A Study Evaluating Dosing Regimens for Treatment With Intravitreal Ranibizumab Injections in Subjects With Macular Edema Following Retinal Vein Occlusion

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01277302
• Collaborator: (none)
• Enrollment: 202
• Locations: 42
• Arms: 3
• Duration (Months): 20
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This was a Phase IV multicenter, randomized, open-label study, with masking of the vision examiner, of the efficacy and safety of intravitreal ranibizumab 0.5 mg in subjects with macular edema following Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO).

Condition or Disease	Intervention/Treatment	Phase
Macular Edema	Drug: Ranibizumab	Phase 4

Detailed Description

This study consisted of 2 study periods, a 7-month fixed treatment period, followed by an 8-month alternate dose regimen period. Subjects could receive up to a maximum of 15 monthly injections of ranibizumab 0.5 mg during the study, 7 injections (Day 0 and at 6 monthly visits) in the fixed treatment period and a maximum of 8 injections in the alternate dose regimen period. During the fixed treatment period, subjects received 7 monthly intravitreal ranibizumab 0.5 mg injections. During the alternate dose regimen period, from Month 7 through Month 14, subjects were evaluated monthly to determine whether they achieved the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria. Subjects continued to receive monthly ranibizumab 0.5 mg monthly injections until the VA-OCT stability criteria were first met. Upon meeting the VA-OCT stability criteria for the first time during the alternate dose regimen period, subjects were randomly assigned in a 1:1 ratio to one of 2 dose regimens, the PRN (pro re nata, "as-needed") or the Monthly regimen.

PRN randomized subjects: Subjects received no injection at the randomization visit and at future monthly visits where the VA-OCT stability criteria were met and received a ranibizumab 0.5 mg injection at future monthly visits if the VA-OCT stability criteria were not met.

Monthly randomized subjects: Subjects continued to receive ranibizumab 0.5 mg injections at each monthly visit.

Monthly non-randomized subjects: Subjects who did not meet the VA-OCT stability criteria at any month from Month 7 through Month 14 were not randomized and received 8 monthly intravitreal ranibizumab 0.5 mg injections.

Study Design

• Study Type: Interventional
• Actual Enrollment: 202 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter Randomized Study Evaluating Dosing Regimens for Treatment With Intravitreal Ranibizumab Injections in Subjects With Macular Edema Following Retinal Vein Occlusion
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ranibizumab 0.5 mg monthly - randomized subjects Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Drug: Ranibizumab; Liquid ranibizumab (10 mg/ml) was supplied in a sterile solution in single-use vials.; Other Names: Lucentis
Experimental: Ranibizumab 0.5 mg PRN - randomized subjects Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm. No injection was given at the randomization visit. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.	Drug: Ranibizumab; Liquid ranibizumab (10 mg/ml) was supplied in a sterile solution in single-use vials.; Other Names: Lucentis
Experimental: Ranibizumab 0.5 mg monthly - non-randomized subjects Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Drug: Ranibizumab; Liquid ranibizumab (10 mg/ml) was supplied in a sterile solution in single-use vials.; Other Names: Lucentis

Outcome Measures

Primary Outcome Measures

1. Trend of Change From Baseline in the Best Corrected Visual Acuity (BCVA) Scores From Month 7 to Month 15 [Baseline to Month 15]

   BCVA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement. The reported data are the observed changes from Baseline in BCVA at Months 7 and 15. For the statistical analysis, the interaction term of treatment by time in a longitudinal model was used to assess whether there was a difference in the trend of change from Baseline in the visual acuity scores from Month 7 to Month 15 between the 2 randomized treatment groups, Monthly and PRN.

Secondary Outcome Measures

1. Visual Acuity Change From Previous Month During the Alternate Dose Regimen Period in Subjects Who Met the VA-OCT Stability Criteria at the Previous Month [Month 7 through Month 15]

   BCVA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement. This outcome measure is not relevant for subjects in the non-randomized group because they never met the VA-OCT stability criteria.

2. Percentage of Participants Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline [Month 7 to Month 15]

   BCVA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.

3. Percentage of Participants With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better [Month 7 to Month 15]

   VA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart starting at a test distance of 4 meters. An increase in the number of lines read correctly by the patient in the ETDRS chart indicates an improvement of vision. The Snellen equivalent of 20/40 or better is 69 or more letters correctly read in the EDTRS chart.

4. Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score [Month 1 to Month 15]

   BCVA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement.

5. Percentage of Participants Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline [Month 7 to Month 15]

   BCVA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.

6. Percentage of Participants With a Central Foveal Thickness of ≤ 300 µm [Month 7 to Month 15]

   Central foveal thickness was assessed monthly in the study eye using spectral-domain optical coherence tomography. Central foveal thickness was computed using the automated Cirrus Review software (DOCTR CZM Cirrus OCT Grader Reading Manual, Version 1.02). All participants in the Monthly and PRN groups had a baseline central foveal thickness > 300 µm at baseline.

7. Mean Change From Baseline in Central Foveal Thickness [Month 1 to Month 15]

   Central foveal thickness was assessed monthly in the study eye using spectral-domain optical coherence tomography. Central foveal thickness was computed using the automated Cirrus Review software (DOCTR CZM Cirrus OCT Grader Reading Manual, Version 1.02). All participants in the Monthly and PRN groups had a baseline central foveal thickness > 300 µm at baseline. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.

8. Percentage of Participants With Intraretinal Edema [Month 7 to Month 15]

   The presence of intraretinal edema was defined as the presence of subretinal fluid, cystoid spaces, or central retinal thickness ≥ 300 µm as evaluated in spectral-domain optical coherence tomography images by the Digital Angiography Reading Center, the central reading center. At baseline, all participants in the Monthly and PRN groups had presence of edema.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

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

Ocular Inclusion Criteria (Study Eye)

• Foveal center-involved macular edema secondary to branch retinal vein occlusion (BRVO) (including hemi-retinal retinal vein occlusion [HRVO]) or central retinal vein occlusion (CRVO).

• Best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) charts of 20/40 to 20/320 (Snellen equivalent) in the study eye.

• Mean central subfield thickness > 300 µm on 2 spectral-domain optical coherence tomography measurements (screening and Day 0 [first day of treatment]).

Exclusion Criteria:

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

• History of any systemic anti-vascular endothelial growth factor (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. History of successfully treated malignancies is not an exclusion criterion.

• Uncontrolled blood pressure.

• Pregnancy or lactation.

• Daily use of oral corticosteroids to treat a chronic condition.

• Required treatment with injectable corticosteroids to treat a musculoskeletal condition.

• Participation in an investigational trial within 30 days prior to Day 0 that involved treatment with any drug or device that has not received regulatory approval at the time of study entry.

Ocular Exclusion Criteria (Study Eye)

• Prior episode of retinal vein occlusion (RVO).

• Brisk afferent pupillary defect.

• History of any previous intravitreal anti-VEGF therapy for RVO in the study eye.

• History of previous therapeutic treatment for RVO, other than anti-VEGF therapy, within 4 months prior to the screening visit, including any intraocular corticosteroids.

• History of previous surgical treatment for RVO, including radial optic neurotomy or sheathotomy.

• History or presence of age-related macular degeneration (AMD) (dry form graded as Age-Related Eye Disease Study [AREDS] Stage 2 or higher or wet form).

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

• History of panretinal scatter photocoagulation or sector laser photocoagulation within 4 months prior to Day 0 or anticipated within the next 4 months following Day 0.

• History of pars plana vitrectomy.

• History of intraocular surgery within 2 months prior to Day 0 or anticipated within the next 7 months following Day 0.

• History of yttrium-aluminum-garnet (YAG) 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 either on clinical examination or spectral-domain optical coherence tomography (SD-OCT), thought to be contributing to macular edema.

• Presence of an ocular condition that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the study.

• Visually significant hemorrhage obscuring the fovea and felt to be a major contributor to reduced visual acuity. The subject should be followed and when the hemorrhage in the fovea clears to the point that it is no longer a major contributor to reduced visual acuity, the subject may be screened for the study.

• Presence of a substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more.

• Intra-ocular pressure (IOP) ≥ 30 mmHg. If a subject's IOP is ≥ 30 mmHg, that subject will be referred for glaucoma treatment and may be re-screened after 1 month.

• Evidence upon examination of pseudoexfoliation.

• Aphakia.

• Evidence upon examination of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

• Evidence upon examination of any diabetic retinopathy, defined as eyes of diabetic patients with more than one microaneurysm outside the area of the vein occlusion (inclusive of both eyes).

• Other relevant ocular disease that may be associated with increased intraocular VEGF levels.

• Improvement of ≥ 10 letters on best-corrected visual acuity ETDRS score between screening and Day 0.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Phoenix	Arizona	United States	85020
2		Tucson	Arizona	United States	85704
3		Beverly Hills	California	United States	90211
4		Chico	California	United States	95973
5		Mountain View	California	United States	94040
6		Oakland	California	United States	94609
7		San Francisco	California	United States	94107
8		Santa Ana	California	United States	92705
9		Santa Barbara	California	United States	93103
10		Torrance	California	United States	90503
11		Colorado Springs	Colorado	United States	80909
12		Golden	Colorado	United States	80401
13		New London	Connecticut	United States	06320
14		Altamonte Springs	Florida	United States	32701
15		Boynton Beach	Florida	United States	33426
16		Lakeland	Florida	United States	33805
17		Augusta	Georgia	United States	30909
18		Chicago	Illinois	United States	60637
19		Baltimore	Maryland	United States	21287
20		Hagerstown	Maryland	United States	21740
21		Boston	Massachusetts	United States	02114
22		Worcester	Massachusetts	United States	01605
23		Jackson	Michigan	United States	49201
24		Edina	Minnesota	United States	55435
25		Las Vegas	Nevada	United States	89144
26		Northfield	New Jersey	United States	08225
27		Teaneck	New Jersey	United States	07666
28		Rochester	New York	United States	14620
29		Charlotte	North Carolina	United States	28210
30		Camp Hill	Pennsylvania	United States	17011
31		Philadelphia	Pennsylvania	United States	19107
32		Pittsburgh	Pennsylvania	United States	15212
33		Pittsburgh	Pennsylvania	United States	15213
34		Ladson	South Carolina	United States	29456
35		West Columbia	South Carolina	United States	29169
36		Rapid City	South Dakota	United States	57701
37		Nashville	Tennessee	United States	37203
38		Abilene	Texas	United States	79606
39		Austin	Texas	United States	78705
40		Houston	Texas	United States	77030
41		San Antonio	Texas	United States	78240
42		The Woodlands	Texas	United States	77384

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Gary Sternberg, M.D., Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT01277302
• Other Study ID Numbers: FVF4967g; ML01296
• First Posted: Jan 14, 2011
• Last Update Posted: Apr 23, 2014
• Last Verified: Mar 1, 2014

• Additional relevant MeSH terms: Macular Edema; Retinal Vein Occlusion; Edema; Ranibizumab

Study Results

Participant Flow

Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects	Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.
Period Title: 7-Month Fixed Treatment Period
STARTED	85	86	31
COMPLETED	85	86	19
NOT COMPLETED	0	0	12
Period Title: 7-Month Fixed Treatment Period
STARTED	85	86	19
COMPLETED	80	82	13
NOT COMPLETED	5	4	6

Baseline Characteristics

Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects	Ranibizumab 0.5 mg Monthly - Non-randomized Subjects	Total
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Total of all reporting groups
Overall Participants	85	86	31	202
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.3 (12.1)	65.2 (12.8)	66.3 (12.3)	66.3 (12.4)
Sex: Female, Male (Count of Participants)
Female	38 44.7%	37 43%	9 29%	84 41.6%
Male	47 55.3%	49 57%	22 71%	118 58.4%

Outcome Measures

1. Primary Outcome

Title	Trend of Change From Baseline in the Best Corrected Visual Acuity (BCVA) Scores From Month 7 to Month 15
Description	BCVA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement. The reported data are the observed changes from Baseline in BCVA at Months 7 and 15. For the statistical analysis, the interaction term of treatment by time in a longitudinal model was used to assess whether there was a difference in the trend of change from Baseline in the visual acuity scores from Month 7 to Month 15 between the 2 randomized treatment groups, Monthly and PRN.
Time Frame	Baseline to Month 15

Outcome Measure Data

Analysis Population Description

Intent-to-treat population, randomized: All enrolled participants who received at least 1 ranibizumab injection in the study and were randomized into the Monthly or PRN treatment groups. The analysis was based on observed data without imputation for missing values.

Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.
Measure Participants	85	86
Month 7 (n=85, 86)	17.5 (12.6)	19.7 (12.6)
Month 15 (n=80, 82)	18.7 (14.1)	21.0 (14.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg Monthly - Randomized Subjects, Ranibizumab 0.5 mg PRN - Randomized Subjects
	Comments	The null hypothesis was that there was no difference in the trend of change from Baseline in the visual acuity scores from Month 7 to Month 15 between the 2 treatment groups as assessed by the interaction term of treatment by time in a longitudinal model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5091
	Comments	This is the p-value of the treatment by time interaction in the longitudinal model. Analysis was not adjusted for multiple comparisons as there was only 1 comparison. p < 0.05 (2-sided) was required for significance.
	Method	Longitudinal mixed model
	Comments	The analysis was stratified by disease (BRVO or CRVO), randomization month, and randomization BCVA score category (≤35, >35 to ≤50, or >50 letters).
Method of Estimation	Estimation Parameter	Estimated interaction effect
	Estimated Value	0.071
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.107
	Estimation Comments

2. Secondary Outcome

Title	Visual Acuity Change From Previous Month During the Alternate Dose Regimen Period in Subjects Who Met the VA-OCT Stability Criteria at the Previous Month
Description	BCVA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement. This outcome measure is not relevant for subjects in the non-randomized group because they never met the VA-OCT stability criteria.
Time Frame	Month 7 through Month 15

Outcome Measure Data

Analysis Population Description

Intent-to-treat population, randomized: All enrolled participants who received at least 1 ranibizumab injection in the study and were randomized into the monthly or PRN treatment groups. The analysis was based on observed data without imputation for missing values.

Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.
Measure Participants	85	86
Month 8 (n=53, 53)	0.4 (3.2)	-3.3 (11.3)
Month 9 (n=49, 40)	0.5 (4.0)	-2.9 (8.6)
Month 10 (n=52, 31)	0.2 (3.4)	-0.5 (4.2)
Month 11 (n=54, 40)	-0.6 (3.7)	0.4 (4.4)
Month 12 (n=46, 44)	-0.2 (3.2)	-1.6 (4.4)
Month 13 (n=50, 41)	0.0 (3.5)	-0.5 (5.2)
Month 14 (n=58, 48)	-0.1 (3.6)	-2.2 (6.1)
Month 15 (n=56, 42)	0.0 (4.4)	-0.4 (4.0)

3. Secondary Outcome

Title	Percentage of Participants Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline
Description	BCVA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time Frame	Month 7 to Month 15

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled participants who received at least 1 ranibizumab injection in the study. The analysis was based on observed data without imputation for missing values.

Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects	Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.
Measure Participants	85	86	31
Month 7 (n=85, 86, 17)	62.4 73.4%	67.4 78.4%	41.2 132.9%
Month 15 (n=80, 82, 13)	66.3 78%	70.7 82.2%	46.2 149%

4. Secondary Outcome

Title	Percentage of Participants With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better
Description	VA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity chart starting at a test distance of 4 meters. An increase in the number of lines read correctly by the patient in the ETDRS chart indicates an improvement of vision. The Snellen equivalent of 20/40 or better is 69 or more letters correctly read in the EDTRS chart.
Time Frame	Month 7 to Month 15

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled participants who received at least 1 ranibizumab injection in the study. The analysis was based on observed data without imputation for missing values.

Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects	Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.
Measure Participants	85	86	31
Month 7 (n=85, 86, 17)	72.9 85.8%	76.7 89.2%	47.1 151.9%
Month 15 (n=80, 82, 13)	71.3 83.9%	76.8 89.3%	46.2 149%

5. Secondary Outcome

Title	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score
Description	BCVA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision. A positive change score indicates improvement.
Time Frame	Month 1 to Month 15

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled participants who received at least 1 ranibizumab injection in the study. The analysis was based on observed data without imputation for missing values.

Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects	Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.
Measure Participants	85	86	31
Month 1 (n=85, 86, 29)	12.2 (10.3)	11.2 (10.4)	10.7 (14.0)
Month 7 (n=85, 86, 17)	17.5 (12.6)	19.7 (12.6)	14.7 (12.0)
Month 15 (n=80, 82, 13)	18.7 (14.1)	21.0 (14.1)	14.5 (14.7)

6. Secondary Outcome

Title	Percentage of Participants Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline
Description	BCVA was measured in the study eye using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) chart starting at a test distance of 4 meters. The BCVA score is the number of letters read correctly by the patient. An increase in the BCVA score indicates an improvement of vision.
Time Frame	Month 7 to Month 15

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled participants who received at least 1 ranibizumab injection in the study. The analysis was based on observed data without imputation for missing values.

Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects	Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.
Measure Participants	85	86	31
Month 7 (n=85, 86, 17)	98.8 116.2%	98.8 114.9%	100.0 322.6%
Month 15 (n=80, 82, 13)	98.8 116.2%	98.8 114.9%	100.0 322.6%

7. Secondary Outcome

Title	Percentage of Participants With a Central Foveal Thickness of ≤ 300 µm
Description	Central foveal thickness was assessed monthly in the study eye using spectral-domain optical coherence tomography. Central foveal thickness was computed using the automated Cirrus Review software (DOCTR CZM Cirrus OCT Grader Reading Manual, Version 1.02). All participants in the Monthly and PRN groups had a baseline central foveal thickness > 300 µm at baseline.
Time Frame	Month 7 to Month 15

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled participants who received at least 1 ranibizumab injection in the study. The analysis was based on observed data without imputation for missing values.

Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects	Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.
Measure Participants	85	86	31
Month 7 (n=85, 86, 17)	88.2 103.8%	94.2 109.5%	52.9 170.6%
Month 15 (n=80, 82, 13)	92.5 108.8%	85.4 99.3%	38.5 124.2%

8. Secondary Outcome

Title	Mean Change From Baseline in Central Foveal Thickness
Description	Central foveal thickness was assessed monthly in the study eye using spectral-domain optical coherence tomography. Central foveal thickness was computed using the automated Cirrus Review software (DOCTR CZM Cirrus OCT Grader Reading Manual, Version 1.02). All participants in the Monthly and PRN groups had a baseline central foveal thickness > 300 µm at baseline. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.
Time Frame	Month 1 to Month 15

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled participants who received at least 1 ranibizumab injection in the study. The analysis was based on observed data without imputation for missing values.

Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects	Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.
Measure Participants	85	86	31
Month 1 (n=85, 86, 29)	-243.0 (172.5)	-214.9 (166.7)	-157.9 (181.8)
Month 7 (n=85, 86, 17)	-279.7 (167.4)	-265.2 (185.9)	-113.9 (184.9)
Month 15 (n=80, 82, 13)	-289.9 (177.2)	-247.8 (207.5)	-93.2 (225.2)

9. Secondary Outcome

Title	Percentage of Participants With Intraretinal Edema
Description	The presence of intraretinal edema was defined as the presence of subretinal fluid, cystoid spaces, or central retinal thickness ≥ 300 µm as evaluated in spectral-domain optical coherence tomography images by the Digital Angiography Reading Center, the central reading center. At baseline, all participants in the Monthly and PRN groups had presence of edema.
Time Frame	Month 7 to Month 15

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All enrolled participants who received at least 1 ranibizumab injection in the study. The analysis was based on observed data without imputation for missing values.

Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects	Ranibizumab 0.5 mg PRN - Randomized Subjects	Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.
Measure Participants	85	86	31
Month 7 (n=85, 86, 17)	31.8 37.4%	30.2 35.1%	100.0 322.6%
Month 15 (n=80, 82, 13)	25.0 29.4%	32.9 38.3%	84.6 272.9%

Adverse Events

Time Frame	Adverse Events were reported beginning at initiation of study treatment up to 30 days following the last administration of study treatment, study discontinuation, or termination, whichever was earlier.
Adverse Event Reporting Description	After this period, only SAEs attributed to prior study treatment were reported. Safety population: All enrolled participants who received at least 1 ranibizumab injection in the study.
Arm/Group Title	Ranibizumab 0.5 mg Monthly - Randomized Subjects		Ranibizumab 0.5 mg PRN - Randomized Subjects		Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
Arm/Group Description	Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria were met and randomization occurred to the monthly arm. At subsequent monthly visits after randomization, injections were given whether the VA-OCT stability criteria were met or not met. Subjects were to receive 15 ranibizumab 0.5 mg injections.		Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections until the first month where the study-specific VA-OCT stability criteria were met and randomization occurred to the PRN arm and no injection was given. At subsequent monthly visits after randomization, injections were given if the VA-OCT stability criteria were not met and no injections were given if the VA-OCT stability criteria were met. Subjects could receive between 7 and a maximum of 14 ranibizumab 0.5 mg injections.		Subjects received at least 7 monthly intravitreal ranibizumab 0.5 mg injections and then never met the study-specific VA-OCT stability criteria from month 7 to month 14. Subjects were to receive 15 ranibizumab 0.5 mg injections.
All Cause Mortality
	Ranibizumab 0.5 mg Monthly - Randomized Subjects		Ranibizumab 0.5 mg PRN - Randomized Subjects		Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Ranibizumab 0.5 mg Monthly - Randomized Subjects		Ranibizumab 0.5 mg PRN - Randomized Subjects		Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/85 (14.1%)		14/86 (16.3%)		11/31 (35.5%)
Blood and lymphatic system disorders
Anaemia	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Cardiac disorders
Angina unstable	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Coronary artery disease	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Sick sinus syndrome	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Eye disorders
Macular hole	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Macular oedema	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Visual acuity reduced	1/85 (1.2%)		3/86 (3.5%)		0/31 (0%)
Iridocyclitis	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Visual acuity reduced	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Gastrointestinal disorders
Intestinal infarction	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
General disorders
Chest pain	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Death	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Non-cardia chest pain	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Pain	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Hepatobiliary disorders
Biliary dyskinesia	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Infections and infestations
Cellulitis	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Diverticulitis	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Injury, poisoning and procedural complications
Fall	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Humerus fracture	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Neck injury	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Wound dehiscence	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Metabolism and nutrition disorders
Hyponatraemia	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Muscle spasms	1/85 (1.2%)		1/86 (1.2%)		0/31 (0%)
Osteolysis	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Pain in extremity	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Pathological fracture	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Periarthritis	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign lymph node neoplasm	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Lung adenocarcinoma	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Lung cancer metastatic	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Lung squamous cell carcinoma stage unspecified	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Meningioma benign	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Prostate cancer	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Spinal cord neoplasm	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Squamous cell carcinoma	1/85 (1.2%)		0/86 (0%)		1/31 (3.2%)
Nervous system disorders
Cerebrovascular accident	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Dementia	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Syncope	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Transient ischaemic attack	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Psychiatric disorders
Depression	0/85 (0%)		1/86 (1.2%)		0/31 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/85 (1.2%)		0/86 (0%)		0/31 (0%)
Pulmonary embolism	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Pulmonary hypertension	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Vascular disorders
Deep vein thrombosis	0/85 (0%)		0/86 (0%)		1/31 (3.2%)
Other (Not Including Serious) Adverse Events
	Ranibizumab 0.5 mg Monthly - Randomized Subjects		Ranibizumab 0.5 mg PRN - Randomized Subjects		Ranibizumab 0.5 mg Monthly - Non-randomized Subjects
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/85 (82.4%)		61/86 (70.9%)		18/31 (58.1%)
Eye disorders
Cataract	9/85 (10.6%)		6/86 (7%)		0/31 (0%)
Cataract cortical	4/85 (4.7%)		5/86 (5.8%)		1/31 (3.2%)
Conjunctival haemorrhage	28/85 (32.9%)		23/86 (26.7%)		9/31 (29%)
Dry eye	4/85 (4.7%)		3/86 (3.5%)		2/31 (6.5%)
Eye irritation	6/85 (7.1%)		5/86 (5.8%)		1/31 (3.2%)
Eye pain	8/85 (9.4%)		14/86 (16.3%)		4/31 (12.9%)
Eye pruritus	1/85 (1.2%)		4/86 (4.7%)		2/31 (6.5%)
Macular fibrosis	9/85 (10.6%)		5/86 (5.8%)		2/31 (6.5%)
Macular hole	1/85 (1.2%)		0/86 (0%)		2/31 (6.5%)
Macular oedema	2/85 (2.4%)		6/86 (7%)		1/31 (3.2%)
Retinal aneurysm	1/85 (1.2%)		5/86 (5.8%)		0/31 (0%)
Retinal depigmentation	2/85 (2.4%)		0/86 (0%)		2/31 (6.5%)
Retinal disorder	7/85 (8.2%)		1/86 (1.2%)		1/31 (3.2%)
Retinal exudates	13/85 (15.3%)		12/86 (14%)		3/31 (9.7%)
Retinal haemorrhage	8/85 (9.4%)		8/86 (9.3%)		0/31 (0%)
Retinal vascular disorder	3/85 (3.5%)		5/86 (5.8%)		0/31 (0%)
Vitreous adhesions	0/85 (0%)		0/86 (0%)		3/31 (9.7%)
Vitreous detachment	11/85 (12.9%)		6/86 (7%)		3/31 (9.7%)
Vitreous floaters	4/85 (4.7%)		6/86 (7%)		1/31 (3.2%)
Cataract	8/85 (9.4%)		5/86 (5.8%)		0/31 (0%)
Dry eye	3/85 (3.5%)		2/86 (2.3%)		2/31 (6.5%)
Retinal haemorrhage	4/85 (4.7%)		6/86 (7%)		0/31 (0%)
Vitreous detachment	7/85 (8.2%)		2/86 (2.3%)		1/31 (3.2%)
Gastrointestinal disorders
Nausea	1/85 (1.2%)		2/86 (2.3%)		2/31 (6.5%)
Infections and infestations
Bronchitis	4/85 (4.7%)		3/86 (3.5%)		2/31 (6.5%)
Nasopharyngitis	10/85 (11.8%)		7/86 (8.1%)		1/31 (3.2%)
Sinusitis	3/85 (3.5%)		6/86 (7%)		2/31 (6.5%)
Upper respiratory tract infection	3/85 (3.5%)		3/86 (3.5%)		3/31 (9.7%)
Urinary tract infection	2/85 (2.4%)		6/86 (7%)		0/31 (0%)
Investigations
Blood pressure increased	2/85 (2.4%)		1/86 (1.2%)		2/31 (6.5%)
Intraocular pressure increased	3/85 (3.5%)		8/86 (9.3%)		1/31 (3.2%)
Musculoskeletal and connective tissue disorders
Back pain	2/85 (2.4%)		5/86 (5.8%)		0/31 (0%)
Osteoarthritis	7/85 (8.2%)		5/86 (5.8%)		0/31 (0%)
Nervous system disorders
Diabetic neuropathy	0/85 (0%)		0/86 (0%)		2/31 (6.5%)
Headache	2/85 (2.4%)		1/86 (1.2%)		2/31 (6.5%)
Renal and urinary disorders
Urinary incontinence	0/85 (0%)		0/86 (0%)		2/31 (6.5%)
Vascular disorders
Hypertension	13/85 (15.3%)		8/86 (9.3%)		2/31 (6.5%)

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.