RESTORE: A 12 Month Core Study to Assess the Efficacy and Safety of Ranibizumab (Intravitreal Injections) in Patients With Visual Impairment Due to Diabetic Macular Edema and a 24 Month Open-label Extension Study

• Sponsor: Novartis (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00687804
• Collaborator: (none)
• Enrollment: 345
• Locations: 13
• Arms: 3
• Duration (Months): 44
• Patients Per Site: 26.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

CRFB002D2301: The core study was designed to confirm the efficacy and safety of ranibizumab (0.5 mg) as adjunctive therapy when added to laser photocoagulation and/or mono-therapy in patients with visual impairment due to diabetic macular edema.

CRFB002D2301E1: A 24 month open-label extension study for participants who completed the 12 month core study evaluated the long-term safety and efficacy of ranibizumab (0.5 mg) as symptomatic treatment for visual impairment due to diabetic macular edema.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Macular Edema	Drug: Ranibizumab; Procedure: Laser; Procedure: Sham laser; Drug: Sham to ranibizumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 345 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-masked, Multicenter, Laser-controlled Phase III Study Assessing the Efficacy and Safety of Ranibizumab (Intravitreal Injections) as Adjunctive and Mono-therapy in Patients With Visual Impairment Due to Diabetic Macular Edema
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ranibizumab 0.5 mg Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Drug: Ranibizumab; 0.5 mg ranibizumab administered by intravitreal injection.; Procedure: Laser; Laser photocoagulation treatment; Procedure: Sham laser; Sham to laser procedure.
Experimental: Ranibizumab 0.5 mg + laser Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Drug: Ranibizumab; 0.5 mg ranibizumab administered by intravitreal injection.; Procedure: Laser; Laser photocoagulation treatment
Active Comparator: Laser Laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Drug: Ranibizumab; 0.5 mg ranibizumab administered by intravitreal injection.; Procedure: Laser; Laser photocoagulation treatment; Drug: Sham to ranibizumab; Sham to ranibizumab administered as an intravitreal injection.

Outcome Measures

Primary Outcome Measures

1. Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12 [Baseline through the end of study (Month 12)]

   Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.

2. Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study [Extension baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months]]

   Participants with ocular (occurring in the eye) serious adverse events (SAEs) and non-serious AEs in the study eye. The study eye is the eye that received the treatment. AEs are the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.

3. Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study [Extension baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months]]

   Participants with non-ocular (not occurring in the eye) serious adverse events (SAEs) and non-serious AEs. AEs are the appearance or worsening of of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.

Secondary Outcome Measures

1. Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12 [Baseline to Month 12]

   Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.

2. Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time [Baseline to Month 12]

   Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.

3. Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye [Baseline to Month 12]

   Retinal thickness was measured using Optical Coherence Tomography (OCT). The images were reviewed by a central reading center to ensure a standardized evaluation.

4. Core Study: Mean Change From Baseline in Patient-reported Visual Functioning [Baseline to Month 12]

   The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) was used to measure a patient's subjective assessment of vision-related quality of life. The 12 subscales in the VFQ-25 are general health, general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated improvement in quality of life due to vision function.

5. Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies [Core baseline (Day 1 of the core study) to Month 36 (end of extension study) [36 months]]

   Participants with ocular (occurring in the eye) serious adverse events (SAEs) and non-serious AEs in the study eye. The study eye is the eye that received the treatment. AEs are the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.

6. Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies [Core baseline (Day 1 of the core study) to Month 36 (end of extension study) [36 Months]]

   Participants with non-ocular (not occurring in the eye) serious adverse events (SAEs) and non-serious AEs. AEs are the appearance or worsening of of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about Adverse Events can be found in the Adverse Event section.

7. Extension Study: Mean Change From Extension Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 [Extension baseline (Month12 -end of core study), Month 36 (end of extension study)]

   Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. An increase in the number of letters read correctly indicates improvement.

8. Extension Study: Mean Change From Core Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36 [Core baseline (Day 1 of the core study), Month 36 (end of extension study)]

   Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. An increase in the number of letters read correctly indicates improvement.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Visual acuity impairment

• Diabetic macular edema in at least one eye

• Type 1 or type 2 diabetes mellitus

• Medication for the diabetes treatment must be stable for the last 3 months

Exclusion Criteria:

• Patients with uncontrolled systemic or ocular diseases

• Laser photocoagulation in the study eye for the last 3 months

• Any history of any intraocular surgery in the study eye within the past 3 months

• Blood pressure > 160/100 mmHg

Extension Inclusion Criteria:

-Completion of the Core Study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Melbourne		Australia
2	Novartis Investigative Site	Leuven		Belgium
3	Novartis Investigative Site	Ontario		Canada
4	Novartis Investigative Site	Paris		France
5	Novartis Investigative Site	Düsseldorf		Germany
6	Novartis Investigative Site	Athens		Greece
7	Novartis Investigative Site	Budapest		Hungary
8	Novartis Investigative Site	Firenze		Italy
9	Novartis Investigative Site	Amsterdam		Netherlands
10	Novartis Investigative Site	Barcelona		Spain
11	Novartis Investigational Site	Zurich		Switzerland
12	Novartis Investigative Site	Ankara		Turkey
13	Novartis Investigative Site	Upton		United Kingdom

Sponsors and Collaborators

• Novartis

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis
• ClinicalTrials.gov Identifier: NCT00687804
• Other Study ID Numbers: CRFB002D2301; EUDRACT: 2007-004877-24; NCT00906464
• First Posted: Jun 2, 2008
• Last Update Posted: Apr 1, 2013
• Last Verified: Mar 1, 2013

• Keywords provided by Novartis: DME; Diabetic; macula; edema; ranibizumab; RESTORE
• Additional relevant MeSH terms: Vision Disorders; Vision, Low; Macular Edema; Edema; Ranibizumab

Study Results

Participant Flow

Pre-assignment Detail	Participants who completed the 12 month randomized core study CRFB002D2301 were eligible to participate in the 24 month open-label extension study CRFB002D2301E1. The reporting groups for the participants in the extension study are according to their assigned treatment groups in the core study.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Laser
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.
Period Title: Core Study
STARTED	116	118	111
COMPLETED	102	103	98
NOT COMPLETED	14	15	13
Period Title: Core Study
STARTED	83	83	74
Did Not Receive Ranibizumab in Extension	16	21	15
COMPLETED	73	72	63
NOT COMPLETED	10	11	11

Baseline Characteristics

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Laser	Total
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Laser photocoagulation treatment was administered on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Total of all reporting groups
Overall Participants	116	118	111	345
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.9 (9.29)	64.0 (8.15)	63.5 (8.81)	63.5 (8.75)
Age, Customized (Number) [Number]
< 55 years	24 20.7%	14 11.9%	13 11.7%	51 14.8%
55 - <65 years	41 35.3%	42 35.6%	53 47.7%	136 39.4%
65 - <75 years	40 34.5%	53 44.9%	31 27.9%	124 35.9%
>=75 years	11 9.5%	9 7.6%	14 12.6%	34 9.9%
Sex: Female, Male (Count of Participants)
Female	43 37.1%	48 40.7%	53 47.7%	144 41.7%
Male	73 62.9%	70 59.3%	58 52.3%	201 58.3%

Outcome Measures

1. Primary Outcome

Title	Core Study: Difference Between the Baseline Level of Visual Acuity (Letters) of the Study Eye and the Mean Visual Acuity Averaged Over All Monthly Post-baseline Assessments From Month 1 to Month 12
Description	Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.
Time Frame	Baseline through the end of study (Month 12)

Outcome Measure Data

Analysis Population Description

Full analysis set consists of all patients who received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Following the intent to treat principle, patients were analyzed according to the treatment assigned. Last Observation Carried Forward (LOCF) imputation was utilized.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Laser
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Laser photocoagulation treatment was administered on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.
Measure Participants	115	118	110
Baseline	64.7 (10.07)	63.4 (9.99)	62.6 (11.01)
Average Month 1 to month 12	70.8 (10.53)	69.2 (11.44)	63.4 (12.26)
Change from Baseline	6.1 (6.43)	5.9 (7.92)	0.8 (8.56)

2. Secondary Outcome

Title	Core Study: Categorized Change in Visual Acuity (Letters) of the Study Eye From Baseline at Month 12
Description	Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

Full analysis set consists of all patients who received at least one application of study treatment and had at least one post-baseline assessment for BCVA. Following the intent to treat principle, patients were analyzed according to the treatment assigned. Last Observation Carried Forward (LOCF) imputation was utilized.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Laser
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Laser photocoagulation treatment was administered on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.
Measure Participants	115	118	110
Gain of ≥ 10 letters	43 37.1%	51 43.2%	17 15.3%
Loss of ≥ 10 letters	4 3.4%	5 4.2%	14 12.6%
Gain of ≥ 15 letters	26 22.4%	27 22.9%	9 8.1%
Loss of ≥ 15 letters	1 0.9%	4 3.4%	9 8.1%

3. Secondary Outcome

Title	Core Study: Mean Change From Baseline in Visual Acuity (Letters) of the Study Eye Over Time
Description	Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

Full analysis set, utilizing last observation carried forward.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Laser
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Laser photocoagulation treatment was administered on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.
Measure Participants	115	118	110
Month 1	2.9 (0.49)	3.1 (0.56)	0.5 (0.64)
Month 2	4.4 (0.64)	4.9 (0.56)	0.4 (0.84)
Month 3	5.9 (0.65)	5.8 (0.65)	-0.5 (0.92)
Month 4	5.3 (0.68)	5.4 (0.69)	0.5 (0.92)
Month 5	5.9 (0.68)	5.7 (0.76)	0.9 (0.88)
Month 6	6.7 (0.68)	6.2 (0.78)	0.9 (0.94)
Month 7	7.0 (0.72)	6.5 (0.84)	1.1 (0.98)
Month 8	7.1 (0.75)	6.4 (1.06)	1.3 (0.96)
Month 9	6.8 (0.76)	6.8 (1.05)	1.4 (0.90)
Month 10	7.3 (0.77)	6.4 (1.04)	0.8 (1.00)
Month 11	6.9 (0.79)	6.8 (1.10)	1.4 (0.95)
Month 12	6.8 (0.77)	6.4 (1.08)	0.9 (1.09)

4. Secondary Outcome

Title	Core Study: Mean Change From Baseline at Month 12 in Central Retinal Thickness of the Study Eye
Description	Retinal thickness was measured using Optical Coherence Tomography (OCT). The images were reviewed by a central reading center to ensure a standardized evaluation.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

The number analyzed is the Full Analysis Set, including patients with a value at both baseline and the Month 12 visit. Last Observation Carried Forward imputation was utilized.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Laser
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Laser photocoagulation treatment was administered on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.
Measure Participants	113	116	108
Baseline	427.1 (118.42)	416.4 (119.91)	412.4 (124.53)
Value at Month 12	308.4 (112.26)	288.2 (90.11)	351.1 (139.91)
Change from Baseline	-118.7 (115.07)	-128.3 (114.34)	-61.3 (132.29)

5. Secondary Outcome

Title	Core Study: Mean Change From Baseline in Patient-reported Visual Functioning
Description	The National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) was used to measure a patient's subjective assessment of vision-related quality of life. The 12 subscales in the VFQ-25 are general health, general vision, ocular pain, near activities, distance activities, social function, mental health, role difficulties, dependency, driving, color vision, and peripheral vision. The scores on the subscales were added together for a total score, which ranged from 0 to 100. A higher score indicated improvement in quality of life due to vision function.
Time Frame	Baseline to Month 12

Outcome Measure Data

Analysis Population Description

The number analyzed is the Full Analysis Set, including the number of patients with a value at both baseline and the Month 12 visit. Last Observation Carried Forward imputation was utilized.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Laser
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.	Laser photocoagulation treatment was administered on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes.
Measure Participants	114	116	108
Baseline	72.8 (16.91)	74.1 (18.06)	73.5 (18.18)
Month 12	77.8 (19.19)	79.5 (17.29)	74.1 (18.80)
Change from Baseline	5.0 (12.97)	5.4 (11.14)	0.6 (12.56)

6. Primary Outcome

Title	Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 24 Month Extension Study
Description	Participants with ocular (occurring in the eye) serious adverse events (SAEs) and non-serious AEs in the study eye. The study eye is the eye that received the treatment. AEs are the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.
Time Frame	Extension baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months]

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who entered the extension and who had at least one safety assessment in the extension study. Participants were grouped according to the treatment assigned in the Core study.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Laser With Ranibizumab in Extension	Laser Without Ranibizumab in Extension
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.
Measure Participants	83	83	59	15
Adverse Events	56.6 48.8%	56.6 48%	52.5 47.3%	40.0 11.6%
Serious Adverse Events	2.4 2.1%	1.2 1%	1.7 1.5%	0.0 0%

7. Secondary Outcome

Title	Extension Study: Percentage of Participants With Ocular Adverse Events (AEs) in the Study Eye in the 36 Months of the Core and Extension Studies
Description	Participants with ocular (occurring in the eye) serious adverse events (SAEs) and non-serious AEs in the study eye. The study eye is the eye that received the treatment. AEs are the appearance or worsening of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.
Time Frame	Core baseline (Day 1 of the core study) to Month 36 (end of extension study) [36 months]

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who entered the extension and who had at least one safety assessment in the extension study. Participants were grouped according to the treatment assigned in the Core study.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Laser With Ranibizumab in Extension	Laser Without Ranibizumab in Extension
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.
Measure Participants	83	83	59	15
Adverse Events	66.3 57.2%	67.5 57.2%	64.4 58%	46.7 13.5%
Serious Adverse Events	2.4 2.1%	3.6 3.1%	5.1 4.6%	0.0 0%

8. Secondary Outcome

Title	Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 36 Months of the Core and Extension Studies
Description	Participants with non-ocular (not occurring in the eye) serious adverse events (SAEs) and non-serious AEs. AEs are the appearance or worsening of of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about Adverse Events can be found in the Adverse Event section.
Time Frame	Core baseline (Day 1 of the core study) to Month 36 (end of extension study) [36 Months]

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who entered the extension and who had at least one safety assessment in the extension study. Participants were grouped according to the treatment assigned in the Core study.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Laser With Ranibizumab in Extension	Laser Without Ranibizumab in Extension
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.
Measure Participants	83	83	59	15
Adverse Events	83.1 71.6%	81.9 69.4%	84.7 76.3%	73.3 21.2%
Serious Adverse Events	36.1 31.1%	37.3 31.6%	42.4 38.2%	13.3 3.9%

9. Primary Outcome

Title	Extension Study: Percentage of Participants With Non-Ocular Adverse Events (AEs) in the 24 Month Extension Study
Description	Participants with non-ocular (not occurring in the eye) serious adverse events (SAEs) and non-serious AEs. AEs are the appearance or worsening of of any undesirable sign, symptom, or medical condition occurring after starting the study drug even if the event is not considered to be related to study drug. A serious adverse event is defined as an event that is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization or is medically significant. Additional information about adverse events can be found in the Adverse Event section.
Time Frame	Extension baseline (Month 12 -end of core study) to Month 36 (end of extension study) [24 Months]

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who entered the extension and who had at least one safety assessment in the extension study. Participants were grouped according to the treatment assigned in the Core study.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Laser With Ranibizumab in Extension	Laser Without Ranibizumab in Extension
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.
Measure Participants	83	83	59	15
Adverse Events	73.5 63.4%	73.5 62.3%	71.2 64.1%	73.3 21.2%
Serious Adverse Events	27.7 23.9%	30.1 25.5%	37.3 33.6%	13.3 3.9%

10. Secondary Outcome

Title	Extension Study: Mean Change From Extension Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36
Description	Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. An increase in the number of letters read correctly indicates improvement.
Time Frame	Extension baseline (Month12 -end of core study), Month 36 (end of extension study)

Outcome Measure Data

Analysis Population Description

Participants from the Safety Population that included all participants who entered the extension and who had at least one safety assessment in the extension study with data available for analyses. Participants were grouped according to the treatment assigned in the Core study.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Active Laser
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.
Measure Participants	83	80	74
Mean (Standard Deviation) [Letters]	0.1 (9.10)	-0.5 (9.19)	3.7 (6.88)

11. Secondary Outcome

Title	Extension Study: Mean Change From Core Study Baseline in Best Corrected Visual Acuity (BCVA) at Month 36
Description	Visual acuity (VA) was assessed on both eyes during every study visit using best correction determined from protocol refraction. VA measurements (number of letters correctly identified) were performed with the patient in a sitting position using Early Treatment Diabetic Retinopathy Study (ETDRS)-like visual acuity testing charts at a testing distance of 4 meters. An increase in the number of letters read correctly indicates improvement.
Time Frame	Core baseline (Day 1 of the core study), Month 36 (end of extension study)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who entered the extension and who had at least one safety assessment in the extension study. Participants were grouped according to the treatment assigned in the Core study.

Arm/Group Title	Ranibizumab 0.5 mg	Ranibizumab 0.5 mg + Laser	Active Laser
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.	Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.
Measure Participants	83	83	74
Mean (Standard Deviation) [Letters]	8.0 (10.09)	6.7 (9.59)	6.0 (9.35)

Adverse Events

Adverse Event Reporting Description	Safety Population included all randomized treated participants. Participants are grouped according to the treatment actually received in the Core Study.
Arm/Group Title	Ranibizumab 0.5 mg		Ranibizumab 0.5 mg + Laser		Laser With Ranibizumab in Extension		Laser Without Ranibizumab in Extension
Arm/Group Description	Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received sham laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.		Ranibizumab 0.5 mg was administered monthly by intravitreal injection in the study eye for 3 months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Patients also received active laser treatment on Day 1 and subsequently at intervals of at least 3 months, if deemed necessary by the evaluating physician. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy		Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.		Active laser photocoagulation treatment was administered on Day 1 and at intervals of at least 3 months, if deemed necessary by the evaluating physician. Patients also received monthly sham intravitreal injection in the study eye for 3 consecutive months. After the third injection, treatment was suspended if either one of the following criteria was met: Improvement in best corrected visual acuity (BCVA) could not be attributed to treatment at the last 2 visits, in the opinion of the investigator, or BCVA > 84 letters (approximate Snellen equivalent of 20/20) was observed at the last 2 last visits. Active/sham laser treatment was always administered before (sham) intravitreal injections. The minimum interval between the 2 treatments was 30 minutes. In the extension study at the investigator's discretion, patients received open-label ranibizumab 0.5 mg intravitreal injections once a month until stable vision was reached (a maximum of 24 injections) and could receive laser therapy.
All Cause Mortality
	Ranibizumab 0.5 mg		Ranibizumab 0.5 mg + Laser		Laser With Ranibizumab in Extension		Laser Without Ranibizumab in Extension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ranibizumab 0.5 mg		Ranibizumab 0.5 mg + Laser		Laser With Ranibizumab in Extension		Laser Without Ranibizumab in Extension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/115 (35.7%)		43/120 (35.8%)		28/59 (47.5%)		7/51 (13.7%)
Blood and lymphatic system disorders
Anaemia	1/115 (0.9%)		1/120 (0.8%)		1/59 (1.7%)		0/51 (0%)
Febrile neutropenia	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Hypochromic anaemia	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Lymphadenopathy	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Spleen disorder	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Splenic infarction	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Cardiac disorders
Acute myocardial infarction	1/115 (0.9%)		0/120 (0%)		2/59 (3.4%)		0/51 (0%)
Angina pectoris	3/115 (2.6%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Angina unstable	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Aortic valve stenosis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Arrhythmia	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Atrial fibrillation	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Cardiac disorder	0/115 (0%)		0/120 (0%)		0/59 (0%)		1/51 (2%)
Cardiac failure	1/115 (0.9%)		1/120 (0.8%)		4/59 (6.8%)		1/51 (2%)
Cardiac failure congestive	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Cardiogenic shock	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Cardiopulmonary failure	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Coronary artery disease	3/115 (2.6%)		1/120 (0.8%)		1/59 (1.7%)		0/51 (0%)
Coronary artery occlusion	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Mitral valve incompetence	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Myocardial infarction	1/115 (0.9%)		4/120 (3.3%)		3/59 (5.1%)		0/51 (0%)
Myocardial ischaemia	1/115 (0.9%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Right ventricular failure	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Tachyarrhythmia	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Congenital, familial and genetic disorders
Spinocerebellar ataxia	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Ear and labyrinth disorders
Deafness	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Vertigo	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Eye disorders
Cataract (Fellow eye)	2/115 (1.7%)		1/120 (0.8%)		1/59 (1.7%)		0/51 (0%)
Cataract (Study eye)	0/115 (0%)		3/120 (2.5%)		2/59 (3.4%)		0/51 (0%)
Cataract subcapsular (Fellow eye)	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Conjunctival haemorrhage (Study eye)	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Corneal oedema (Study eye)	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Diabetic retinal oedema (Fellow eye)	1/115 (0.9%)		1/120 (0.8%)		1/59 (1.7%)		0/51 (0%)
Lenticular opacities (Study eye)	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Vitreous adhesions (Study eye)	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Vitreous haemorrhage (Fellow eye)	2/115 (1.7%)		0/120 (0%)		1/59 (1.7%)		1/51 (2%)
Vitreous haemorrhage (Study eye)	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Gastrointestinal disorders
Abdominal hernia	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Abdominal pain	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Abdominal pain upper	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Colonic polyp	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Constipation	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Diarrhoea	0/115 (0%)		1/120 (0.8%)		1/59 (1.7%)		0/51 (0%)
Gastric haemorrhage	0/115 (0%)		0/120 (0%)		0/59 (0%)		1/51 (2%)
Gastric ulcer	0/115 (0%)		0/120 (0%)		0/59 (0%)		1/51 (2%)
Gastrointestinal necrosis	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Gastrointestinal obstruction	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Hernial eventration	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Intestinal obstruction	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Nausea	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Oesophagitis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Pancreatitis acute	0/115 (0%)		0/120 (0%)		0/59 (0%)		1/51 (2%)
Subileus	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Umbilical hernia	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Vomiting	1/115 (0.9%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
General disorders
Chest discomfort	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Malaise	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Multi-organ failure	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Oedema peripheral	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Polyserositis	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Pyrexia	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Hepatobiliary disorders
Bile duct obstruction	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Cholecystitis	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Cholelithiasis	1/115 (0.9%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Hepatic function abnormal	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Infections and infestations
Appendicitis	2/115 (1.7%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Biliary sepsis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Bronchitis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Cellulitis	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Cholecystitis infective	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Gas gangrene	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Gastroenteritis	1/115 (0.9%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Gastroenteritis norovirus	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Infection	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Localised infection	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Lower respiratory tract infection	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Mediastinitis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Osteomyelitis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Otitis media	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Pneumonia	0/115 (0%)		1/120 (0.8%)		3/59 (5.1%)		0/51 (0%)
Pneumonia cytomegaloviral	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Pseudomonas infection	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Sepsis	1/115 (0.9%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Soft tissue infection	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Staphylococcal infection	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Systemic candida	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Urinary tract infection	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Injury, poisoning and procedural complications
Back injury	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Contusion	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Coronary artery restenosis	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Eye injury (Fellow eye)	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Eye injury (Study eye)	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Eyelid injury (Study eye)	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Fall	3/115 (2.6%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Femoral neck fracture	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Femur fracture	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Head injury	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Lower limb fracture	1/115 (0.9%)		2/120 (1.7%)		0/59 (0%)		0/51 (0%)
Lumbar vertebral fracture	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Meniscus lesion	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Open wound	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Periorbital haematoma (Study eye)	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Post procedural complication	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Radius fracture	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Road traffic accident	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Spinal cord injury	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Tendon rupture	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Investigations
Blood calcium increased	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Blood glucose increased	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Blood urea increased	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Body temperature decreased	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Metabolism and nutrition disorders
Dehydration	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Diabetes mellitus	0/115 (0%)		2/120 (1.7%)		0/59 (0%)		0/51 (0%)
Diabetic foot	2/115 (1.7%)		0/120 (0%)		3/59 (5.1%)		1/51 (2%)
Hyperglycaemia	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Hyperkalaemia	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Hyperuricaemia	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Hypoglycaemia	1/115 (0.9%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Obesity	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Type 2 diabetes mellitus	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/115 (0%)		3/120 (2.5%)		1/59 (1.7%)		0/51 (0%)
Lumbar spinal stenosis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Osteoarthritis	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Osteochondrosis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Spinal column stenosis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Spinal osteoarthritis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Spondylolisthesis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Gastric cancer	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Hepatic neoplasm	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Malignant neoplasm of ampulla of Vater	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Multiple myeloma	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Pancreatic carcinoma	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Prostate cancer	1/115 (0.9%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Rectal cancer	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Renal cancer	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Urethral neoplasm	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Uterine leiomyoma	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Nervous system disorders
Carotid artery stenosis	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		1/51 (2%)
Cerebral artery embolism	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Cerebrovascular accident	3/115 (2.6%)		1/120 (0.8%)		1/59 (1.7%)		0/51 (0%)
Cerebrovascular disorder	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Diabetic neuropathy	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Dizziness	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Embolic stroke	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Hepatic encephalopathy	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Loss of consciousness	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Subarachnoid haemorrhage	2/115 (1.7%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Syncope	1/115 (0.9%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Transient ischaemic attack	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Psychiatric disorders
Depression	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Renal and urinary disorders
Acute prerenal failure	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Bladder prolapse	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Calculus urinary	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Nephrolithiasis	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Polyuria	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Renal colic	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Renal failure	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Renal failure acute	1/115 (0.9%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Renal failure chronic	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		1/51 (2%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/115 (0.9%)		1/120 (0.8%)		1/59 (1.7%)		0/51 (0%)
Epistaxis	2/115 (1.7%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Nasal septum deviation	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Pulmonary embolism	2/115 (1.7%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Pulmonary haematoma	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Pulmonary oedema	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Respiratory arrest	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Sleep apnoea syndrome	0/115 (0%)		0/120 (0%)		0/59 (0%)		1/51 (2%)
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Dermatitis	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Skin hypertrophy	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Skin ulcer	0/115 (0%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Vascular disorders
Arterial thrombosis limb	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Deep vein thrombosis	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Hypertension	1/115 (0.9%)		2/120 (1.7%)		1/59 (1.7%)		0/51 (0%)
Hypertensive crisis	0/115 (0%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Hypotension	1/115 (0.9%)		0/120 (0%)		1/59 (1.7%)		0/51 (0%)
Peripheral arterial occlusive disease	1/115 (0.9%)		1/120 (0.8%)		1/59 (1.7%)		0/51 (0%)
Varicose vein	1/115 (0.9%)		0/120 (0%)		0/59 (0%)		0/51 (0%)
Other (Not Including Serious) Adverse Events
	Ranibizumab 0.5 mg		Ranibizumab 0.5 mg + Laser		Laser With Ranibizumab in Extension		Laser Without Ranibizumab in Extension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	79/115 (68.7%)		83/120 (69.2%)		50/59 (84.7%)		31/51 (60.8%)
Blood and lymphatic system disorders
Anaemia	2/115 (1.7%)		6/120 (5%)		3/59 (5.1%)		1/51 (2%)
Eye disorders
Blepharitis (Fellow eye)	1/115 (0.9%)		1/120 (0.8%)		3/59 (5.1%)		1/51 (2%)
Cataract (Fellow eye)	10/115 (8.7%)		12/120 (10%)		7/59 (11.9%)		5/51 (9.8%)
Cataract (Study eye)	9/115 (7.8%)		17/120 (14.2%)		9/59 (15.3%)		4/51 (7.8%)
Conjunctival haemorrhage (Study eye)	9/115 (7.8%)		13/120 (10.8%)		0/59 (0%)		0/51 (0%)
Conjunctival hyperaemia (Study eye)	9/115 (7.8%)		8/120 (6.7%)		5/59 (8.5%)		2/51 (3.9%)
Conjunctivitis (Fellow eye)	4/115 (3.5%)		6/120 (5%)		3/59 (5.1%)		1/51 (2%)
Diabetic retinal oedema (Fellow eye)	12/115 (10.4%)		19/120 (15.8%)		11/59 (18.6%)		3/51 (5.9%)
Diabetic retinal oedema (Study eye)	7/115 (6.1%)		6/120 (5%)		3/59 (5.1%)		1/51 (2%)
Diabetic retinopathy (Fellow eye)	4/115 (3.5%)		6/120 (5%)		4/59 (6.8%)		2/51 (3.9%)
Diabetic retinopathy (Study eye)	3/115 (2.6%)		8/120 (6.7%)		3/59 (5.1%)		2/51 (3.9%)
Dry eye (Fellow eye)	5/115 (4.3%)		4/120 (3.3%)		3/59 (5.1%)		3/51 (5.9%)
Dry eye (Study eye)	5/115 (4.3%)		4/120 (3.3%)		3/59 (5.1%)		3/51 (5.9%)
Eye discharge (Study eye)	4/115 (3.5%)		6/120 (5%)		1/59 (1.7%)		1/51 (2%)
Eye haemorrhage (Fellow eye)	2/115 (1.7%)		3/120 (2.5%)		3/59 (5.1%)		0/51 (0%)
Eye haemorrhage (Study eye)	2/115 (1.7%)		3/120 (2.5%)		3/59 (5.1%)		0/51 (0%)
Eye irritation (Study eye)	3/115 (2.6%)		2/120 (1.7%)		3/59 (5.1%)		0/51 (0%)
Eye pain (Study eye)	15/115 (13%)		11/120 (9.2%)		13/59 (22%)		2/51 (3.9%)
Eye pruritus (Study eye)	3/115 (2.6%)		3/120 (2.5%)		5/59 (8.5%)		1/51 (2%)
Foreign body sensation in eyes (Study eye)	5/115 (4.3%)		8/120 (6.7%)		2/59 (3.4%)		0/51 (0%)
Lacrimation increased (Study eye)	3/115 (2.6%)		6/120 (5%)		5/59 (8.5%)		0/51 (0%)
Macular fibrosis (Study eye)	2/115 (1.7%)		2/120 (1.7%)		5/59 (8.5%)		0/51 (0%)
Punctate keratitis (Fellow eye)	1/115 (0.9%)		6/120 (5%)		0/59 (0%)		0/51 (0%)
Retinal aneurysm (Study eye)	0/115 (0%)		3/120 (2.5%)		3/59 (5.1%)		1/51 (2%)
Retinal exudates (Fellow eye)	7/115 (6.1%)		3/120 (2.5%)		3/59 (5.1%)		1/51 (2%)
Retinal exudates (Study eye)	4/115 (3.5%)		2/120 (1.7%)		5/59 (8.5%)		1/51 (2%)
Retinal haemorrhage (Fellow eye)	4/115 (3.5%)		8/120 (6.7%)		2/59 (3.4%)		0/51 (0%)
Vision blurred (Study eye)	2/115 (1.7%)		4/120 (3.3%)		3/59 (5.1%)		2/51 (3.9%)
Visual acuity reduced (Fellow eye)	4/115 (3.5%)		3/120 (2.5%)		3/59 (5.1%)		2/51 (3.9%)
Visual acuity reduced (Study eye)	1/115 (0.9%)		2/120 (1.7%)		1/59 (1.7%)		3/51 (5.9%)
Vitreous haemorrhage (Study eye)	1/115 (0.9%)		1/120 (0.8%)		3/59 (5.1%)		0/51 (0%)
Gastrointestinal disorders
Gastrooesophageal reflux disease	3/115 (2.6%)		0/120 (0%)		3/59 (5.1%)		0/51 (0%)
Nausea	6/115 (5.2%)		5/120 (4.2%)		2/59 (3.4%)		3/51 (5.9%)
Vomiting	2/115 (1.7%)		1/120 (0.8%)		2/59 (3.4%)		3/51 (5.9%)
Infections and infestations
Bronchitis	6/115 (5.2%)		4/120 (3.3%)		1/59 (1.7%)		2/51 (3.9%)
Influenza	12/115 (10.4%)		8/120 (6.7%)		8/59 (13.6%)		5/51 (9.8%)
Nasopharyngitis	18/115 (15.7%)		21/120 (17.5%)		15/59 (25.4%)		8/51 (15.7%)
Pneumonia	2/115 (1.7%)		2/120 (1.7%)		0/59 (0%)		3/51 (5.9%)
Injury, poisoning and procedural complications
Fall	4/115 (3.5%)		5/120 (4.2%)		4/59 (6.8%)		1/51 (2%)
Investigations
Blood glucose increased	1/115 (0.9%)		3/120 (2.5%)		3/59 (5.1%)		1/51 (2%)
Intraocular pressure increased (Fellow eye)	3/115 (2.6%)		6/120 (5%)		0/59 (0%)		1/51 (2%)
Musculoskeletal and connective tissue disorders
Arthralgia	6/115 (5.2%)		1/120 (0.8%)		3/59 (5.1%)		0/51 (0%)
Back pain	7/115 (6.1%)		5/120 (4.2%)		8/59 (13.6%)		1/51 (2%)
Muscle spasms	0/115 (0%)		1/120 (0.8%)		4/59 (6.8%)		0/51 (0%)
Pain in extremity	6/115 (5.2%)		1/120 (0.8%)		0/59 (0%)		0/51 (0%)
Nervous system disorders
Dizziness	2/115 (1.7%)		2/120 (1.7%)		3/59 (5.1%)		1/51 (2%)
Headache	4/115 (3.5%)		5/120 (4.2%)		5/59 (8.5%)		1/51 (2%)
Renal and urinary disorders
Renal failure	1/115 (0.9%)		2/120 (1.7%)		4/59 (6.8%)		1/51 (2%)
Respiratory, thoracic and mediastinal disorders
Cough	3/115 (2.6%)		4/120 (3.3%)		4/59 (6.8%)		1/51 (2%)
Vascular disorders
Hypertension	15/115 (13%)		11/120 (9.2%)		6/59 (10.2%)		6/51 (11.8%)

Limitations/Caveats

[Not Specified]

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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.