A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus (RISE)

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00473330
• Collaborator: (none)
• Enrollment: 377
• Arms: 3
• Duration (Months): 65.1

Study Details

Study Description

Brief Summary

This study is a Phase III, double-masked, multicenter, randomized, sham injection-controlled study of the efficacy and safety of ranibizumab injection in patients with clinically significant macular edema with center involvement (CSME-CI) secondary to diabetes mellitus (Type 1 or 2). This study is identical in design to study NCT00473382 (Protocol ID FVF4168g).

The open-label extension phase of the study was stopped after receiving FDA approval of the study drug (ranibizumab) for diabetic macular edema.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus; Macular Edema	Drug: Ranibizumab; Drug: Sham injection	Phase 3

Detailed Description

This study is composed of 3 phases: (1) A 24-month controlled treatment period (monthly treatment with ranibizumab 0.3 mg, ranibizumab 0.5 mg, or sham injection) followed by (2) a 12-month treatment period in which patients randomized to the sham group who had not discontinued from treatment (still masked) could choose to receive monthly ranibizumab 0.5 mg while the 2 ranibizumab treatment groups continued on the same treatment they received in the first 2 years. Patients who had not discontinued treatment by Month 36 were eligible to continue treatment with ranibizumab 0.5 mg as needed (pro re nata, PRN) in (3) an extension phase of the study for up to 2 more years, resulting in up to 5 years possible total treatment time for some patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 377 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Double-masked, Multicenter, Randomized, Sham Injection-controlled Study of the Efficacy and Safety of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Nov 1, 2010
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ranibizumab 0.3 mg Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.	Drug: Ranibizumab; Sterile solution for intravitreal injection.; Other Names: Lucentis
Experimental: Ranibizumab 0.5 mg Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.	Drug: Ranibizumab; Sterile solution for intravitreal injection.; Other Names: Lucentis
Sham Comparator: Sham injection/ranibizumab 0.5 mg Patients received a sham intravitreal injection monthly for 24 months. Patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.	Drug: Sham injection

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24 [Baseline to Month 24]

   BCVA was measured 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.

Secondary Outcome Measures

1. Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48 [Baseline to Month 48]

   BCVA was measured 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.

2. Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48 [Months 24, 36, and 48]

   VA was measured 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.

3. Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48 [Baseline to Month 48]

   BCVA was measured 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.

4. Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline [Baseline to Month 36]

   BCVA was measured 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. Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48 [Baseline to Month 48]

   Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.

6. Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36 [Baseline to Month 36]

   The severity of diabetic retinopathy was graded on a 10-point scale by the central reading center by comparing patient fundus photographic images with a set of standard images. 1=diabetic retinopathy (DR) severity level 10, 12 (DR absent), 2=DR severity level 14A-14C, 14Z, 15, 20 (DR questionable, microaneurysms only), 3=DR severity level 35A-35F (mild non-proliferative [NP]DR), 4=DR severity level 43A, 43B (moderate NPDR), 5=DR severity level 47A-47D (moderately severe NPDR), 6=DR severity level 53A-53E (severe NPDR), 7=DR severity level 60, 61A, 61B (mild proliferative [P]DR), 8=DR severity level 65A-65C (moderate PDR), 9=DR severity level 71A-71D (high-risk PDR), 10=DR severity level 90 (cannot grade). A lower score indicates less severe diabetic retinopathy.

7. Percentage of Patients With Resolution of Leakage at Month 24 [Baseline to Month 24]

   Resolution of leakage was defined as total area of fluorescein leakage in the central, inner, and outer subfields of the 0 Disc Area. Leakage was assessed in fluorescein angiographic images by the central reading center.

8. Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36 [Baseline to Month 36]

   The need for macular laser treatment was evaluated by the masked (evaluating) physician. Macular laser was administered per protocol-specified objective and subjective criteria starting at Month 3.

9. Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48 [Baseline to Month 48]

   BCVA was measured 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.

10. Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48 [Month 36 to Month 48]

    BCVA was measured 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.

11. Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48 [Month 36 to Month 48]

    BCVA was measured 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.

12. Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48 [Month 36 to Month 48]

    Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.

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 written informed consent and, at U.S. sites, Health Insurance Portability and Accountability Act (HIPAA) authorization, and in other countries, as applicable according to national laws.

• Age ≥ 18 years.

• Diabetes mellitus (Type 1 or 2) .

• Retinal thickening secondary to diabetes mellitus (DME) involving the center of the fovea with central macular thickness ≥ 275 µm in the center subfield as assessed on optical coherence tomography (OCT).

• Best corrected visual acuity (BCVA) score in the study eye of 20/40 to 20/320 approximate Snellen equivalent using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at an initial testing distance of 4 meters.

• Decrease in vision determined to be primarily the result of DME and not to other causes.

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

• Ability (in the opinion of the investigator) and willingness to return for all scheduled visits and assessments.

Exclusion Criteria:

• History of vitreoretinal surgery in the study eye.

• Panretinal photocoagulation (PRP) or macular laser photocoagulation in the study eye within 3 months of screening.

• Previous use of intraocular corticosteroids in the study eye (eg, triamcinolone acetonide [TA]) within 3 months of screening.

• Previous treatment with anti-angiogenic drugs in either eye (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc) within 3 months of the Day 0 (first day of treatment) visit.

• Proliferative diabetic retinopathy (PDR) in the study eye, with the exception of inactive, regressed PDR.

• Iris neovascularization, vitreous hemorrhage, traction retinal detachment, or preretinal fibrosis involving the macula in the study eye.

Concurrent Ocular Conditions

• Vitreomacular traction or epiretinal membrane in the study eye.

• Ocular inflammation (including trace or above) in the study eye.

• History of idiopathic or autoimmune uveitis in either eye.

• Structural damage to the center of the macula in the study eye that is likely to preclude improvement in VA following the resolution of macular edema, including atrophy of the retinal pigment epithelium (RPE), subretinal fibrosis, or organized hard-exudate plaque.

• Ocular disorders in the study eye that may confound interpretation of study results, including retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization (CNV) of any cause (eg, age-related macular degeneration (AMD), ocular histoplasmosis, or pathologic myopia).

• Concurrent disease in the study eye that would compromise visual acuity or require medical or surgical intervention during the study period.

• Cataract surgery in the study eye within 3 months, yttrium-aluminum-garnet (YAG) laser capsulotomy within the past 2 months, or any other intraocular surgery within the 90 days preceding Day 0.

• Aphakia or absence of the posterior capsule in the study eye.

• Uncontrolled glaucoma or previous filtration surgery in the study eye.

• Spherical equivalent of the refractive error in the study eye of more than -8 diopters myopia.

• Evidence at examination of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye or current treatment for serious systemic infection.

• Uncontrolled blood pressure.

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

• Uncontrolled diabetes mellitus.

• Renal failure requiring dialysis or renal transplant.

• Participation in an investigational trial within 30 days prior to screening that involved treatment with any drug (excluding vitamins and minerals) or device.

• History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use an investigational drug, might affect interpretation of the results of the study, or renders the subject at high risk from treatment complications.

• Pregnancy or lactation.

• History of allergy to fluorescein.

• History of allergy to ranibizumab injection or related molecule.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Jason Ehrlich, M.D., Ph.D., Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT00473330
• Other Study ID Numbers: FVF4170g
• First Posted: May 15, 2007
• Last Update Posted: Apr 17, 2017
• Last Verified: Mar 1, 2017

• Keywords provided by Genentech, Inc.: Lucentis; DME; Diabetes; Vision loss
• Additional relevant MeSH terms: Macular Edema; Diabetes Mellitus; Edema; Ranibizumab

Study Results

Participant Flow

Recruitment Details	Patients were recruited from study sites in the United States and Argentina. There were 10 patients from Argentina.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.	Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.	Patients received a sham intravitreal injection monthly for 24 months. Patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.
Period Title: Core Study
STARTED	125	125	127
COMPLETED	98	100	86
NOT COMPLETED	27	25	41
Period Title: Core Study
STARTED	89	79	77
COMPLETED	63	59	50
NOT COMPLETED	26	20	27
Period Title: Core Study
STARTED	89	79	77
COMPLETED	1	1	0
NOT COMPLETED	88	78	77

Baseline Characteristics

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection	Total
Arm/Group Description	Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 24 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.	Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 24 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months.	Total of all reporting groups
Overall Participants	125	125	127	377
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.7 (8.9)	62.8 (10.0)	61.8 (9.8)	62.1 (9.6)
Sex: Female, Male (Count of Participants)
Female	52 41.6%	60 48%	53 41.7%	165 43.8%
Male	73 58.4%	65 52%	74 58.3%	212 56.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Month 24
Description	BCVA was measured 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	Baseline to Month 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection
Arm/Group Description	Patients received ranibizumab 0.3 mg monthly administered intravitreally for 24 months.	Patients received ranibizumab 0.5 mg monthly administered intravitreally for 24 months.	Patients received a sham intravitreal injection monthly for 24 months.
Measure Participants	125	125	127
Number (95% Confidence Interval) [Percentage of patients]	44.8	39.2	18.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.3 mg, Sham Injection
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	An adjustment was made for multiple treatment comparisons of the ranibizumab dose groups with the control group.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Difference in percentage at Month 24
	Estimated Value	24.3
	Confidence Interval	(2-Sided) 95%; 13.8 to 34.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Sham Injection
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	An adjustment was made for multiple treatment comparisons of the ranibizumab dose groups with the control group.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Difference in percentage at Month 24
	Estimated Value	20.9
	Confidence Interval	(2-Sided) 95%; 10.7 to 31.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

2. Secondary Outcome

Title	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24, 36, and 48
Description	BCVA was measured 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	Baseline to Month 48

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Measure Participants	125	125	127	127
Month 24	12.5 (14.1)	11.9 (12.1)	2.6 (13.9)	NA (NA)
Month 36	14.2 (12.8)	11.0 (12.9)	NA (NA)	4.3 (14.9)
Month 48 (n=62,56,0,48)	13.8 (12.2)	14.4 (11.8)	NA (NA)	10.2 (11.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.3 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	ANOVA
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.6
	Confidence Interval	(2-Sided) 95%; 6.1 to 13.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	ANOVA
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.4
	Confidence Interval	(2-Sided) 95%; 6.2 to 12.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Patients With a Visual Acuity (VA) Snellen Equivalent of 20/40 or Better at Months 24, 36, and 48
Description	VA was measured 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	Months 24, 36, and 48

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Measure Participants	125	125	127	127
Month 24	60.0	63.2	37.8	NA
Month 36	63.2	59.2	NA	42.5
Month 48 (n=62,56,0,48)	62.9	73.2	NA	54.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.3 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Difference in percentage at Month 24
	Estimated Value	24.4
	Confidence Interval	(2-Sided) 95%; 13.4 to 35.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Difference in percentage at Month 24
	Estimated Value	25.1
	Confidence Interval	(2-Sided) 95%; 14.0 to 36.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

4. Secondary Outcome

Title	Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 24, 36, and 48
Description	BCVA was measured 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	Baseline to Month 48

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Measure Participants	125	125	127	127
Month 24	97.6	97.6	89.8	NA
Month 36	99.2	97.6	NA	91.3
Month 48 (n=62,56,0,48)	100.0	100.0	NA	97.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.3 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0086
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Difference in percentage at Month 24
	Estimated Value	8.2
	Confidence Interval	(2-Sided) 95%; 2.4 to 14.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0126
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Difference in percentage at Month 24
	Estimated Value	7.8
	Confidence Interval	(2-Sided) 95%; 2.0 to 13.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

5. Secondary Outcome

Title	Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) Score at Months 24 and 36 in Patients With Focal Edema at Baseline
Description	BCVA was measured 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	Baseline to Month 36

Outcome Measure Data

Analysis Population Description

Subgroup of the intent-to-treat population: All randomized patients with focal edema at baseline, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.	Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Measure Participants	54	55	57	57
Month 24	11.9 (14.2)	9.8 (11.3)	2.0 (14.3)	NA (NA)
Month 36	14.3 (11.2)	9.7 (12.6)	NA (NA)	4.6 (14.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.3 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	ANOVA
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.7
	Confidence Interval	(2-Sided) 95%; 4.3 to 15.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	ANOVA
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.2
	Confidence Interval	(2-Sided) 95%; 3.3 to 13.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Mean Change From Baseline in Central Foveal Thickness at Months 24, 36, and 48
Description	Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.
Time Frame	Baseline to Month 48

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 24-month outcome measures, data in this column represents efficacy data at Month 24. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Measure Participants	125	125	127	127
Month 24	-250.6 (212.2)	-253.1 (183.7)	-133.4 (209.0)	NA (NA)
Month 36	-261.2 (196.5)	-269.1 (178.9)	NA (NA)	-200.1 (215.6)
Month 48 (n=59,55,0,47)	-233.3 (186.8)	-301.2 (155.6)	NA (NA)	-281.3 (171.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.3 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	ANCOVA
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-107.9
	Confidence Interval	(2-Sided) 95%; -149.2 to -66.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here. The statistical analysis was not performed at Month 48.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	ANCOVA
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-119.1
	Confidence Interval	(2-Sided) 95%; -159.6 to -78.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Patients With a ≥ 3-step Worsening From Baseline in the Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale Score for Eyes at Months 24 and 36
Description	The severity of diabetic retinopathy was graded on a 10-point scale by the central reading center by comparing patient fundus photographic images with a set of standard images. 1=diabetic retinopathy (DR) severity level 10, 12 (DR absent), 2=DR severity level 14A-14C, 14Z, 15, 20 (DR questionable, microaneurysms only), 3=DR severity level 35A-35F (mild non-proliferative [NP]DR), 4=DR severity level 43A, 43B (moderate NPDR), 5=DR severity level 47A-47D (moderately severe NPDR), 6=DR severity level 53A-53E (severe NPDR), 7=DR severity level 60, 61A, 61B (mild proliferative [P]DR), 8=DR severity level 65A-65C (moderate PDR), 9=DR severity level 71A-71D (high-risk PDR), 10=DR severity level 90 (cannot grade). A lower score indicates less severe diabetic retinopathy.
Time Frame	Baseline to Month 36

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.	Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Measure Participants	117	115	115	115
Month 24 (n=117, 115, 115)	0.9	1.7	4.3	NA
Month 36 (n-117, 115, 115)	1.7	1.7	NA	4.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.3 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1590
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Difference in percentage at Month 24
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 95%; -6.7 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2721
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Difference in percentage at Month 24
	Estimated Value	-2.5
	Confidence Interval	(2-Sided) 95%; -6.5 to 1.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

8. Secondary Outcome

Title	Percentage of Patients With Resolution of Leakage at Month 24
Description	Resolution of leakage was defined as total area of fluorescein leakage in the central, inner, and outer subfields of the 0 Disc Area. Leakage was assessed in fluorescein angiographic images by the central reading center.
Time Frame	Baseline to Month 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection
Arm/Group Description	Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.	Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months.
Measure Participants	123	123	126
Number (95% Confidence Interval) [Percentage of patients]	30.1	26.0	1.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.3 mg, Sham Injection
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Difference in percentage at Month 24
	Estimated Value	29.5
	Confidence Interval	(2-Sided) 95%; 21.1 to 38.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Sham Injection
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	Cochran-Mantel-Haenszel
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Difference in percentage at Month 24
	Estimated Value	24.2
	Confidence Interval	(2-Sided) 95%; 16.7 to 31.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	The percentage for each group and the difference in percentage between groups were estimated using the weighted average of the observed percentages and the differences in observed percentages over the strata using the Cochran-Mantel-Haenszel weights.

9. Secondary Outcome

Title	Mean Number of Macular Laser Treatments From Baseline Through Months 24 and 36
Description	The need for macular laser treatment was evaluated by the masked (evaluating) physician. Macular laser was administered per protocol-specified objective and subjective criteria starting at Month 3.
Time Frame	Baseline to Month 36

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed using the last observation carried forward method.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.	Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. For 24-month outcome measures, data in this column represents efficacy data at Month 24.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. For 36-month outcome measures, data in this column represents efficacy data at Month 36.
Measure Participants	125	125	127	127
Month 24	0.8 (1.2)	0.8 (1.3)	1.8 (1.8)	NA (NA)
Month 36	0.8 (1.4)	0.9 (1.5)	NA (NA)	1.9 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.3 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	ANOVA
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -1.4 to -0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ranibizumab 0.5 mg, Sham Injection
	Comments	The analysis summarized in this section is for the Month 24 time point, comparing the outcome for patients randomized to ranibizumab versus sham injections during the controlled treatment period. The statistical analysis for the Outcome Measure at Month 36 is not shown here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	To manage the type I error rate while testing multiple secondary efficacy endpoints for statistical significance, a type I error management plan was implemented. Secondary endpoints were prioritized and tested using a hierarchical testing procedure.
	Method	ANOVA
	Comments	The analysis was stratified by baseline BCVA score (≤55, >55 letters), baseline HbA1c (≤8%, >8%), and prior therapy for ME in the study eye (yes, no).
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -1.5 to -0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Percentage of Patients Who Gained ≥ 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score From Baseline at Months 36 and 48
Description	BCVA was measured 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	Baseline to Month 48

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. Missing data were imputed up to Month 36 using the last observation carried forward method. The Month 48 outcome measures are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 36-month outcome measures, data in this column represents efficacy data at Month 36. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Measure Participants	125	125	127
Month 36	51.2	41.6	22.0
Month 48 (n=62,56,48)	50.0	48.2	22.9

11. Secondary Outcome

Title	Mean Change From Month 36 in Best Corrected Visual Acuity (BCVA) Score in the Study Eye at Month 48
Description	BCVA was measured 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 36 to Month 48

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata. PRN) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Measure Participants	62	56	48
Mean (Standard Deviation) [Letters]	-1.7 (7.5)	0.8 (7.1)	1.3 (5.4)

12. Secondary Outcome

Title	Percentage of Patients Who Lost < 15 Letters in Their Best Corrected Visual Acuity (BCVA) Score in the Study Eye From Month 36 at Month 48
Description	BCVA was measured 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 36 to Month 48

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata. PRN) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Measure Participants	62	56	48
Number (95% Confidence Interval) [Percentage of participants]	93.5 74.8%	96.4 77.1%	100.0 78.7%

13. Secondary Outcome

Title	Mean Change From Month 36 in Central Foveal Thickness in the Study Eye at Month 48
Description	Central foveal thickness was assessed in optical coherence tomographic images by the central reading center. A decrease in foveal thickness suggests a reduction in macular edema. A negative change score indicates improvement.
Time Frame	Month 36 to Month 48

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, whether or not treatment was received. The Month 48 data are based on the observed data for patients enrolled in the open-label extension phase; missing data were not imputed.

Arm/Group Title	Ranibizumab 0.3 mg	Ranibizumab 0.5 mg	Sham Injection/Ranibizumab 0.5 mg
Arm/Group Description	Patients randomized to this group received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata. PRN) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.	Patients randomized to this group received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. For 48-month outcome measures, data in this column represents efficacy data at Month 48 for subjects enrolled in the open-label extension.
Measure Participants	59	55	47
Mean (Standard Deviation) [µm]	23.3 (119.0)	4.2 (78.6)	29.6 (89.2)

Adverse Events

Time Frame	Adverse events were recorded from the first day of treatment through Month 60. The sham Months 0-36 group includes patients randomized to sham. The sham Months 0-24 group includes patients who received sham during the first 24 months of the study.
Adverse Event Reporting Description	The adverse events tables have been updated to MedDRA version 15.1 to include safety data from the open-label extension phase. Late reported adverse events from the 36-month period have also been included. Safety-evaluable population: All randomized patients who received at least 1 study treatment.
Arm/Group Title	Sham Injection - Months 0-24		Sham Injection/Ranibizumab 0.5 mg - Months 0-36		Ranibizumab 0.3 mg - Months 0-36		Ranibizumab 0.5 mg - Months 0-36		Sham Injection/Ranibizumab 0.5 mg - Months 37-60		Ranibizumab 0.3 mg - Months 37-60		Ranibizumab 0.5 mg - Months 37-60
Arm/Group Description	Patients received a sham intravitreal injection monthly for 24 months. Data in this column represent the safety data in the sham group during the first 24 months of the trial when patients were receiving only sham injections. Safety data shown here are also included in the Sham/Ranibizumab 0.5 mg - Months 0-36 column.		Patients received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Data in this column represent the safety data in the sham group during the entire 36 months of the trial; most patients crossed over to receive ranibizumab 0.5 mg monthly in the third year.		Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months.		Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months.		Patients received a sham intravitreal injection monthly for 24 months. Although still masked, patients who had not discontinued treatment by Month 24 could choose to receive ranibizumab 0.5 mg monthly administered intravitreally for the subsequent 12 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. Data in this column represent the safety data during the open-label extension phase (after Month 36).		Patients received ranibizumab 0.3 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. Data in this column represent the safety data during the open-label extension phase (after Month 36).		Patients received ranibizumab 0.5 mg monthly administered intravitreally for 36 months. Patients who had not discontinued treatment by Month 36 could enter the open-label extension phase to receive ranibizumab 0.5 mg as needed (pro re nata [PRN]) for up to 24 additional months. Data in this column represent the safety data during the open-label extension phase (after Month 36).
All Cause Mortality
	Sham Injection - Months 0-24		Sham Injection/Ranibizumab 0.5 mg - Months 0-36		Ranibizumab 0.3 mg - Months 0-36		Ranibizumab 0.5 mg - Months 0-36		Sham Injection/Ranibizumab 0.5 mg - Months 37-60		Ranibizumab 0.3 mg - Months 37-60		Ranibizumab 0.5 mg - Months 37-60
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Sham Injection - Months 0-24		Sham Injection/Ranibizumab 0.5 mg - Months 0-36		Ranibizumab 0.3 mg - Months 0-36		Ranibizumab 0.5 mg - Months 0-36		Sham Injection/Ranibizumab 0.5 mg - Months 37-60		Ranibizumab 0.3 mg - Months 37-60		Ranibizumab 0.5 mg - Months 37-60
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/124 (37.9%)		59/124 (47.6%)		60/125 (48%)		69/125 (55.2%)		18/76 (23.7%)		26/90 (28.9%)		23/79 (29.1%)
Blood and lymphatic system disorders
Anaemia	1/124 (0.8%)		1/124 (0.8%)		1/125 (0.8%)		5/125 (4%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Haemorrhagic anaemia	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Leukocytosis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cardiac disorders
Acute myocardial infarction	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		4/125 (3.2%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Angina pectoris	2/124 (1.6%)		3/124 (2.4%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		3/90 (3.3%)		0/79 (0%)
Angina unstable	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Arrhythmia	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		1/125 (0.8%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Atrial fibrillation	2/124 (1.6%)		2/124 (1.6%)		3/125 (2.4%)		2/125 (1.6%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Atrial flutter	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Atrioventricular block complete	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Bradycardia	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cardiac arrest	1/124 (0.8%)		1/124 (0.8%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Cardiac failure acute	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cardiac failure congestive	2/124 (1.6%)		4/124 (3.2%)		7/125 (5.6%)		7/125 (5.6%)		1/76 (1.3%)		4/90 (4.4%)		2/79 (2.5%)
Congestive cardiomyopathy	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Coronary artery disease	1/124 (0.8%)		2/124 (1.6%)		6/125 (4.8%)		3/125 (2.4%)		1/76 (1.3%)		0/90 (0%)		2/79 (2.5%)
Coronary artery occlusion	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Heart valve incompetence	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Ischaemic cardiomyopathy	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Myocardial infarction	3/124 (2.4%)		3/124 (2.4%)		6/125 (4.8%)		1/125 (0.8%)		1/76 (1.3%)		2/90 (2.2%)		1/79 (1.3%)
Ventricular fibrillation	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Ventricular tachycardia	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Atrioventricular block second degree	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Cardiomyopathy	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Cardiomegaly	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Congenital, familial and genetic disorders
Haemorrhagic arteriovenous malformation	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Ear and labyrinth disorders
Vertigo	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Eye disorders
Cataract (F)	1/124 (0.8%)		3/124 (2.4%)		3/125 (2.4%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cataract (S)	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Choroidal neovascularisation (S)	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Corneal degeneration (S)	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cystoid macular oedema (F)	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Diabetic retinal oedema (F)	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Diabetic retinal oedema (S)	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Glaucoma (F)	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Iritis (S)	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Macular oedema (F)	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Macular oedema (S)	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Optic ischaemic neuropathy (F)	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Posterior capsule opacification (S)	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Retinal detachment (F)	0/124 (0%)		0/124 (0%)		2/125 (1.6%)		2/125 (1.6%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Retinal detachment (S)	1/124 (0.8%)		2/124 (1.6%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Retinal haemorrhage (F)	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Retinal haemorrhage (S)	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Retinal neovascularisation (F)	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Retinal tear (S)	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Visual acuity reduced (F)	1/124 (0.8%)		3/124 (2.4%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		1/79 (1.3%)
Visual acuity reduced (S)	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Vitreous detachment (S)	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Vitreous haemorrhage (F)	2/124 (1.6%)		3/124 (2.4%)		4/125 (3.2%)		3/125 (2.4%)		0/76 (0%)		1/90 (1.1%)		1/79 (1.3%)
Vitreous haemorrhage (S)	5/124 (4%)		5/124 (4%)		0/125 (0%)		3/125 (2.4%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Macular hole (S)	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Blindness (S)	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Ulcerative keratitis (S)	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Corneal epithelium defect (F)	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Corneal oedema (F)	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Gastrointestinal disorders
Abdominal pain	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Abdominal pain upper	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Ascites	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Colitis ischaemic	0/124 (0%)		0/124 (0%)		2/125 (1.6%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Colitis ulcerative	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Colonic polyp	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Constipation	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Duodenal ulcer haemorrhage	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Erosive oesophagitis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Gastric ulcer	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Gastritis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		1/76 (1.3%)		0/90 (0%)		1/79 (1.3%)
Gastrointestinal haemorrhage	0/124 (0%)		1/124 (0.8%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Haematemesis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Impaired gastric emptying	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Large intestine perforation	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Lower gastrointestinal haemorrhage	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Pancreatitis	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Pancreatitis acute	0/124 (0%)		0/124 (0%)		0/125 (0%)		2/125 (1.6%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Rectal haemorrhage	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Retroperitoneal haemorrhage	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Small intestinal obstruction	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Upper gastrointestinal haemorrhage	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
General disorders
Chest pain	0/124 (0%)		1/124 (0.8%)		2/125 (1.6%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Death	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
General physical health deterioration	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Oedema peripheral	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Pyrexia	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Chest discomfort	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Non-cardiac chest pain	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		1/79 (1.3%)
Device malfunction	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		1/90 (1.1%)		0/79 (0%)
Hepatobiliary disorders
Cholecystitis	1/124 (0.8%)		2/124 (1.6%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cholecystitis acute	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cholecystitis chronic	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cholelithiasis	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Hepatic cirrhosis	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Infections and infestations
Abscess limb	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Abscess oral	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Acute sinusitis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Bronchitis	0/124 (0%)		0/124 (0%)		2/125 (1.6%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Bronchopneumonia	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cardiac infection	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cellulitis	1/124 (0.8%)		1/124 (0.8%)		2/125 (1.6%)		4/125 (3.2%)		1/76 (1.3%)		1/90 (1.1%)		1/79 (1.3%)
Cholecystitis infective	1/124 (0.8%)		1/124 (0.8%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Clostridial infection	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Clostridium difficile colitis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Device related infection	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Device related sepsis	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Diabetic foot infection	0/124 (0%)		0/124 (0%)		0/125 (0%)		2/125 (1.6%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Empyema	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Endophthalmitis (F)	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Endophthalmitis (S)	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Gangrene	1/124 (0.8%)		1/124 (0.8%)		1/125 (0.8%)		0/125 (0%)		2/76 (2.6%)		0/90 (0%)		1/79 (1.3%)
Gas gangrene	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Gastroenteritis	0/124 (0%)		0/124 (0%)		0/125 (0%)		2/125 (1.6%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Gastroenteritis viral	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Gastrointestinal infection	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Helicobacter gastritis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Herpes zoster	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Keratitis bacterial (S)	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Lobar pneumonia	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Localised infection	2/124 (1.6%)		2/124 (1.6%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Osteomyelitis	0/124 (0%)		0/124 (0%)		2/125 (1.6%)		0/125 (0%)		0/76 (0%)		2/90 (2.2%)		1/79 (1.3%)
Pelvic abscess	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Pneumonia	3/124 (2.4%)		3/124 (2.4%)		6/125 (4.8%)		5/125 (4%)		2/76 (2.6%)		2/90 (2.2%)		1/79 (1.3%)
Pneumonia staphylococcal	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Sepsis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Septic shock	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Staphylococcal infection	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Urinary tract infection bacterial	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Bacterial infection	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Pneumonia bacterial	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Postoperative abscess	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Urosepsis	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Diverticulitis	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Peritonitis	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Injury, poisoning and procedural complications
Ankle fracture	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Arteriovenous fistula site haematoma	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cataract traumatic (S)	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Comminuted fracture	0/124 (0%)		0/124 (0%)		2/125 (1.6%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Fall	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Femoral neck fracture	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Femur fracture	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Foreign body	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Hip fracture	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Limb crushing injury	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Limb injury	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Medication error (S)	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		2/125 (1.6%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Overdose	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Postoperative ileus	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Road traffic accident	0/124 (0%)		1/124 (0.8%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Toxicity to various agents	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Upper limb fracture	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Humerus fracture	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Investigations
Blood glucose increased	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Blood potassium increased	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Full blood count decreased	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Intraocular pressure increased (S)	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Troponin I increased	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Metabolism and nutrition disorders
Dehydration	1/124 (0.8%)		2/124 (1.6%)		1/125 (0.8%)		2/125 (1.6%)		1/76 (1.3%)		1/90 (1.1%)		0/79 (0%)
Diabetes mellitus	0/124 (0%)		0/124 (0%)		2/125 (1.6%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Diabetes mellitus inadequate control	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Diabetic ketoacidosis	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		2/125 (1.6%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Hyperglycaemia	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Hypoglycaemia	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		2/125 (1.6%)		0/76 (0%)		1/90 (1.1%)		1/79 (1.3%)
Hyponatraemia	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Hyponatraemic syndrome	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Failure to thrive	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Hyperkalaemia	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Musculoskeletal and connective tissue disorders
Arthritis	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Back pain	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cervical spinal stenosis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Costochondritis	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Muscle spasms	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Muscular weakness	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Rhabdomyolysis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Rheumatoid arthritis	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Neuropathic arthropathy	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Crystal arthropathy	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Basal cell carcinoma	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Breast cancer	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Breast cancer metastatic	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Colon cancer	0/124 (0%)		0/124 (0%)		0/125 (0%)		2/125 (1.6%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Gastrointestinal neoplasm	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Hepatic neoplasm malignant	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Lung neoplasm malignant	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Melanoma recurrent	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Prostate cancer	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Rectal cancer	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Thyroid cancer	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Ovarian neoplasm	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Lung squamous cell carcinoma stage unspecified	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Ovarian cancer metastatic	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Nervous system disorders
Cerebrovascular accident	1/124 (0.8%)		1/124 (0.8%)		1/125 (0.8%)		5/125 (4%)		1/76 (1.3%)		1/90 (1.1%)		1/79 (1.3%)
Convulsion	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Diabetic hyperosmolar coma	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Dizziness	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Hypoaesthesia	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Ischaemic stroke	1/124 (0.8%)		2/124 (1.6%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Lacunar infarction	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Metabolic encephalopathy	0/124 (0%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Presyncope	0/124 (0%)		0/124 (0%)		0/125 (0%)		2/125 (1.6%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Syncope	1/124 (0.8%)		1/124 (0.8%)		2/125 (1.6%)		3/125 (2.4%)		0/76 (0%)		1/90 (1.1%)		1/79 (1.3%)
Transient ischaemic attack	3/124 (2.4%)		3/124 (2.4%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		2/90 (2.2%)		0/79 (0%)
Embolic stroke	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Haemorrhage intracranial	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		1/90 (1.1%)		0/79 (0%)
Intraventricular haemorrhage	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Subarachnoid haemorrhage	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Intracranial aneurysm	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Carotid artery stenosis	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Status epilepticus	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Dysarthria	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Psychiatric disorders
Anxiety	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Confusional state	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Delusion	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Depression	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Schizophrenia	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Major depression	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Renal and urinary disorders
Diabetic nephropathy	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Haematuria	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Nephrolithiasis	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Nephrotic syndrome	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Renal artery arteriosclerosis	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Renal failure	1/124 (0.8%)		3/124 (2.4%)		4/125 (3.2%)		2/125 (1.6%)		0/76 (0%)		1/90 (1.1%)		3/79 (3.8%)
Renal failure acute	2/124 (1.6%)		2/124 (1.6%)		3/125 (2.4%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Renal failure chronic	0/124 (0%)		1/124 (0.8%)		4/125 (3.2%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Stress urinary incontinence	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/124 (0%)		1/124 (0.8%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Endometrial hyperplasia	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Asthma	1/124 (0.8%)		1/124 (0.8%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Chronic obstructive pulmonary disease	2/124 (1.6%)		2/124 (1.6%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Hypoxia	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		1/125 (0.8%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Pleural effusion	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Pulmonary embolism	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Pulmonary oedema	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Pulmonary thrombosis	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Respiratory distress	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Respiratory failure	0/124 (0%)		0/124 (0%)		2/125 (1.6%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Pneumonia aspiration	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		1/90 (1.1%)		0/79 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	1/124 (0.8%)		1/124 (0.8%)		3/125 (2.4%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Decubitus ulcer	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		1/90 (1.1%)		1/79 (1.3%)
Surgical and medical procedures
Toe amputation	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Intra-ocular injection (S)	0/124 (0%)		0/124 (0%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Vascular disorders
Accelerated hypertension	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Aortic stenosis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Arterial occlusive disease	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Arteriosclerosis	0/124 (0%)		0/124 (0%)		2/125 (1.6%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Deep vein thrombosis	0/124 (0%)		0/124 (0%)		0/125 (0%)		2/125 (1.6%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Femoral artery occlusion	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Hypertension	0/124 (0%)		0/124 (0%)		2/125 (1.6%)		5/125 (4%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Hypertensive emergency	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Hypotension	0/124 (0%)		1/124 (0.8%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Intermittent claudication	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Orthostatic hypotension	0/124 (0%)		0/124 (0%)		1/125 (0.8%)		0/125 (0%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Peripheral arterial occlusive disease	1/124 (0.8%)		1/124 (0.8%)		0/125 (0%)		0/125 (0%)		1/76 (1.3%)		0/90 (0%)		0/79 (0%)
Thrombosis	0/124 (0%)		0/124 (0%)		0/125 (0%)		1/125 (0.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Other (Not Including Serious) Adverse Events
	Sham Injection - Months 0-24		Sham Injection/Ranibizumab 0.5 mg - Months 0-36		Ranibizumab 0.3 mg - Months 0-36		Ranibizumab 0.5 mg - Months 0-36		Sham Injection/Ranibizumab 0.5 mg - Months 37-60		Ranibizumab 0.3 mg - Months 37-60		Ranibizumab 0.5 mg - Months 37-60
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	122/124 (98.4%)		122/124 (98.4%)		123/125 (98.4%)		121/125 (96.8%)		60/76 (78.9%)		76/90 (84.4%)		69/79 (87.3%)
Blood and lymphatic system disorders
Anaemia	11/124 (8.9%)		14/124 (11.3%)		20/125 (16%)		20/125 (16%)		2/76 (2.6%)		4/90 (4.4%)		3/79 (3.8%)
Cardiac disorders
Cardiac failure congestive	3/124 (2.4%)		7/124 (5.6%)		3/125 (2.4%)		13/125 (10.4%)		2/76 (2.6%)		3/90 (3.3%)		0/79 (0%)
Coronary artery disease	2/124 (1.6%)		2/124 (1.6%)		3/125 (2.4%)		7/125 (5.6%)		1/76 (1.3%)		3/90 (3.3%)		2/79 (2.5%)
Endocrine disorders
Hypothyroidism	1/124 (0.8%)		2/124 (1.6%)		9/125 (7.2%)		6/125 (4.8%)		0/76 (0%)		1/90 (1.1%)		2/79 (2.5%)
Eye disorders
Blepharitis (F)	1/124 (0.8%)		2/124 (1.6%)		7/125 (5.6%)		9/125 (7.2%)		1/76 (1.3%)		1/90 (1.1%)		1/79 (1.3%)
Blepharitis (S)	1/124 (0.8%)		2/124 (1.6%)		8/125 (6.4%)		7/125 (5.6%)		2/76 (2.6%)		1/90 (1.1%)		1/79 (1.3%)
Cataract (F)	25/124 (20.2%)		28/124 (22.6%)		30/125 (24%)		23/125 (18.4%)		3/76 (3.9%)		3/90 (3.3%)		2/79 (2.5%)
Cataract (S)	20/124 (16.1%)		21/124 (16.9%)		28/125 (22.4%)		21/125 (16.8%)		7/76 (9.2%)		4/90 (4.4%)		2/79 (2.5%)
Cataract cortical (F)	8/124 (6.5%)		9/124 (7.3%)		7/125 (5.6%)		7/125 (5.6%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Cataract cortical (S)	9/124 (7.3%)		10/124 (8.1%)		9/125 (7.2%)		8/125 (6.4%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cataract nuclear (F)	6/124 (4.8%)		8/124 (6.5%)		6/125 (4.8%)		4/125 (3.2%)		0/76 (0%)		3/90 (3.3%)		1/79 (1.3%)
Cataract nuclear (S)	7/124 (5.6%)		8/124 (6.5%)		6/125 (4.8%)		6/125 (4.8%)		0/76 (0%)		3/90 (3.3%)		1/79 (1.3%)
Cataract subcapsular (F)	7/124 (5.6%)		5/124 (4%)		5/125 (4%)		5/125 (4%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Cataract subcapsular (S)	4/124 (3.2%)		4/124 (3.2%)		9/125 (7.2%)		9/125 (7.2%)		1/76 (1.3%)		4/90 (4.4%)		0/79 (0%)
Conjunctival haemorrhage (F)	2/124 (1.6%)		12/124 (9.7%)		19/125 (15.2%)		19/125 (15.2%)		8/76 (10.5%)		11/90 (12.2%)		9/79 (11.4%)
Conjunctival haemorrhage (S)	40/124 (32.3%)		45/124 (36.3%)		70/125 (56%)		66/125 (52.8%)		6/76 (7.9%)		13/90 (14.4%)		12/79 (15.2%)
Cystoid macular oedema (F)	8/124 (6.5%)		10/124 (8.1%)		12/125 (9.6%)		12/125 (9.6%)		0/76 (0%)		2/90 (2.2%)		0/79 (0%)
Cystoid macular oedema (S)	5/124 (4%)		6/124 (4.8%)		8/125 (6.4%)		4/125 (3.2%)		0/76 (0%)		4/90 (4.4%)		2/79 (2.5%)
Diabetic retinal oedema (F)	19/124 (15.3%)		22/124 (17.7%)		23/125 (18.4%)		23/125 (18.4%)		3/76 (3.9%)		5/90 (5.6%)		5/79 (6.3%)
Diabetic retinal oedema (S)	7/124 (5.6%)		7/124 (5.6%)		7/125 (5.6%)		10/125 (8%)		2/76 (2.6%)		7/90 (7.8%)		4/79 (5.1%)
Diabetic retinopathy (F)	15/124 (12.1%)		16/124 (12.9%)		12/125 (9.6%)		9/125 (7.2%)		3/76 (3.9%)		3/90 (3.3%)		1/79 (1.3%)
Diabetic retinopathy (S)	8/124 (6.5%)		8/124 (6.5%)		2/125 (1.6%)		4/125 (3.2%)		3/76 (3.9%)		1/90 (1.1%)		0/79 (0%)
Dry eye (F)	6/124 (4.8%)		7/124 (5.6%)		12/125 (9.6%)		10/125 (8%)		1/76 (1.3%)		1/90 (1.1%)		3/79 (3.8%)
Dry eye (S)	7/124 (5.6%)		8/124 (6.5%)		13/125 (10.4%)		11/125 (8.8%)		1/76 (1.3%)		3/90 (3.3%)		3/79 (3.8%)
Eye irritation (S)	9/124 (7.3%)		9/124 (7.3%)		13/125 (10.4%)		12/125 (9.6%)		2/76 (2.6%)		3/90 (3.3%)		6/79 (7.6%)
Eye pain (F)	4/124 (3.2%)		7/124 (5.6%)		10/125 (8%)		13/125 (10.4%)		3/76 (3.9%)		7/90 (7.8%)		5/79 (6.3%)
Eye pain (S)	24/124 (19.4%)		28/124 (22.6%)		35/125 (28%)		30/125 (24%)		3/76 (3.9%)		5/90 (5.6%)		7/79 (8.9%)
Eye pruritus (S)	8/124 (6.5%)		8/124 (6.5%)		7/125 (5.6%)		5/125 (4%)		2/76 (2.6%)		3/90 (3.3%)		2/79 (2.5%)
Foreign body sensation in eyes (S)	6/124 (4.8%)		6/124 (4.8%)		17/125 (13.6%)		8/125 (6.4%)		1/76 (1.3%)		3/90 (3.3%)		1/79 (1.3%)
Lacrimation increased (S)	8/124 (6.5%)		8/124 (6.5%)		8/125 (6.4%)		15/125 (12%)		1/76 (1.3%)		0/90 (0%)		1/79 (1.3%)
Macular fibrosis (F)	13/124 (10.5%)		14/124 (11.3%)		15/125 (12%)		15/125 (12%)		2/76 (2.6%)		0/90 (0%)		2/79 (2.5%)
Macular fibrosis (S)	7/124 (5.6%)		10/124 (8.1%)		8/125 (6.4%)		17/125 (13.6%)		2/76 (2.6%)		1/90 (1.1%)		1/79 (1.3%)
Macular oedema (F)	40/124 (32.3%)		47/124 (37.9%)		45/125 (36%)		46/125 (36.8%)		5/76 (6.6%)		9/90 (10%)		11/79 (13.9%)
Macular oedema (S)	24/124 (19.4%)		26/124 (21%)		25/125 (20%)		29/125 (23.2%)		3/76 (3.9%)		9/90 (10%)		8/79 (10.1%)
Ocular hyperaemia (S)	14/124 (11.3%)		14/124 (11.3%)		20/125 (16%)		14/125 (11.2%)		1/76 (1.3%)		2/90 (2.2%)		2/79 (2.5%)
Photophobia (S)	1/124 (0.8%)		1/124 (0.8%)		7/125 (5.6%)		5/125 (4%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Posterior capsule opacification (F)	3/124 (2.4%)		4/124 (3.2%)		10/125 (8%)		4/125 (3.2%)		0/76 (0%)		1/90 (1.1%)		3/79 (3.8%)
Retinal aneurysm (F)	5/124 (4%)		6/124 (4.8%)		10/125 (8%)		6/125 (4.8%)		0/76 (0%)		1/90 (1.1%)		1/79 (1.3%)
Retinal aneurysm (S)	3/124 (2.4%)		4/124 (3.2%)		10/125 (8%)		6/125 (4.8%)		0/76 (0%)		1/90 (1.1%)		1/79 (1.3%)
Retinal exudates (F)	24/124 (19.4%)		27/124 (21.8%)		22/125 (17.6%)		15/125 (12%)		3/76 (3.9%)		1/90 (1.1%)		0/79 (0%)
Retinal exudates (S)	25/124 (20.2%)		28/124 (22.6%)		28/125 (22.4%)		24/125 (19.2%)		1/76 (1.3%)		4/90 (4.4%)		2/79 (2.5%)
Retinal haemorrhage (F)	24/124 (19.4%)		25/124 (20.2%)		24/125 (19.2%)		37/125 (29.6%)		4/76 (5.3%)		3/90 (3.3%)		3/79 (3.8%)
Retinal haemorrhage (S)	24/124 (19.4%)		26/124 (21%)		19/125 (15.2%)		20/125 (16%)		3/76 (3.9%)		3/90 (3.3%)		5/79 (6.3%)
Retinal neovascularisation (F)	15/124 (12.1%)		19/124 (15.3%)		12/125 (9.6%)		18/125 (14.4%)		2/76 (2.6%)		2/90 (2.2%)		1/79 (1.3%)
Retinal neovascularisation (S)	16/124 (12.9%)		18/124 (14.5%)		0/125 (0%)		6/125 (4.8%)		2/76 (2.6%)		3/90 (3.3%)		1/79 (1.3%)
Vision blurred (F)	5/124 (4%)		6/124 (4.8%)		7/125 (5.6%)		6/125 (4.8%)		1/76 (1.3%)		2/90 (2.2%)		1/79 (1.3%)
Vision blurred (S)	7/124 (5.6%)		7/124 (5.6%)		15/125 (12%)		11/125 (8.8%)		0/76 (0%)		4/90 (4.4%)		2/79 (2.5%)
Visual acuity reduced (S)	8/124 (6.5%)		10/124 (8.1%)		8/125 (6.4%)		7/125 (5.6%)		1/76 (1.3%)		1/90 (1.1%)		1/79 (1.3%)
Vitreous detachment (F)	16/124 (12.9%)		18/124 (14.5%)		20/125 (16%)		23/125 (18.4%)		2/76 (2.6%)		0/90 (0%)		2/79 (2.5%)
Vitreous detachment (S)	18/124 (14.5%)		19/124 (15.3%)		21/125 (16.8%)		20/125 (16%)		1/76 (1.3%)		2/90 (2.2%)		3/79 (3.8%)
Vitreous floaters (F)	5/124 (4%)		8/124 (6.5%)		15/125 (12%)		10/125 (8%)		4/76 (5.3%)		7/90 (7.8%)		2/79 (2.5%)
Vitreous floaters (S)	7/124 (5.6%)		10/124 (8.1%)		22/125 (17.6%)		20/125 (16%)		2/76 (2.6%)		6/90 (6.7%)		4/79 (5.1%)
Vitreous haemorrhage (F)	8/124 (6.5%)		11/124 (8.9%)		10/125 (8%)		10/125 (8%)		1/76 (1.3%)		5/90 (5.6%)		1/79 (1.3%)
Vitreous haemorrhage (S)	16/124 (12.9%)		18/124 (14.5%)		4/125 (3.2%)		6/125 (4.8%)		1/76 (1.3%)		2/90 (2.2%)		2/79 (2.5%)
Gastrointestinal disorders
Constipation	4/124 (3.2%)		5/124 (4%)		13/125 (10.4%)		15/125 (12%)		4/76 (5.3%)		3/90 (3.3%)		1/79 (1.3%)
Diarrhoea	5/124 (4%)		7/124 (5.6%)		12/125 (9.6%)		15/125 (12%)		3/76 (3.9%)		4/90 (4.4%)		4/79 (5.1%)
Dyspepsia	3/124 (2.4%)		4/124 (3.2%)		7/125 (5.6%)		1/125 (0.8%)		2/76 (2.6%)		2/90 (2.2%)		1/79 (1.3%)
Gastrooesophageal reflux disease	7/124 (5.6%)		11/124 (8.9%)		13/125 (10.4%)		11/125 (8.8%)		3/76 (3.9%)		5/90 (5.6%)		3/79 (3.8%)
Nausea	10/124 (8.1%)		13/124 (10.5%)		16/125 (12.8%)		18/125 (14.4%)		5/76 (6.6%)		7/90 (7.8%)		5/79 (6.3%)
Vomiting	7/124 (5.6%)		7/124 (5.6%)		8/125 (6.4%)		11/125 (8.8%)		3/76 (3.9%)		3/90 (3.3%)		4/79 (5.1%)
General disorders
Oedema peripheral	6/124 (4.8%)		8/124 (6.5%)		8/125 (6.4%)		13/125 (10.4%)		1/76 (1.3%)		6/90 (6.7%)		2/79 (2.5%)
Pain	2/124 (1.6%)		4/124 (3.2%)		5/125 (4%)		8/125 (6.4%)		0/76 (0%)		2/90 (2.2%)		2/79 (2.5%)
Immune system disorders
Seasonal allergy	4/124 (3.2%)		6/124 (4.8%)		11/125 (8.8%)		7/125 (5.6%)		2/76 (2.6%)		3/90 (3.3%)		2/79 (2.5%)
Infections and infestations
Bronchitis	5/124 (4%)		9/124 (7.3%)		8/125 (6.4%)		9/125 (7.2%)		6/76 (7.9%)		3/90 (3.3%)		4/79 (5.1%)
Influenza	1/124 (0.8%)		3/124 (2.4%)		10/125 (8%)		11/125 (8.8%)		0/76 (0%)		1/90 (1.1%)		5/79 (6.3%)
Nasopharyngitis	9/124 (7.3%)		13/124 (10.5%)		18/125 (14.4%)		25/125 (20%)		6/76 (7.9%)		2/90 (2.2%)		11/79 (13.9%)
Pneumonia	7/124 (5.6%)		8/124 (6.5%)		7/125 (5.6%)		5/125 (4%)		1/76 (1.3%)		2/90 (2.2%)		1/79 (1.3%)
Sinusitis	9/124 (7.3%)		11/124 (8.9%)		6/125 (4.8%)		7/125 (5.6%)		2/76 (2.6%)		1/90 (1.1%)		3/79 (3.8%)
Upper respiratory tract infection	7/124 (5.6%)		8/124 (6.5%)		11/125 (8.8%)		11/125 (8.8%)		2/76 (2.6%)		4/90 (4.4%)		4/79 (5.1%)
Urinary tract infection	9/124 (7.3%)		12/124 (9.7%)		5/125 (4%)		14/125 (11.2%)		2/76 (2.6%)		3/90 (3.3%)		6/79 (7.6%)
Injury, poisoning and procedural complications
Corneal abrasion (S)	7/124 (5.6%)		7/124 (5.6%)		4/125 (3.2%)		4/125 (3.2%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Fall	4/124 (3.2%)		6/124 (4.8%)		3/125 (2.4%)		7/125 (5.6%)		3/76 (3.9%)		4/90 (4.4%)		6/79 (7.6%)
Investigations
Blood glucose increased	6/124 (4.8%)		6/124 (4.8%)		8/125 (6.4%)		12/125 (9.6%)		5/76 (6.6%)		3/90 (3.3%)		2/79 (2.5%)
Intraocular pressure increased (F)	4/124 (3.2%)		6/124 (4.8%)		13/125 (10.4%)		8/125 (6.4%)		0/76 (0%)		0/90 (0%)		2/79 (2.5%)
Intraocular pressure increased (S)	3/124 (2.4%)		9/124 (7.3%)		26/125 (20.8%)		20/125 (16%)		0/76 (0%)		5/90 (5.6%)		2/79 (2.5%)
Metabolism and nutrition disorders
Diabetes mellitus	8/124 (6.5%)		12/124 (9.7%)		17/125 (13.6%)		13/125 (10.4%)		2/76 (2.6%)		3/90 (3.3%)		5/79 (6.3%)
Hypercholesterolaemia	6/124 (4.8%)		7/124 (5.6%)		11/125 (8.8%)		9/125 (7.2%)		0/76 (0%)		3/90 (3.3%)		2/79 (2.5%)
Hyperkalaemia	6/124 (4.8%)		8/124 (6.5%)		4/125 (3.2%)		2/125 (1.6%)		2/76 (2.6%)		1/90 (1.1%)		3/79 (3.8%)
Hyperlipidaemia	6/124 (4.8%)		7/124 (5.6%)		5/125 (4%)		6/125 (4.8%)		0/76 (0%)		0/90 (0%)		1/79 (1.3%)
Hypoglycaemia	5/124 (4%)		6/124 (4.8%)		8/125 (6.4%)		2/125 (1.6%)		2/76 (2.6%)		1/90 (1.1%)		2/79 (2.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/124 (3.2%)		5/124 (4%)		7/125 (5.6%)		11/125 (8.8%)		5/76 (6.6%)		0/90 (0%)		1/79 (1.3%)
Back pain	8/124 (6.5%)		13/124 (10.5%)		5/125 (4%)		8/125 (6.4%)		2/76 (2.6%)		4/90 (4.4%)		3/79 (3.8%)
Pain in extremity	3/124 (2.4%)		4/124 (3.2%)		3/125 (2.4%)		7/125 (5.6%)		2/76 (2.6%)		1/90 (1.1%)		2/79 (2.5%)
Nervous system disorders
Dizziness	7/124 (5.6%)		10/124 (8.1%)		4/125 (3.2%)		6/125 (4.8%)		1/76 (1.3%)		2/90 (2.2%)		5/79 (6.3%)
Headache	14/124 (11.3%)		20/124 (16.1%)		11/125 (8.8%)		9/125 (7.2%)		6/76 (7.9%)		2/90 (2.2%)		2/79 (2.5%)
Neuropathy peripheral	3/124 (2.4%)		4/124 (3.2%)		8/125 (6.4%)		8/125 (6.4%)		0/76 (0%)		1/90 (1.1%)		0/79 (0%)
Psychiatric disorders
Anxiety	5/124 (4%)		6/124 (4.8%)		5/125 (4%)		10/125 (8%)		0/76 (0%)		2/90 (2.2%)		5/79 (6.3%)
Depression	7/124 (5.6%)		9/124 (7.3%)		8/125 (6.4%)		10/125 (8%)		1/76 (1.3%)		1/90 (1.1%)		4/79 (5.1%)
Insomnia	7/124 (5.6%)		11/124 (8.9%)		7/125 (5.6%)		5/125 (4%)		3/76 (3.9%)		5/90 (5.6%)		2/79 (2.5%)
Renal and urinary disorders
Renal failure	7/124 (5.6%)		9/124 (7.3%)		9/125 (7.2%)		6/125 (4.8%)		0/76 (0%)		0/90 (0%)		0/79 (0%)
Renal failure chronic	3/124 (2.4%)		3/124 (2.4%)		7/125 (5.6%)		10/125 (8%)		3/76 (3.9%)		3/90 (3.3%)		2/79 (2.5%)
Respiratory, thoracic and mediastinal disorders
Cough	4/124 (3.2%)		7/124 (5.6%)		12/125 (9.6%)		8/125 (6.4%)		0/76 (0%)		1/90 (1.1%)		4/79 (5.1%)
Dyspnoea	3/124 (2.4%)		5/124 (4%)		5/125 (4%)		8/125 (6.4%)		0/76 (0%)		3/90 (3.3%)		6/79 (7.6%)
Vascular disorders
Hypertension	23/124 (18.5%)		28/124 (22.6%)		27/125 (21.6%)		30/125 (24%)		6/76 (7.9%)		8/90 (8.9%)		8/79 (10.1%)

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.