Efficacy & Safety Trial of Intravitreal Injections Combin... | NCT01552408

NCT01552408

Status Module

Sponsor/Collaborators Module

Name	Class
Genentech, Inc.	INDUSTRY

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
0.3 mg Ranibizumab	Active Comparator	Cohort 1: Subjects will receive 4 IVT of 0.3 mg ranibizumab every 28 days (+/- 7 days), then will be seen monthly (+/- 7 days) & will receive IVT of 0.3 mg ranibizumab on a pro re nata (PRN) schedule per retreatment criteria.	Drug: 0.3 mg ranibizumab
Targeted PRP with 0.3 mg Ranibizumab	Experimental	Cohort 2: Subjects will receive 4 it of 0.3 mg ranibizumab every 28 days (+/- 7 days), then will then be seen monthly (+/- 7 days) & receive IVT of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at Day 7 they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide field angiography. Ultra wide field angiography will be performed every 3 months to indicate areas of peripheral ischemia, which will be selectively be treated with PRP at Month 6, Month 18, and Month 25, preserving areas of more perfused retina.	Drug: 0.3 mg ranibizumab Procedure: Targeted Pan Retinal Photocoagulation

Interventions

Name	Type	Description	Arm Group Labels	Other Names
0.3 mg ranibizumab	Drug	Cohort 1: Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Total Number of Ranibizumab Injections in Each of the Two Cohorts in a 36 Month Period	Assess the number of ranibizumab injections in the ranibizumab and targeted panretinal photocoagulation (PRP) with ranibizumab cohorts through Month 36.	36 Months
Mean Change Over Time in Early Treatment Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS BCVA) Through Month 36	Evaluate the mean change over time in ETDRS BCVA in the ranibizumab and targeted PRP with ranibizumab cohorts through Month 36.	36 Months
Incidence and Severity of Ocular and Non-ocular Adverse Events (AE's) Through Month 36.	Incidence and severity of ocular and non-ocular adverse events (AE's) in the monotherapy and combination cohorts through Month 36.	36 Months

Secondary Outcomes

Measure	Description	Time Frame
Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA.	Percentage of patients in the ranibizumab and targeted PRP with ranibizumab cohorts who experience a loss of 15 or more letters from Baseline to Month 12, 24, and 36 in ETDRS BCVA.	Month 12, 24, and 36

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Willingness to provide signed informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization.
Age ≥ 18 years
Diabetes Mellitus (Type 1 or 2). The following will be considered as sufficient evidence that diabetes is present:
- Current regular use of insulin for the treatment of diabetes
- Current regular use of oral antihyperglycemic agents for the treatment of diabetes
- Documented diabetes according to the American Diabetes Association and/or World Health Organization criteria.
BCVA score in the study eye of 20/32 to 20/320 approximate snellen equivalent using the ETDRS protocol at an initial testing distance of 4 meters, confirmed by the investigator.
High Definition OCT (Spectralis) central retinal thickness measurement of ≥ 300 µm
Decrease in visual acuity is determined to be primarily the result of DME and not to other cause.
Ability and willingness to return for all scheduled visits and assessments.
Clear ocular media and adequate pupillary dilatation to permit good quality fundus photography.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from this study:

General Exclusion Criteria

Pregnancy (positive pregnancy test) or lactation
Sexually active women of childbearing potential* who are unwilling to practice adequate contraception or abstinence during the study. (*Although no birth control method is 100% effective, the following are considered adequate means of contraception: surgical sterilization, use of oral contraceptives, barrier contraception using either a condom or diaphragm with spermicidal gel, intrauterine devices, or contraceptive hormone implants or patches. A subject's primary care physician, obstetrician, or gynecologist should be consulted regarding an appropriate form of birth control)
Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated
Participation in another simultaneous medical investigation or trial] Ocular Exclusion Criteria
Prior Ocular Treatment:
- History of vitrectomy surgery in the study eye
- Any pan-retinal photocoagulation in the study eye
- Prior treatment with intraocular or subconjunctival steroids in the study eye 4 months prior to screen
- Previous treatment with antiangiogenic drugs in either eye (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc.) within 2 months of Day 0 visit
- Systemic corticosteroids 4 months prior to screen

Concurrent Ocular Conditions:

Any concurrent ocular condition in the study eye (e.g., cataract or age-related macular degeneration) that, in the opinion of the investigator could: require medical or surgical intervention during the study period to prevent or treat visual loss that might result from that condition; or, if allowed to progress untreated, could likely contribute to a loss of at least 2 Snellen equivalent lines of BCVA over the study period
Active intraocular inflammation (grade trace or above) in the study eye
Current vitreous hemorrhage in the study eye
History of rhegmatogenous retinal detachment or macular hole (Stage 3 or 4) in the study eye
Active infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye
Aphakia or absence of the posterior capsule in the study eye
Intraocular surgery (including cataract surgery) in the study eye within 2 months preceding Day 0
Uncontrolled glaucoma in the study eye (defined as IOP ≥ 30 mmHg despite treatment with anti-glaucoma medication)
History of glaucoma-filtering surgery in the study eye
History of corneal transplant in the study eye
High Risk PDR: New vessels within one disc diameter of the optic nerve head that are larger than one-third disc area
Vitreous or preretinal hemorrhage associated with less extensive NVD or with NVE one-half disc area or more in size
Extensive damage to the fovea vascular zone as determined by the principal investigator or designated site personnel
Spherical equivalent of the refractive error in the study eye of more that -8.00 diopter of myopia
Vitreomacular traction (vitreomacular attachment ok) Concurrent Systemic Conditions
Uncontrolled blood pressure (defined as systolic > 180 mmHg and/or diastolic > 110 mmHg while patient is seated. *If a subject's initial reading exceeds these values, a second reading may be taken 30 or more minutes later. If the subject's blood pressure needs to be controlled by antihypertensive medication, the subject can become eligible if medication is taken continuously for at least 30 days prior to Day 0
Atrial fibrillation not managed by subject's primary care physician or cardiologist within 3 months of screening visit
History of stroke within the last 3 months of screening visit
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 of an investigational drug or that might affect the interpretation of the results of the study or renders the patient at high risk for treatment complications
Current treatment for active systemic infection
Active malignancy
History of allergy to fluorescein, not amenable to treatment
Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality to be analyzed and graded.
Previous participation in any studies of investigational drugs within 1 month preceding Day 0 (excluding vitamins and minerals)

Contacts/Locations Module

Name	Affiliation	Role
David M Brown, MD	Director Greater Houston Research	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Retina Consultants of Houston		Houston	Texas	77030	United States
Retina Consultants of Houston

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
7487599	Background	Klein R, Meuer SM, Moss SE, Klein BE. Retinal microaneurysm counts and 10-year progression of diabetic retinopathy. Arch Ophthalmol. 1995 Nov;113(11):1386-91. doi: 10.1001/archopht.1995.01100110046024.
7643896	Background	Klein M. Prevention and treatment of the complications of diabetes mellitus. N Engl J Med. 1995 Sep 21;333(12):802. doi: 10.1056/NEJM199509213331215. No abstract available.

IPD Sharing Statement Module

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Uploaded Document Information

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Jun 10, 2014

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

FG00020 subjects20 units

FG00120 subjects20 units

Type of Units Analyzed

Arm/Group Information

ID	Title	Description
BG000	0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.
BG001	Targeted PRP With 0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide 200º field angiography (see Appendix C). After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.
BG002	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Customized

Mean

Full Range

years

Eyes

Units	Counts
Participants	BG00020 BG00120 BG00229
Eyes	BG000

Title

Denominators

Categories

Title	Measurements
	OG00024.4(10 to 34) OG00127.1(12 to 36)

Primary

Mean Change Over Time in Early Treatment Diabetic Retinopathy Study Best Corrected Visual Acuity (ETDRS BCVA) Through Month 36

Evaluate the mean change over time in ETDRS BCVA in the ranibizumab and targeted PRP with ranibizumab cohorts through Month 36.

All participants were included in analysis. Among participants who failed to complete the study, the last observation was carried forward for analysis at Month 36.

Posted

Mean

Standard Deviation

letters

36 Months

ID	Title	Description
OG000	0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.
OG001	Targeted PRP With 0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide 200º field angiography (see Appendix C). After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.

Primary

Incidence and Severity of Ocular and Non-ocular Adverse Events (AE's) Through Month 36.

Incidence and severity of ocular and non-ocular adverse events (AE's) in the monotherapy and combination cohorts through Month 36.

Posted

Count of Participants

Participants

36 Months

ID	Title	Description
OG000	0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.
OG001	Targeted PRP With 0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide 200º field angiography (see Appendix C). After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.

Secondary

Patients Who Experience a Loss of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA.

Percentage of patients in the ranibizumab and targeted PRP with ranibizumab cohorts who experience a loss of 15 or more letters from Baseline to Month 12, 24, and 36 in ETDRS BCVA.

All participants were included in analysis. Due to participant attrition and missed visits, the population analyzed at each time point is equal to or smaller than the population still enrolled at that time point.

Posted

Count of Participants

Participants

Month 12, 24, and 36

ID	Title	Description
OG000	0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.
OG001	Targeted PRP With 0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide 200º field angiography (see Appendix C). After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.

Secondary

Determine Percentage of Patients Who Experience a Gain of 15 or More Letters From Baseline to Month 12, 24, and 36 in ETDRS BCVA

Determine percentage of patients who experience a gain of 15 or more letters from Baseline to Month 12, 24, and 36 in ETDRS BCVA in the ranibizumab and targeted PRP with ranibizumab cohorts.

Posted

Count of Participants

Participants

Month 12, 24, and 36

ID	Title	Description
OG000	0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.
OG001	Targeted PRP With 0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide 200º field angiography (see Appendix C). After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.

Secondary

Evaluate Mean Change in Central Retinal Thickness Over Time Through Month 12, 24, and 36 as Assessed by High Resolution OCT's.

Evaluate mean change in central retinal thickness in the ranibizumab and targeted PRP with ranibizumab cohorts over time through Month 12, 24, and 36 as assessed by high resolution OCT's.

Posted

Mean

Standard Deviation

microns

Month 12, 24, and 36

ID	Title	Description
OG000	0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.
OG001	Targeted PRP With 0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide 200º field angiography (see Appendix C). After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.

Secondary

Patients With Persistent Macular Edema Post-intravitreal Injection.

Percentage of patients with persistent macular edema post-intravitreal injection in the ranibizumab and targeted PRP with ranibizumab cohorts.

Posted

Count of Participants

Participants

Month 36

ID	Title	Description
OG000	0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.
OG001	Targeted Pan-retinal Photocoagulation With 0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a pro re nata (PRN) schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide 200º field angiography (see Appendix C). After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.

Secondary

Mean Change in Peripheral Visual Field as Measured by Goldmann Visual Field at Screen and Month and 36.

Mean change in peripheral visual field as measured by Goldmann visual field at screen and Month 36 in the ranibizumab and targeted PRP with ranibizumab cohorts.

Participants that had poor fix (resulting in inaccurate results), missing baseline results, or missing Month 36 results were excluded.

Posted

Mean

Standard Deviation

degrees squared

36 Months

ID	Title	Description
OG000	0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.
OG001	Targeted PRP With 0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide 200º field angiography (see Appendix C). After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity.	0	20	9	20	12	20
EG001	Targeted PRP With 0.3 mg Ranibizumab	Subjects will receive 4 mandatory intravitreal injections of 0.3 mg ranibizumab every 28 days (+/- 7 days). They will then be seen monthly (+/- 7 days) and will receive intravitreal injections of 0.3 mg ranibizumab on a PRN schedule per retreatment criteria based on the evaluating Investigator's assessment of disease activity. In addition, at V3 (Day 7) they will receive targeted pan-retinal photocoagulation (PRP) based on ultra wide 200º field angiography (see Appendix C). After the first session of PRP, subject's will have ultra wide 200º field angiography performed every 3 months to indicate areas of peripheral ischemia, which will be selectively treated at V9 (Month 6), V21 (Month 18), and V28 (Month 25), preserving areas of more perfused retina. This will minimize any visual field loss secondary to nonselective pan-retinal photocoagulation.	0	20	10	20	13	20

Serious Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Neovascular glaucoma	Eye disorders	Systematic Assessment	EG0002 events2 affected20 at risk EG0010 events0 affected20 at risk
Vitreous hemorrhage with acute vision loss	Eye disorders	Systematic Assessment	EG0000 events0 affected20 at risk EG0011 events1 affected20 at risk
Sepsis	Immune system disorders	Systematic Assessment	EG0001 events1 affected20 at risk EG0011 events1 affected20 at risk
Systolic heart failure	Cardiac disorders	Systematic Assessment	EG0001 events1 affected20 at risk EG0011 events1 affected20 at risk
Atrial flutter	Cardiac disorders	Systematic Assessment	EG0001 events1 affected20 at risk EG0011 events1 affected20 at risk
Coronary artery disease	Cardiac disorders	Systematic Assessment	EG0000 events0 affected20 at risk EG0011 events1 affected20 at risk
Pneumonia	Respiratory, thoracic and mediastinal disorders	Systematic Assessment	EG0002 events2 affected20 at risk EG0011 events1 affected20 at risk
Osteomyelitits	Musculoskeletal and connective tissue disorders	Systematic Assessment	EG0003 events3 affected20 at risk EG0011 events1 affected20 at risk
Cellulitis	Skin and subcutaneous tissue disorders	Systematic Assessment	EG0002 events2 affected20 at risk EG0011 events1 affected20 at risk
Worsening renal failure	Renal and urinary disorders	Systematic Assessment	EG0003 events3 affected20 at risk EG0014 events4 affected20 at risk

Other Adverse Events

Term	Organ System	Assessment Type	Statistical Information
Vitreous hemorrhage	Eye disorders	Systematic Assessment	EG0002 events2 affected20 at risk EG0012 events2 affected20 at risk
Neovascularization elsewhere	Eye disorders	Systematic Assessment	EG0004 events4 affected20 at risk EG0010 events0 affected20 at risk
Neovascularization of the disc	Eye disorders	Systematic Assessment	EG0002 events2 affected20 at risk EG0010 events0 affected20 at risk
Neovascularization of the iris	Eye disorders	Systematic Assessment	EG0002 events1 affected20 at risk EG0010 events0 affected20 at risk
Worsening glaucoma	Eye disorders	Systematic Assessment	EG0003 events3 affected20 at risk EG0010 events0 affected20 at risk
Worsening cataract	Eye disorders	Systematic Assessment	EG0003 events3 affected20 at risk EG0016 events6 affected20 at risk
Posterior vitreous detachment	Eye disorders	Systematic Assessment	EG0004 events4 affected20 at risk EG0015 events5 affected20 at risk
Epiretinal membrane	Eye disorders	Systematic Assessment	EG0001 events1 affected20 at risk EG0013 events3 affected20 at risk
Hyphema	Eye disorders	Systematic Assessment	EG0002 events2 affected20 at risk EG0010 events0 affected20 at risk
Dilated pupil	Eye disorders	Systematic Assessment	EG0000 events0 affected20 at risk EG0011 events1 affected20 at risk

The key limitation is the small population size analyzed through 3 years; subject attrition due to elderly population.

Certain Agreements

ID	Term
D003930	Diabetic Retinopathy
D008269	Macular Edema

Ancestor Terms

ID	Term
D012164	Retinal Diseases
D005128	Eye Diseases
D003925	Diabetic Angiopathies
D014652	Vascular Diseases
D002318	Cardiovascular Diseases
D048909	Diabetes Complications
D003920	Diabetes Mellitus
D004700	Endocrine System Diseases
D008268	Macular Degeneration
D012162	Retinal Degeneration

ID	Term
D000069579	Ranibizumab

Ancestor Terms

ID	Term
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins