received at least one dose of ranibizumab

Arm/Group Title	Ranibizumab
Arm/Group Description	Patients treated with a single ranibizumab 0.5 mg/0.05ml intravitreal injection. Further injections might be required when monitoring reveals disease activity.
Measure Participants	200
Mean (Standard Deviation) [injections]	2.41 (1.53)

4. Secondary Outcome

Title	Time to Re-treatment
Description	Time to re-treatment, defined as time in months from the data of first dose of ranibizumab to the date of re-treatment, was evaluated.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all subjects who received at least one dose of ranibizumab

Arm/Group Title	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	130
Mean (Standard Deviation) [Months]	2.56 (2.17)

5. Secondary Outcome

Title	Number of Patients Having Ocular and/or Systemic Adverse Event (AE)
Description	Number of patients with any systemic AE, with serious systemic AE, with an ocular AE, with an ocular serious AE are reported
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

Safety Population: all subjects who received at least one dose of ranibizumab and had at least one post-baseline safety assessment.

Arm/Group Title	Ranibizumab
Arm/Group Description	Patients treated with a single ranibizumab 0.5 mg/0.05ml intravitreal injection. Further injections might be required when monitoring reveals disease activity.
Measure Participants	200
Any systemic Adverse Event	30
Serious systemic Adverse Event	5
Ocular Adverse Event	41
Ocular serious adverse event	2

6. Secondary Outcome

Title	Change in Patient Quality of Life From Baseline to Month 2 and Month 12
Description	Patient quality of life was assessed by Impact of Vision Impairment (IVI) questionnaire. IVI is a 32-item instrument, either self- or interviewer-administered, developed to measure the impact of vision impairment on daily activities in five domains. The 32 items were divided into 5 domains as follows: Leisure and work (items 1 to 5), Social and consumer interaction (items 6 to 10 and items 23-24), Household and personal care (items 11 to 14 and items 20-21), Mobility (items 15 to 19 and item 22), Emotional reaction to vision loss (items 25 to 32). Responses to the IVI items were rated on a five-category Likert scale: not at all, 0; hardly at all, 1; a little, 2; a fair amount, 3; a lot, 4; and can't do because of eyesight, 5. Total score was an arithmetic average of the items rated between 0 (the best score) and 5 (the worst score). A negative change indicates improvement. Data was computed on items with non missing response
Time Frame	Baseline, Month 2, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all subjects who received at least one dose of ranibizumab with data at both timepoints.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Change at Month 2	-0.40 (0.68)	-0.15 (0.60)
Change at month 12	-0.54 (0.91)	-0.36 (0.81)

7. Primary Outcome

Title	Number of Patients Treated and Re-treated Based on Presence/Absence of Macular Edema
Description	Presence of macular edema from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of macular edema (Yes/No). For retreated patients, the presence/absence of macular edema was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable
Time Frame	Screening, Month 2, Month 6, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab and underwent OCT at that time point.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Screening: Macular Edema, No	38	63
Screening: Macular Edema, Yes	28	65
Screening: Macular Edema, NE	3	1
Month 2: Macular Edema, No	59	103
Month 2: Macular Edema, Yes	3	24
Month 2: Macular Edema, NE	1	2
Month 6: Macular Edema, No	57	101
Month 6: Macular Edema, Yes	2	24
Month 6: Macular Edema, NE	1	1
Month 12: Macular Edema, No	56	108
Month 12: Macular Edema, Yes	4	15
Month 12: Macular Edema, NE	1	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab: Treated Once, Ranibizumab: Re-treated Once
	Comments	Presence vs. absence of macular edema.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	9.33
	Confidence Interval	(2-Sided) 95%; 3.18 to 27.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Primary Outcome

Title	Number of Patients Treated and Re-treated Based on Presence/Absence of Cysts
Description	Presence of cysts from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of cysts (Yes/No). For retreated patients, the presence/absence of cysts was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable
Time Frame	Screening, Month 2, Month 6, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab and underwent OCT at that time point.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Screening: Cysts, No	41	79
Screening: Cysts, Yes	27	50
Screening: Cysts, NE	1	0
Month 2: Cysts, No	60	94
Month 2: Cysts, Yes	2	32
Month 2: Cysts, NE	1	2
Month 2: Cysts, Missing	0	1
Month 6: Cysts, No	57	98
Month 6: Cysts, Yes	2	27
Month 6: Cysts, NE	1	1
Month 12: Cysts, No	57	97
Month 12: Cysts, Yes	3	26
Month 12: Cysts, NE	1	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab: Treated Once, Ranibizumab: Re-treated Once
	Comments	Presence vs. absence of cysts.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	12.66
	Confidence Interval	(2-Sided) 95%; 3.76 to 42.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Primary Outcome

Title	Number of Patients Treated and Re-treated Based on Presence/Absence of Intra-retinal Fluid
Description	Presence of Intra-retinal fluid from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of Intra-retinal fluid (Yes/No). For retreated patients, the presence/absence of Intra-retinal fluid was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis. *NE = Not evaluable
Time Frame	Screening, Month 2, Month 6, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab and underwent OCT at that time point.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Screening: Intra-retinal fluid, No	19	37
Screening: Intra-retinal fluid, Yes	49	90
Screening: Intra-retinal fluid, NE	1	2
Month 2: Intra-retinal fluid, No	55	77
Month 2: Intra-retinal fluid, Yes	7	50
Month 2: Intra-retinal fluid, NE	1	2
Month 6: Intra-retinal fluid, No	57	85
Month 6: Intra-retinal fluid, Yes	1	38
Month 6: Intra-retinal fluid, NE	2	3
Month 12: Intra-retinal fluid, No	58	96
Month 12: Intra-retinal fluid, Yes	2	26
Month 12: Intra-retinal fluid, NE	1	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab: Treated Once, Ranibizumab: Re-treated Once
	Comments	Presence vs. absence of intra-retinal fluid.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	49.80
	Confidence Interval	(2-Sided) 95%; 11.62 to 213.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Primary Outcome

Title	Change in Central Subfield Thickness (CSFT)
Description	Central subfield thickness (CSFT) from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of change in CSFT versus previous visit. For retreated patients, the change in CSFT was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.
Time Frame	Screening, Month 2, Month 6, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab and underwent OCT at that time point and previous visit.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Month 2 Vs. Screening : CSFT	-16.15 (86.65)	-34.28 (78.01)
Month 6 Vs. Month 2: CSFT	-11.04 (61.06)	-15.83 (70.74)
Month 12 Vs. Month 6: CSFT	1.29 (62.55)	8.64 (76.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab: Treated Once, Ranibizumab: Re-treated Once
	Comments	Change in Central subfield thickness vs previous visit.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1514
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.99 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Primary Outcome

Title	Change in Central Subfield Volume (CSV)
Description	Central subfield volume (CSV) from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of change in CSV versus previous visit. For retreated patients, the change in CSV was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.
Time Frame	Screening, Month 2, Month 6, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab and underwent OCT at that time point and the previous visit.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Month 2 Vs. Screening : CSV	-0.02 (0.06)	-0.02 (0.06)
Month 6 Vs. Month 2: CSV	-0.00 (0.04)	-0.01 (0.07)
Month 12 Vs. Month 6: CSV	-0.00 (0.04)	0.01 (0.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab: Treated Once, Ranibizumab: Re-treated Once
	Comments	Change in Central subfield volume vs previous visit.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1265
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; 0.00 to 5.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Primary Outcome

Title	Number of Patients Treated and Re-treated Based on Presence/Absence of Sub-retinal Fluid
Description	Presence of sub-retinal fluid from optical coherence tomography (OCT) was assessed at screening (14 to 3 days before baseline visit), month 2, month 6 and month 12. The regression model for sub-retinal fluid was not valid because "Yes" was reported in almost all subjects causing a quasi-complete separation of data points. *NE = Not evaluable
Time Frame	Screening, Month 2, Month 6, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab and underwent OCT at that time point.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Screening: Sub-retinal fluid, No	43	65
Screening: Sub-retinal fluid, Yes	25	61
Screening: Sub-retinal fluid, NE	1	3
Month 2: Sub-retinal fluid, No	58	108
Month 2: Sub-retinal fluid, Yes	2	17
Month 2: Sub-retinal fluid, NE	3	4
Month 6: Sub-retinal fluid, No	58	109
Month 6: Sub-retinal fluid, Yes	0	14
Month 6: Sub-retinal fluid, NE	2	3
Month 12: Sub-retinal fluid, No	60	113
Month 12: Sub-retinal fluid, Yes	0	8
Month 12: Sub-retinal fluid, NE	1	3

13. Primary Outcome

Title	Number of Patients Treated and Re-treated Based on Presence/Absence of Clinically Significant Abnormalities
Description	Presence of clinically significant abnormalities was assessed at baseline, month 1, month 2, month 3, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of presence of clinically significant abnormalities (Yes/No). For retreated patients, the presence/absence of clinically significant abnormalities was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.
Time Frame	Baseline, Month 1, Month 2, Month 3, Month 6, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab and underwent ocular examination during that time point.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Baseline: Clinically Significant Abnormal, No	61	103
Baseline: Clinically Significant Abnormal, Yes	9	27
Baseline: Clinically Significant Abnormal, Missing	0	0
Month 1: Clinically Significant Abnorma, No	60	106
Month 1: Clinically Significant Abnormal, Yes	6	24
Month 1: Clinically Significant Abnormal, Missing	4	0
Month 2: Clinically Significant Abnormal, No	60	103
Month 2: Clinically Significant Abnormal, Yes	5	26
Month 2:Clinically Significant Abnormal, Missing	5	1
Month 3: Clinically Significant Abnormal, No	56	108
Month 3: Clinically Significant Abnormal, Yes	7	20
Month 3: Clinically Significant Abnormal, Missing	7	2
Month 6: Clinically Significant Abnormal, No	59	110
Month 6: Clinically Significant Abnormal, Yes	3	18
Month 6: Clinically Significant Abnormal, Missing	8	2
Month 12: Clinically Significant Abnormal, No	61	116
Month 12: Clinically Significant Abnormal, Yes	2	12
Month 12: Clinically Significant Abnormal, Missing	7	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab: Treated Once, Ranibizumab: Re-treated Once
	Comments	Presence vs. absence of clinically significant abnormalities.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0103
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	6.91
	Confidence Interval	(2-Sided) 95%; 1.58 to 30.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Primary Outcome

Title	Number of Patients Treated and Re-treated Based on Improvement in Best Corrective Visual Acuity (BCVA) < 5 Letters
Description	Improvement in BCVA < 5 letters (Yes/No) was assessed at month1, month 2, month 3, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of improvement in BCVA < 5 letters (Yes/No) which was reported as Gain >= 5 letters versus Gain < 5 letters. For retreated patients, Gain >= 5 letters and Gain < 5 letters were considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.
Time Frame	Baseline, Month 1, Month 2, Month 3, Month 6, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab with improvement in BCVA < 5 letters from baseline at that time point.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Month 1: Gain >= 5 letters	37	69
Month 1: Gain < 5 letters	14	28
Month 2: Gain >= 5 letters	38	70
Month 2: Gain < 5 letters	12	25
Month 3: Gain >= 5 letters	37	74
Month 3: Gain < 5 letters	15	20
Month 6: Gain >= 5 letters	40	70
Month 6: Gain < 5 letters	8	22
Month 12: Gain >= 5 letters	43	69
Month 12: Gain < 5 letters	8	23

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab: Treated Once, Ranibizumab: Re-treated Once
	Comments	Gain < 5 letters vs. Gain >= 5 letters.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0854
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.19
	Confidence Interval	(2-Sided) 95%; 0.90 to 5.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Primary Outcome

Title	Number of Patients Treated and Re-treated Based on Improvement in Best Corrective Visual Acuity (BCVA) < 10 Letters
Description	Improvement in BCVA < 10 letters (Yes/No) was assessed at month1, month 2, month 3, month 6 and month 12. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of improvement in BCVA < 10 letters (Yes/No) which was reported as Gain >= 10 letters versus Gain < 10 letters. For retreated patients, Gain >= 10 letters and Gain < 10 letters were considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.
Time Frame	Baseline, Month 1, Month 2, Month 3, Month 6, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab with improvement in BCVA < 10 letters from baseline to that time point.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Month 1: Gain >= 10 letters	13	27
Month 1: Gain < 10 letters	38	70
Month 2: Gain >= 10 letters	20	40
Month 2: Gain < 10 letters	30	55
Month 3: Gain >= 10 letters	22	41
Month 3: Gain < 10 letters	30	53
Month 6: Gain >= 10 letters	29	50
Month 6: Gain < 10 letters	19	42
Month 12: Gain >= 10 letters	28	48
Month 12: Gain < 10 letters	23	44

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab: Treated Once, Ranibizumab: Re-treated Once
	Comments	Gain < 10 letters vs. Gain >= 10 letters.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0114
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.52
	Confidence Interval	(2-Sided) 95%; 1.23 to 5.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Primary Outcome

Title	Number of Patients in Different Categories of Changes From Baseline in BCVA
Description	Changes from baseline in BCVA are described for the ETDRS parameter considering the following categories at each assessment: "no change" if the change was equal to 0 letter, "worsening" if change < 0 letter , "improvement" if change > 0 letter. A univariate logistic regression model was applied expressing the presence/absence of the first retreatment in function of change from baseline in BCVA (improved/worsened/stable) which was reported as Improved versus no change and worsened versus no change. For retreated patients, this variable was considered at the closest time-point to the first re-treatment: the last scheduled assessment immediately before the first re-treatment was considered. For treated patients, the last scheduled assessment available was considered. In case of missing value on the scheduled assessment, the value was considered as missing for this analysis.
Time Frame	Baseline, Month 1, Month 2, Month 3, Month 6, Month 12

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): all patients who received at least one dose of ranibizumab and evaluable BCVA at baseline and that time point.

Arm/Group Title	Ranibizumab: Treated Once	Ranibizumab: Re-treated Once
Arm/Group Description	Patients treated only once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.	Patients treated more than once with a single ranibizumab 0.5 mg/0.05ml intravitreal injection.
Measure Participants	70	130
Month 1: No change	7	18
Month 1: Worsening	8	15
Month 1: Improvement	51	97
Month 2: No change	6	9
Month 2: Worsening	9	25
Month 2: Improvement	50	95
Month 3: No change	3	9
Month 3: Worsening	8	25
Month 3: Improvement	52	94
Month 6: No change	5	6
Month 6: Worsening	9	30
Month 6: Improvement	48	92
Month 12: No change	3	7
Month 12: Worsening	9	29
Month 12: Improvement	51	92

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab: Treated Once, Ranibizumab: Re-treated Once
	Comments	Change from baseline in BCVA: Improved vs. No change. For retreated subjects, the last scheduled assessment prior to the first retreatment was considered. For subjects treated only once, the last scheduled assessment available was considered.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0049
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.25 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab: Treated Once, Ranibizumab: Re-treated Once
	Comments	Change from baseline in BCVA: Worsened vs. No change
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0461
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	5.53
	Confidence Interval	(2-Sided) 95%; 0.69 to 44.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected from time of treatment until exit from the study (approximately 12 months)
Adverse Event Reporting Description	Safety Population: All subjects who received at least one dose of ranibizumab and had at least one post-baseline safety assessment.
Arm/Group Title	Ranibizumab
Arm/Group Description	All subjects who received at least one dose of ranibizumab and had at least one post-baseline safety assessment.
All Cause Mortality
	Ranibizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ranibizumab
	Affected / at Risk (%)	# Events
Total	7/200 (3.5%)
Cardiac disorders
Atrioventricular block	1/200 (0.5%)
Cardiac arrest	1/200 (0.5%)
Hepatobiliary disorders
Cholecystitis acute	1/200 (0.5%)
Infections and infestations
Klebsiella sepsis	1/200 (0.5%)
Injury, poisoning and procedural complications
Expired product administered (Study Eye)	2/200 (1%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/200 (0.5%)
Reproductive system and breast disorders
Ovarian cyst	1/200 (0.5%)
Other (Not Including Serious) Adverse Events
	Ranibizumab
	Affected / at Risk (%)	# Events
Total	26/200 (13%)
Eye disorders
Choroidal neovascularisation (Non-study Eye)	3/200 (1.5%)
Choroidal neovascularisation (Study Eye)	7/200 (3.5%)
Conjunctival haemorrhage (Study Eye)	4/200 (2%)
Conjunctival hyperaemia (Both Eyes)	5/200 (2.5%)
Ocular hypertension (Both Eyes)	4/200 (2%)
Infections and infestations
Influenza	7/200 (3.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.