A Study of the Efficacy and Safety of Ranibizumab Injection in Patients With Macular Edema Secondary to Central Retinal Vein Occlusion (CRUISE)

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00485836
• Collaborator: (none)
• Enrollment: 392
• Arms: 3
• Duration (Months): 29

Study Details

Study Description

Brief Summary

This was a Phase III, multicenter, randomized, double-masked, sham injection-controlled study of the efficacy and safety of intravitreal ranibizumab compared with sham injections in patients with macular edema secondary to central retinal vein occlusion (CRVO); 392 patients with CRVO were enrolled at 95 investigational sites in the United States. The study included a treatment period (6 months) and an observation period (6 months).

Condition or Disease	Intervention/Treatment	Phase
Macular Edema; Retinal Vein Occlusion	Drug: Sham injection; Drug: Ranibizumab injection 0.3 mg; Drug: Ranibizumab injection 0.5 mg	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 392 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Multicenter, Randomized, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab Injection Compared With Sham in Subjects With Macular Edema Secondary to Central Retinal Vein Occlusion
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Sham Comparator: Sham injection	Drug: Sham injection; Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.; Other Names: Lucentis
Experimental: Ranibizumab injection 0.3 mg	Drug: Ranibizumab injection 0.3 mg; Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
Experimental: Ranibizumab injection 0.5 mg	Drug: Ranibizumab injection 0.5 mg; Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.; Other Names: Lucentis

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at 6 Months [Baseline and 6 months]

   BCVA score in the study eye was based on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters.

Secondary Outcome Measures

1. Percentage of Participants Who Gained ≥ 15 Letters in BCVA Score at Month 6 Compared With Baseline [Baseline and 6 months]

   BCVA score based on the ETDRS visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters.

2. Percentage of Participants Who Lost < 15 Letters in BCVA Score at Month 6 Compared With Baseline [Baseline and 6 months]

   BCVA score based on the ETDRS visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters.

3. Percentage of Participants With a Central Foveal Thickness of ≤ 250 μm at Month 6 [6 months]

   A central reading center assessed all optical coherence tomography (OCT) images. Central foveal thickness was defined as the center point thickness.

4. Mean Absolute Change From Baseline in Central Foveal Thickness at Month 6 [Baseline and 6 months]

   A central reading center assessed all OCT images. Central foveal thickness was defined as the center point thickness.

5. Mean Change From Baseline in the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) Near Activities Subscale Score at Month 6 [Baseline and 6 months]

   The NEI VFQ-25 (v. 2000; Interviewer Format) consisted of the base set of 25 questions, plus the optional additional questions (where questions A3, A4, and A5 pertained to the Near Activities Subscale). Scores ranged from 0 to 100; a higher score represented better functioning.

6. Mean Change From Baseline in the NEI VFQ-25 Distance Activities Subscale Score at Month 6 [Baseline and 6 months]

   The NEI VFQ-25 (v. 2000; Interviewer Format) consisted of the base set of 25 questions, plus the optional additional questions (where questions A6, A7, and A8 pertained to the Distance Activities Subscale). Scores ranged from 0 to 100; a higher score represented better functioning.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Willingness to provide signed Informed Consent Form

• Age ≥ 18 years

• For sexually active women of childbearing potential, use of an appropriate form of contraception (or abstinence) for the duration of the study

• Ability and willingness to return for all scheduled visits and assessments

Ocular Inclusion Criterion (Study Eye):

• Foveal center-involved macular edema secondary to CRVO

• BCVA using ETDRS charts of 20/40 to 20/320 (Snellen equivalent)

• Mean central subfield thickness ≥ 250 μm on two optical coherence tomography (OCT) measurements (at screening [confirmed by the central reading center] and Day 0 [confirmed by the evaluating physician])

• Media clarity, pupillary dilation, and participant cooperation sufficient to obtain adequate fundus photographs

Exclusion Criteria:

• History of cerebral vascular accident or myocardial infarction within 3 months prior to Day 0

• History of any anti-vascular endothelial growth factor (VEGF) or treatment in the fellow eye within 3 months prior to Day 0

• History of any systemic anti-VEGF or pro-VEGF treatment within 6 months prior to Day 0

• History of allergy to fluorescein

• History of allergy to ranibizumab injection or related molecule

• Relevant systemic disease that may be associated with increased systemic VEGF levels (namely, all active malignancies); history of successfully treated malignancies is not an exclusion criterion.

• Uncontrolled blood pressure

• Pregnancy or lactation

• Any condition that, in the opinion of the investigator, would preclude participation in the study (e.g., chronic alcoholism or drug abuse, personality disorder or use of major tranquilizers, indicated difficulty in long-term follow-up, and likelihood of survival of less than 1 year)

• Participation in an investigational trial within 30 days prior to Day 0 that involved treatment with any drug (excluding vitamins and minerals) or device that has not received regulatory approval at time of study entry

Ocular Exclusion Criteria (Study Eye):

• Prior episode of retinal vein occlusion (RVO)

• Brisk afferent pupillary defect

• History of radial optic neurotomy or sheathotomy

• History or presence of age-related macular degeneration (AMD; dry or wet form)

• History of any anti-VEGF treatment in the study eye within 3 months prior to Day 0

• History of laser photocoagulation for macular edema within 4 months prior to Day 0

• History of panretinal scatter photocoagulation or sector laser photocoagulation within 3 months prior to randomization or anticipated within the next 4 months following randomization

• History of intraocular corticosteroid use within 3 months prior to Day 0

• History of pars plana vitrectomy

• History of intraocular surgery (including cataract extraction, scleral buckle, etc.) within 2 months prior to Day 0 or anticipated within the next 7 months following Day 0

• History of yttrium-aluminum-garnet capsulotomy performed within 2 months prior to Day 0

• Previous filtration surgery in the study eye

• History of herpetic ocular infection

• History of ocular toxoplasmosis

• History of rhegmatogenous retinal detachment

• History of idiopathic central serous chorioretinopathy

• Evidence upon examination of vitreoretinal interface disease (e.g., vitreomacular traction, epiretinal membrane), either on clinical examination or OCT, thought to be contributing to macular edema

• An eye that, in the investigator's opinion, would not benefit from resolution of macular edema, such as eyes with foveal atrophy, dense pigmentary changes, or dense subfoveal hard exudates

• Presence of an ocular condition that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the study (e.g., uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass syndrome, or prior macula-off rhegmatogenous retinal detachment)

• Visually significant hemorrhage obscuring the fovea and felt to be a major contributor to reduced visual acuity

• Presence of a substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e., a 20/40 cataract)

• Aphakia

• Relevant ocular disease that may be associated with increased intraocular VEGF levels (namely, uveitis, neovascular glaucoma, neovascular AMD, diabetic retinopathy, diabetic maculopathy, or ocular ischemic syndrome)

• Improvement of > 10 letters on best corrected visual acuity (BCVA) between screening and Day 0

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Roman Rubio, M.D., Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT00485836
• Other Study ID Numbers: FVF4166g
• First Posted: Jun 13, 2007
• Last Update Posted: Jul 28, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by Genentech, Inc.: CRVO; RVO; Lucentis; Edema
• Additional relevant MeSH terms: Macular Edema; Retinal Vein Occlusion; Edema; Ranibizumab

Study Results

Participant Flow

Recruitment Details	Please note that although the table below is titled "Overall Study," the completion rates are for the 6-month Treatment Period only (i.e., does not include the 6-month Observation Period data).

Arm/Group Title	Sham Injection	Ranibizumab Injection 0.3 mg	Ranibizumab Injection 0.5 mg
Arm/Group Description	Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.	Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.	Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
Period Title: Overall Study
STARTED	130	132	130
Received Study Drug (Safety Population)	129	132	129
COMPLETED	115	129	119
NOT COMPLETED	15	3	11

Baseline Characteristics

Arm/Group Title	Sham Injection	Ranibizumab Injection 0.3 mg	Ranibizumab Injection 0.5 mg	Total
Arm/Group Description	Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.	Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.	Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.	Total of all reporting groups
Overall Participants	130	132	130	392
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.4 (13.1)	69.7 (11.6)	67.6 (12.4)	67.6 (12.5)
Age, Customized (participants) [Number]
< 45 years	10 7.7%	5 3.8%	5 3.8%	20 5.1%
45 to < 65 years	50 38.5%	36 27.3%	46 35.4%	132 33.7%
65 to < 85 years	67 51.5%	80 60.6%	71 54.6%	218 55.6%
≥ 85 years	3 2.3%	11 8.3%	8 6.2%	22 5.6%
Sex: Female, Male (Count of Participants)
Female	58 44.6%	61 46.2%	50 38.5%	169 43.1%
Male	72 55.4%	71 53.8%	80 61.5%	223 56.9%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at 6 Months
Description	BCVA score in the study eye was based on the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Intent to treat (randomized) population. Missing values were imputed using the last-observation-carried-forward (LOCF) method.

Arm/Group Title	Sham Injection	Ranibizumab Injection 0.3 mg	Ranibizumab Injection 0.5 mg
Arm/Group Description	Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.	Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.	Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
Measure Participants	130	132	130
Baseline	49.2 (14.7)	47.4 (14.8)	48.1 (14.6)
Mean Change from Baseline at Month 6	0.8 (16.2)	12.7 (15.9)	14.9 (13.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.3 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The Hochberg-Bonferroni multiple comparison procedure was used to adjust for comparisons of the two ranibizumab groups with the sham-injection group to maintain an overall type I error rate of 0.05.
	Method	ANOVA
	Comments	Stratified by baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters).
Method of Estimation	Estimation Parameter	Difference in Least Squares means
	Estimated Value	11.5
	Confidence Interval	() 95%; 7.7 to 15.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The Hochberg-Bonferroni multiple comparison procedure was used to adjust for comparisons of the two ranibizumab groups with the sham-injection group to maintain an overall type I error rate of 0.05.
	Method	ANOVA
	Comments	Stratified by baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters).
Method of Estimation	Estimation Parameter	Difference in Least Squares means
	Estimated Value	13.8
	Confidence Interval	() 95%; 10.3 to 17.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants Who Gained ≥ 15 Letters in BCVA Score at Month 6 Compared With Baseline
Description	BCVA score based on the ETDRS visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Intent to treat (randomized) population. Missing values were imputed using the LOCF method.

Arm/Group Title	Sham Injection	Ranibizumab Injection 0.3 mg	Ranibizumab Injection 0.5 mg
Arm/Group Description	Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.	Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.	Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
Measure Participants	130	132	130
Number (95% Confidence Interval) [Percentage of participants]	16.9 13%	46.2 35%	47.7 36.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.3 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel χ²
	Comments	Stratified by baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters).
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	29.3
	Confidence Interval	() 95%; 18.8 to 39.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Weighted estimates adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) using Cochran-Mantel-Haenszel weights.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel χ²
	Comments	Stratified by baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters).
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	30.3
	Confidence Interval	() 95%; 19.6 to 40.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Weighted estimates adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) using Cochran-Mantel-Haenszel weights.

3. Secondary Outcome

Title	Percentage of Participants Who Lost < 15 Letters in BCVA Score at Month 6 Compared With Baseline
Description	BCVA score based on the ETDRS visual acuity charts (number of correct letters) and assessed at a starting distance of 4 meters.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Intent to treat (randomized) population. Missing values were imputed using the LOCF method.

Arm/Group Title	Sham Injection	Ranibizumab Injection 0.3 mg	Ranibizumab Injection 0.5 mg
Arm/Group Description	Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.	Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.	Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
Measure Participants	130	132	130
Number (95% Confidence Interval) [Percentage of participants]	84.6 65.1%	96.2 72.9%	98.5 75.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.3 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	Cochran-Mantel-Haenszel χ²
	Comments	Stratified by baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters).
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	11.3
	Confidence Interval	() 95%; 4.3 to 18.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Weighted estimates adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) using Cochran-Mantel-Haenszel weights.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel χ²
	Comments	Stratified by baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters).
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	13.6
	Confidence Interval	() 95%; 7.2 to 20.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Weighted estimates adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) using Cochran-Mantel-Haenszel weights.

4. Secondary Outcome

Title	Percentage of Participants With a Central Foveal Thickness of ≤ 250 μm at Month 6
Description	A central reading center assessed all optical coherence tomography (OCT) images. Central foveal thickness was defined as the center point thickness.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Intent to treat (randomized) population. Missing values were imputed using the LOCF method.

Arm/Group Title	Sham Injection	Ranibizumab Injection 0.3 mg	Ranibizumab Injection 0.5 mg
Arm/Group Description	Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.	Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.	Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
Measure Participants	130	132	130
Number (95% Confidence Interval) [Percentage of participants]	23.1 17.8%	75.0 56.8%	76.9 59.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.3 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel χ²
	Comments	Stratified by baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters).
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	51.9
	Confidence Interval	() 95%; 41.6 to 62.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Weighted estimates adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) using Cochran-Mantel-Haenszel weights.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel χ²
	Comments	Stratified by baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters).
Method of Estimation	Estimation Parameter	Difference in percentage
	Estimated Value	54.0
	Confidence Interval	() 95%; 44.0 to 64.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Weighted estimates adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) using Cochran-Mantel-Haenszel weights.

5. Secondary Outcome

Title	Mean Absolute Change From Baseline in Central Foveal Thickness at Month 6
Description	A central reading center assessed all OCT images. Central foveal thickness was defined as the center point thickness.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Intent to treat (randomized) population. Missing values were imputed using the LOCF method.

Arm/Group Title	Sham Injection	Ranibizumab Injection 0.3 mg	Ranibizumab Injection 0.5 mg
Arm/Group Description	Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.	Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.	Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
Measure Participants	129	131	130
Baseline	687.0 (237.6)	679.9 (242.2)	688.7 (253.1)
Mean Absolute Change from Baseline at Month 6	-167.7 (308.4)	-433.7 (295.9)	-452.3 (257.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.3 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Pairwise ANCOVA models adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) and baseline value of central foveal thickness.
Method of Estimation	Estimation Parameter	Difference in Least Squares means
	Estimated Value	-272.2
	Confidence Interval	() 95%; -329.9 to -214.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	Pairwise ANCOVA models adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) and baseline value of central foveal thickness.
Method of Estimation	Estimation Parameter	Difference in Least Squares means
	Estimated Value	-283.8
	Confidence Interval	() 95%; -337.8 to -229.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Mean Change From Baseline in the National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) Near Activities Subscale Score at Month 6
Description	The NEI VFQ-25 (v. 2000; Interviewer Format) consisted of the base set of 25 questions, plus the optional additional questions (where questions A3, A4, and A5 pertained to the Near Activities Subscale). Scores ranged from 0 to 100; a higher score represented better functioning.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Intent to treat (randomized) population; however, patients without a baseline score were excluded from analysis.

Arm/Group Title	Sham Injection	Ranibizumab Injection 0.3 mg	Ranibizumab Injection 0.5 mg
Arm/Group Description	Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.	Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.	Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
Measure Participants	127	130	128
Baseline at Month 6	69.9 (22.6)	71.2 (22.2)	70.7 (20.3)
Change from baseline at Month 6	5.1 (17.1)	10.2 (17.4)	9.3 (18.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.3 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0019
	Comments
	Method	ANCOVA
	Comments	Pairwise ANCOVA models adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) and baseline Near Activities Subscale score.
Method of Estimation	Estimation Parameter	Difference in Least Squares means
	Estimated Value	5.8
	Confidence Interval	() 95%; 2.1 to 9.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0099
	Comments
	Method	ANCOVA
	Comments	Pairwise ANCOVA models adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) and baseline Near Activities Subscale score.
Method of Estimation	Estimation Parameter	Difference in Least Squares means
	Estimated Value	4.9
	Confidence Interval	() 95%; 1.2 to 8.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Mean Change From Baseline in the NEI VFQ-25 Distance Activities Subscale Score at Month 6
Description	The NEI VFQ-25 (v. 2000; Interviewer Format) consisted of the base set of 25 questions, plus the optional additional questions (where questions A6, A7, and A8 pertained to the Distance Activities Subscale). Scores ranged from 0 to 100; a higher score represented better functioning.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

Intent to treat (randomized) population; however, patients without a baseline score were excluded from analysis.

Arm/Group Title	Sham Injection	Ranibizumab Injection 0.3 mg	Ranibizumab Injection 0.5 mg
Arm/Group Description	Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.	Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.	Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
Measure Participants	127	130	128
Baseline at Month 6	77.0 (22.5)	77.3 (19.8)	77.0 (19.7)
Change from baseline at Month 6	2.8 (15.6)	8.9 (13.7)	6.7 (16.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.3 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANCOVA
	Comments	Pairwise ANCOVA models adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) and baseline Distance Activities Subscale score.
Method of Estimation	Estimation Parameter	Difference in Least Squares means
	Estimated Value	6.3
	Confidence Interval	() 95%; 3.1 to 9.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, Ranibizumab Injection 0.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0199
	Comments
	Method	ANCOVA
	Comments	Pairwise ANCOVA models adjusted for baseline visual acuity score (≤ 34, 35-54, ≥ 55 letters) and baseline Distance Activities Subscale score.
Method of Estimation	Estimation Parameter	Difference in Least Squares means
	Estimated Value	4.1
	Confidence Interval	() 95%; 0.7 to 7.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	Investigators assessed the occurrence of AE/SAEs at all study visits. Summaries are for the safety-evaluable population and include events regardless of relation to study drug or location (e.g. non-study eye events are included). For each AE/SAE, the number of patients experiencing the event, not the number of occurrences of the event, is reported.
Arm/Group Title	Sham Injection		Ranibizumab Injection 0.3 mg		Ranibizumab Injection 0.5 mg
Arm/Group Description	Sham injection in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six sham injections.		Ranibizumab injection 0.3 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.		Ranibizumab injection 0.5 mg in a single-dose regimen given every month (Day 0 through the Month 5 visit), for a total of six injections.
All Cause Mortality
	Sham Injection		Ranibizumab Injection 0.3 mg		Ranibizumab Injection 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Sham Injection		Ranibizumab Injection 0.3 mg		Ranibizumab Injection 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/129 (10.1%)		16/132 (12.1%)		13/129 (10.1%)
Cardiac disorders
Cardiomyopathy	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Arteriosclerosis Coronary Artery	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Coronary Artery Disease	2/129 (1.6%)		1/132 (0.8%)		1/129 (0.8%)
Cardiac Failure Congestive	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Acute Coronary Syndrome	1/129 (0.8%)		0/132 (0%)		0/129 (0%)
Angina Pectoris	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Myocardial Infarction	0/129 (0%)		1/132 (0.8%)		1/129 (0.8%)
Atrial Fibrillation	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Supraventricular Tachycardia	1/129 (0.8%)		0/132 (0%)		0/129 (0%)
Endocrine disorders
Inappropriate Antidiuretic Hormone Secretion	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Eye disorders
Blindness Unilateral	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Vitreous Hemorrhage	1/129 (0.8%)		0/132 (0%)		0/129 (0%)
Corneal Edema	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Iris Neovascularization	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Retinal Disorder	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Macular Ischemia	1/129 (0.8%)		0/132 (0%)		0/129 (0%)
Retinal Artery Occlusion	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Retinal Vascular Disorder	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Retinal Vascular Occlusion	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Retinal Vein Occlusion	2/129 (1.6%)		1/132 (0.8%)		1/129 (0.8%)
Maculopathy	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Retinal Depigmentation	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Macular Edema	2/129 (1.6%)		2/132 (1.5%)		0/129 (0%)
Gastrointestinal disorders
Colitis	0/129 (0%)		1/132 (0.8%)		1/129 (0.8%)
Umbilical Hernia	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
General disorders
Chest Pain	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Immune system disorders
Food Allergy	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Infections and infestations
Diverticulitis	1/129 (0.8%)		0/132 (0%)		1/129 (0.8%)
Cellulitis	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Bronchitis	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Injury, poisoning and procedural complications
Lead Dislodgement	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Hip Fracture	1/129 (0.8%)		0/132 (0%)		0/129 (0%)
Humerus Fracture	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Metabolism and nutrition disorders
Hyponatremia	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Musculoskeletal and connective tissue disorders
Spinal Osteoarthritis	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Lumbar Spinal Stenosis	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon Cancer	1/129 (0.8%)		0/132 (0%)		0/129 (0%)
Gastric Cancer	1/129 (0.8%)		0/132 (0%)		0/129 (0%)
Uterine Leiomyoma	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Nervous system disorders
Syncope	0/129 (0%)		2/132 (1.5%)		0/129 (0%)
Transient Ischemic Attack	0/129 (0%)		0/132 (0%)		1/129 (0.8%)
Renal and urinary disorders
Urinary Retention	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Renal Failure Acute	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Vascular disorders
Venous Occlusion	1/129 (0.8%)		0/132 (0%)		0/129 (0%)
Deep Vein Thrombosis	0/129 (0%)		1/132 (0.8%)		0/129 (0%)
Hypertension	1/129 (0.8%)		0/132 (0%)		0/129 (0%)
Other (Not Including Serious) Adverse Events
	Sham Injection		Ranibizumab Injection 0.3 mg		Ranibizumab Injection 0.5 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	116/129 (89.9%)		113/132 (85.6%)		111/129 (86%)
Eye disorders
Conjunctival Hemorrhage	43/129 (33.3%)		57/132 (43.2%)		53/129 (41.1%)
Eye Irritation	6/129 (4.7%)		6/132 (4.5%)		10/129 (7.8%)
Eye Pain	14/129 (10.9%)		12/132 (9.1%)		24/129 (18.6%)
Foreign Body Sensation in Eyes	5/129 (3.9%)		4/132 (3%)		9/129 (7%)
Iris Neovascularization	9/129 (7%)		2/132 (1.5%)		1/129 (0.8%)
Macular Edema	11/129 (8.5%)		7/132 (5.3%)		4/129 (3.1%)
Maculopathy	13/129 (10.1%)		21/132 (15.9%)		19/129 (14.7%)
Myodesopsia	5/129 (3.9%)		9/132 (6.8%)		12/129 (9.3%)
Ocular Vascular Disorder	0/129 (0%)		2/132 (1.5%)		8/129 (6.2%)
Optic Disc Vascular Disorder	8/129 (6.2%)		7/132 (5.3%)		2/129 (1.6%)
Retinal Depigmentation	8/129 (6.2%)		12/132 (9.1%)		10/129 (7.8%)
Retinal Exudates	18/129 (14%)		36/132 (27.3%)		25/129 (19.4%)
Retinal Hemorrhage	17/129 (13.2%)		15/132 (11.4%)		16/129 (12.4%)
Retinal Pigmentation	4/129 (3.1%)		7/132 (5.3%)		2/129 (1.6%)
Retinal Vascular Disorder	19/129 (14.7%)		21/132 (15.9%)		19/129 (14.7%)
Vitreous Detachment	6/129 (4.7%)		1/132 (0.8%)		8/129 (6.2%)
Vitreous Hemorrhage	8/129 (6.2%)		5/132 (3.8%)		7/129 (5.4%)
Infections and infestations
Nasopharyngitis	3/129 (2.3%)		8/132 (6.1%)		7/129 (5.4%)
Investigations
Intraocular Pressure Increased	5/129 (3.9%)		11/132 (8.3%)		11/129 (8.5%)
Vascular disorders
Hypertension	8/129 (6.2%)		4/132 (3%)		3/129 (2.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.