LRTforDME+PRP: Laser-Ranibizumab-Triamcinolone for Proliferative Diabetic Retinopathy

• Sponsor: Jaeb Center for Health Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT00445003
• Collaborator: National Eye Institute (NEI) (NIH), Genentech, Inc. (Industry), Allergan (Industry)
• Enrollment: 333
• Locations: 56
• Arms: 3
• Duration (Months): 40
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of the study is to find out if treatment with an intravitreal injection of triamcinolone or an intravitreal injection of ranibizumab can prevent loss of vision caused by panretinal photocoagulation treatment. At the present time, it is not known whether intravitreal steroid or anti-vascular endothelial growth factor (anti-VEGF) injections are beneficial in preventing vision loss after panretinal photocoagulation (PRP) treatment. It is possible that one or both of the types of injections will prevent vision loss after PRP treatment. However, it is not known whether the benefits of the injections will outweigh the risks. It is possible that because of side effects, the injections may not be as good as laser alone in treating the diabetic retinopathy.

Condition or Disease	Intervention/Treatment	Phase
Proliferative Diabetic Retinopathy; Diabetic Macular Edema	Drug: Ranibizumab; Drug: Triamcinolone Acetonide; Behavioral: Sham injection; Procedure: Focal/grid laser	Phase 3

Detailed Description

Proliferative diabetic retinopathy (PDR) is manifested in retinal neovascularization at the disc (NVD) or elsewhere (NVE). Vitreous hemorrhage or tractional detachment from PDR is a leading cause of severe visual loss and new onset blindness. Without intervention, 60 percent of individuals with diabetic retinopathy will eventually develop PDR, resulting in significant visual loss in nearly fifty percent.

Proliferative diabetic retinopathy is currently treated with panretinal photocoagulation (PRP) which destroys areas of the retina but preserves central vision. PRP is most effectively seen in a regression of new vessels, stabilization of the neovascularization, and reduced risk of visual loss. However, the treatment is associated with unavoidable side effects including macular edema with transient or permanent central vision loss, diminished vision loss, and night vision loss. The treatment applies laser burns to the peripheral retinal tissue, destroying outer photoreceptors and retinal pigment epithelium of the retina, and is thought to exert its effect by increasing oxygen delivery to the inner retina and decreasing viable hypoxic cells which are producing growth factors such as VEGF. Studies have implicated vascular endothelial growth factor (VEGF) as the substance leading to neovascularization and/or increased vascular permeability. Thus, it is reasonable to expect that inhibition of VEGF could reduce both PDR and transient vision loss from macular edema. There are several anti-VEGF drugs. Ranibizumab is the drug to be evaluated in this trial. In one trial of ranibizumab on DME, ten patients with chronic DME received a series of 0.5 mg intraocular injections. The treatments were well tolerated with no ocular or systemic adverse events. Since intraocular injections of ranibizumab significantly reduced foveal thickness and improved visual acuity in all ten patients, there is strong rationale to consider this drug as adjunctive therapy to PRP in a attempt to reduce the acute, transient edema that may occur with PRP.

Similarly, corticosteroids, a class of substances with anti-inflammatory properties, have demonstrated to inhibit the expression of VEGF. Triamcinolone acetonide is often used as a periocular injection for the treatment of cystoid macular edema (CME) secondary to uveitis. Clinically, triamcinolone acetonide is used in the treatment of proliferative vitreoretinopathy and choroidal neovascularization. Studies on patients with proliferative diabetic retinopathy randomly assigned to receive 4 mg triamcinolone 10 to 15 days prior to PRP treatment showed a reduction in central macular thickening, and fluorescein leakage was greater in the injection group than in the control group at 9 and 12 months follow up. Mean visual acuity improved by one line in the injection group and worsened by two lines in the control group.

In summary, there is strong rationale that using either intravitreal ranibizumab or intravitreal triamcinolone acetonide as an adjunct to PRP could reduce the magnitude of vision loss.

This study is being conducted to determine whether intravitreal injection of an anti-VEGF drug or an intravitreal injection of a corticosteroid can reduce the occurrence of macular edema and visual acuity impairment following PRP. Subjects will be randomly assigned with equal probability to one of the following three injection groups:

• Intravitreal injection of 0.5 mg ranibizumab (Lucentis™) at baseline and 4 weeks

• Intravitreal injection of 4 mg triamcinolone acetonide at baseline and sham injection at 4 weeks

• Sham injection at baseline and 4 weeks

The initial injection (or sham) is given on the day of randomization. Focal (macular) photocoagulation is given 7 to 10 days following the injection. Panretinal (scatter) photocoagulation can be initiated either on the same day as the focal photocoagulation (immediately following the focal photocoagulation) or on a subsequent day but must be initiated within 14 days of the baseline injection. Required follow-up visits occur at 4, 14, 34 and 56 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 333 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Intravitreal Ranibizumab or Triamcinolone Acetonide as Adjunctive Treatment to Panretinal Photocoagulation for Proliferative Diabetic Retinopathy
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Oct 1, 2009
• Actual Study Completion Date: Jul 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sham injection plus laser Sham injection at baseline and 4 weeks. Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.	Behavioral: Sham injection; Sham injection at baseline and 4 weeks; Procedure: Focal/grid laser; Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
Experimental: 0.5mg Ranibizumab plus laser Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks. Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.	Drug: Ranibizumab; Intravitreal injection of 0.5 mg ranibizumab at baseline and 4 weeks; Other Names: Lucentis™ ; Procedure: Focal/grid laser; Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.
Active Comparator: 4-mg Triamcinolone Acetonide plus Laser 4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks. Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.	Drug: Triamcinolone Acetonide; Intravitreal injection of 4 mg triamcinolone acetonide at baseline and sham injection at 4 weeks; Other Names: corticosteroid ; Procedure: Focal/grid laser; Focal/grid laser for diabetic macular edema was performed 3 days to 10 days after the injection for all treatment groups.

Outcome Measures

Primary Outcome Measures

1. Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 14 Weeks [baseline to 14 weeks]

   Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.

Secondary Outcome Measures

1. Additional Treatments for Diabetic Macular Edema [14 weeks to 56-weeks]

   Each combination of treatment is only counted once per treatment eye. Participants could have 2 study eyes, with random assignments to different treatments.

2. Change in Optical Coherence Tomography Central Subfield Thickness [Baseline to 14 weeks]

3. Total Optical Coherence Tomography Retinal Volume [Baseline to 14-weeks]

   Missing/ungradable as follows: Sham = 49, Ranibizumab = 37, Triamcinolone = 39. Visits occured between 70 days and 153 days from randomization adjusted for baseline optical coherence tomography (OCT) retinal volume, OCT retinal thickness and visual acuity, number of planned panretinal photocoagulation sittings, and correlation between 2 study eyes. Confidence intervals are adjusted for multiple comparisons.

4. Change in Visual Acuity From Baseline [baseline to 56-weeks]

   Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.

5. Eyes With Anti-vascular Endothelial Growth Factor Treatment for Diabetic Macular Edema [14 weeks to 56-weeks]

6. Number of Eyes With Additional Number of Treatments for Diabetic Macular Edema [14 weeks to 56-weeks]

   Treatments include any type or combination of treatment for diabetic macular edema. Eyes were only counted once, when receiving a combination of treatments.

7. Change in Optical Coherence Tomography Retinal Volume [Baseline to 14 weeks]

   Missing or un-gradable data as follows for the sham plus focal/grid/panretinal photocoagulation laser, triamcinolone plus focal/grid panretinal photocoagulation laser, and Ranibizumab groups were 49, 37, and 39, respectively

Eligibility Criteria

Criteria

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

General Inclusion Criteria

• Age >= 18 years

• Diagnosis of diabetes mellitus (type 1 or type 2)

• Fellow eye (if not a study eye) meets criteria.

• Able and willing to provide informed consent. Study Eye Inclusion Criteria Subjects may have one or two study eyes. Subjects with two study eyes will be randomly assigned to receive sham injection at baseline and 4 weeks in one eye and either ranibizumab or triamcinolone in the other eye.

• Presence of severe nonproliferative or proliferative diabetic retinopathy for which investigator intends to complete panretinal photocoagulation within 49 days after randomization.

• Diabetic macular edema(DME) present on clinical exam and central subfield thickness on Optical Coherence Tomography (OCT) >250 microns, within 8 days of randomization.

• Best corrected Electronic-Early Treatment Diabetic Retinopathy Study visual acuity letter score >=24 (i.e., 20/320 or better), within 8 days of randomization.

• Media clarity, pupillary dilation, and subject cooperation sufficient to administer panretinal photocoagulation and obtain adequate fundus photographs and OCT.

• If prior macular photocoagulation has been performed, the investigator believes that the study eye may possibly benefit from additional focal photocoagulation.

General Exclusion Criteria

• Significant renal disease, defined as a history of chronic renal failure requiring dialysis or kidney transplant.

• A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control).

• Participation in an investigational trial within 30 days of randomization that involved treatment with any drug that has not received regulatory approval at the time of study entry.

• Known allergy to any component of the study drugs.

• Blood pressure > 180/110 (systolic above 180 or diastolic above 110).

• Major surgery within 28 days prior to randomization or major surgery planned during the next 6 months.

• Myocardial infarction, other cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 4 months prior to randomization.

• Systemic anti-vascular endothelial growth factor(VEGF) or pro-VEGF treatment within 4 months prior to randomization.

• For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 12 months.

• Subject is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the 12 months of the study.

Study Eye Exclusion Criteria, Study eye only:

• Prior panretinal photocoagulation that was sufficiently extensive that the investigator does not believe that at least 1200 additional burns are needed or possible within 49 days after randomization.

• Macular edema is considered to be due to a cause other than diabetic macular edema.

• An ocular condition is present such that, in the opinion of the investigator, preventing visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, non-retinal condition).

• An ocular condition is present (other than diabetes) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., retinal vein or artery occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.).

• Substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e., cataract would be reducing acuity to 20/40 or worse if eye was otherwise normal).

• History of treatment for DME at any time in the past 4 months (such as focal/grid macular photocoagulation, intravitreal or peribulbar corticosteroids, anti-VEGF drugs, or any other treatment).

• History of major ocular surgery (including vitrectomy, cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or anticipated within the next 6 months following randomization.

• History of Yttrium Aluminum Garnet capsulotomy performed within 2 months prior to randomization.

• Aphakia.

• Intraocular pressure >= 25 mmHg.

• History of open-angle glaucoma (either primary open-angle glaucoma or other cause of open-angle glaucoma; note: angle-closure glaucoma is not an exclusion criterion).

• History of steroid-induced intraocular pressure elevation that required intraocular pressure-lowering treatment.

• History of prior herpetic ocular infection.

• Exam evidence of ocular toxoplasmosis.

• Exam evidence of pseudoexfoliation.

• Exam evidence of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.

Fellow Eye Criteria

• Intraocular pressure < 25 mmHg.

• No history of open-angle glaucoma (either primary open-angle glaucoma or other cause of open-angle glaucoma; note: angle-closure glaucoma is not an exclusion criterion).

• No history of steroid-induced intraocular pressure elevation that required intraocular pressure-lowering treatment.

• No exam evidence of pseudoexfoliation.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sall Research Medical Center	Artesia	California	United States	90701
2	Retina-Vitreous Associates Medical Group	Beverly Hills	California	United States	90211
3	University of California, Irvine	Irvine	California	United States	92697
4	Loma Linda University Health Care, Dept. of Ophthalmology	Loma Linda	California	United States	92354
5	Southern California Desert Retina Consultants, MC	Palm Springs	California	United States	92262
6	California Retina Consultants	Santa Barbara	California	United States	93103
7	Bay Area Retina Associates	Walnut Creek	California	United States	94598
8	Eldorado Retina Associates, P.C.	Louisville	Colorado	United States	80027
9	Retina Consultants of Southwest Florida	Fort Myers	Florida	United States	33912
10	Retina Vitreous Consultants	Ft. Lauderdale	Florida	United States	33334
11	Central Florida Retina Institute	Lakeland	Florida	United States	33805
12	Southeast Retina Center, P.C.	Augusta	Georgia	United States	30909
13	University of Illinois at Chicago Medical Center	Chicago	Illinois	United States	60612
14	Illinois Retina Associates	Joliet	Illinois	United States	60435
15	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana	United States	46280
16	John-Kenyon American Eye Institute	New Albany	Indiana	United States	47150
17	Medical Associates Clinic, P.C.	Dubuque	Iowa	United States	52002
18	Paducah Retinal Center	Paducah	Kentucky	United States	42001
19	Maine Vitreoretinal Consultants	Bangor	Maine	United States	04401
20	Elman Retina Group, P.A.	Baltimore	Maryland	United States	21237
21	Wilmer Ophthalmological Institute at Johns Hopkins	Baltimore	Maryland	United States	21287-9277
22	Retina Consultants of Delmarva, P.A.	Salisbury	Maryland	United States	21801
23	Ophthalmic Consultants of Boston	Boston	Massachusetts	United States	02114
24	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
25	Retina Center, PA	Minneapolis	Minnesota	United States	55404
26	University of Minnesota	Minneapolis	Minnesota	United States	55455
27	Eyesight Ophthalmic Services, PA	Portsmouth	New Hampshire	United States	03801
28	The New York Eye and Ear Infirmary/Faculty Eye Practice	New York	New York	United States	10003
29	Retina-Vitreous Surgeons of Central New York, PC	Syracuse	New York	United States	13224
30	University of North Carolina, Dept of Ophthalmology	Chapel Hill	North Carolina	United States	27599-7040
31	Charlotte Eye, Ear, Nose and Throat Assoc., PA	Charlotte	North Carolina	United States	28210
32	Horizon Eye Care, PA	Charlotte	North Carolina	United States	28211
33	Wake Forest University Eye Center	Winston-Salem	North Carolina	United States	27157
34	Case Western Reserve University	Cleveland	Ohio	United States	44106
35	OSU Eye Physicians and Surgeons, LLC.	Dublin	Ohio	United States	43017
36	Retina Northwest, PC	Portland	Oregon	United States	97210
37	Casey Eye Institute	Portland	Oregon	United States	97239
38	Penn State College of Medicine	Hershey	Pennsylvania	United States	17033
39	University of Pennsylvania Scheie Eye Institute	Philadelphia	Pennsylvania	United States	19104
40	Retina Consultants	Providence	Rhode Island	United States	02903
41	Palmetto Retina Center	Columbia	South Carolina	United States	29169
42	Carolina Retina Center	Columbia	South Carolina	United States	29223
43	Southeastern Retina Associates, PC	Kingsport	Tennessee	United States	37660
44	Southeastern Retina Associates, P.C.	Knoxville	Tennessee	United States	37909
45	West Texas Retina Consultants P.A.	Abilene	Texas	United States	79605
46	Texas Retina Associates	Arlington	Texas	United States	76012
47	Retina Research Center	Austin	Texas	United States	78705
48	Texas Retina Associates	Dallas	Texas	United States	75231
49	Retina and Vitreous of Texas	Houston	Texas	United States	77025
50	Vitreoretinal Consultants	Houston	Texas	United States	77030
51	Texas Retina Associates	Lubbock	Texas	United States	79424
52	Valley Retina Institute	McAllen	Texas	United States	78503
53	Retinal Consultants of San Antonio	San Antonio	Texas	United States	78240
54	Virginia Retina Center	Leesburg	Virginia	United States	20176
55	University of Washington Medical Center	Seattle	Washington	United States	98195
56	University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service	Madison	Wisconsin	United States	53705

Sponsors and Collaborators

• Jaeb Center for Health Research
• National Eye Institute (NEI)
• Genentech, Inc.
• Allergan

Investigators

• Study Chair: Alexander J. Brucker, M.D., Scheie Eye Institute
• Study Chair: Joseph Googe, Jr., M.D., Southeastern Retina Associates, P.C.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bressler SB, Almukhtar T, Aiello LP, Bressler NM, Ferris FL 3rd, Glassman AR, Greven CM; Diabetic Retinopathy Clinical Research Network. Green or yellow laser treatment for diabetic macular edema: exploratory assessment within the Diabetic Retinopathy Clinical Research Network. Retina. 2013 Nov-Dec;33(10):2080-8. doi: 10.1097/IAE.0b013e318295f744.
• Bressler SB, Almukhtar T, Bhorade A, Bressler NM, Glassman AR, Huang SS, Jampol LM, Kim JE, Melia M; Diabetic Retinopathy Clinical Research Network Investigators. Repeated intravitreous ranibizumab injections for diabetic macular edema and the risk of sustained elevation of intraocular pressure or the need for ocular hypotensive treatment. JAMA Ophthalmol. 2015 May;133(5):589-97. doi: 10.1001/jamaophthalmol.2015.186.
• Bressler SB, Melia M, Glassman AR, Almukhtar T, Jampol LM, Shami M, Berger BB, Bressler NM; Diabetic Retinopathy Clinical Research Network. RANIBIZUMAB PLUS PROMPT OR DEFERRED LASER FOR DIABETIC MACULAR EDEMA IN EYES WITH VITRECTOMY BEFORE ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY. Retina. 2015 Dec;35(12):2516-28. doi: 10.1097/IAE.0000000000000617.
• Bressler SB, Qin H, Beck RW, Chalam KV, Kim JE, Melia M, Wells JA 3rd; Diabetic Retinopathy Clinical Research Network. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Arch Ophthalmol. 2012 Sep;130(9):1153-61.
• Bressler SB, Qin H, Melia M, Bressler NM, Beck RW, Chan CK, Grover S, Miller DG; Diabetic Retinopathy Clinical Research Network. Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. JAMA Ophthalmol. 2013 Aug;131(8):1033-40. doi: 10.1001/jamaophthalmol.2013.4154.
• Diabetic Retinopathy Clinical Research Network; Writing Committee, Aiello LP, Beck RW, Bressler NM, Browning DJ, Chalam KV, Davis M, Ferris FL 3rd, Glassman AR, Maturi RK, Stockdale CR, Topping TM. Rationale for the diabetic retinopathy clinical research network treatment protocol for center-involved diabetic macular edema. Ophthalmology. 2011 Dec;118(12):e5-14. doi: 10.1016/j.ophtha.2011.09.058.
• Glassman AR, Stockdale CR, Beck RW, Baker C, Bressler NM; Diabetic Retinopathy Clinical Research Network. Evaluation of masking study participants to intravitreal injections in a randomized clinical trial. Arch Ophthalmol. 2012 Feb;130(2):190-4. doi: 10.1001/archophthalmol.2011.387.

• Responsible Party: Jaeb Center for Health Research
• ClinicalTrials.gov Identifier: NCT00445003
• Other Study ID Numbers: NEI-134; U10EY018817-03; U10EY014229-07; U10EY014231-09
• First Posted: Mar 8, 2007
• Last Update Posted: Aug 26, 2016
• Last Verified: Aug 1, 2016

• Keywords provided by Jaeb Center for Health Research: Diabetic Retinopathy; Diabetic Macular Edema; Lucentis; Ranibizumab; Triamcinolone; Panretinal Photocoagulation; Combination Therapy; pdr
• Additional relevant MeSH terms: Macular Edema; Retinal Diseases; Diabetic Retinopathy; Triamcinolone; Triamcinolone Acetonide; Triamcinolone hexacetonide; Ranibizumab; Triamcinolone diacetate

Study Results

Participant Flow

Recruitment Details	Data from 1 clinical site where a majority of eyes were judged not to meet the Optical Coherence Tomography eligibility criterion of central subfield >=250 microns when graded manually at a central reading center (14 eyes of 10 subjects) are excluded from all analysis except for safety data.
Pre-assignment Detail	Participants with 2 study eyes enrolled each eye in a different arm. Each treatment arm includes no more than 1 study eye for a given participant, and thus the numbers of eyes is equal to the number of participants in each arm.

Arm/Group Title	Sham Injection	0.5mg Ranibizumab	4-mg Triamcinolone Acetonided
Arm/Group Description	Sham injection at baseline and 4 weeks	Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks	4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks
Period Title: Overall Study
STARTED	123	113	109
COMPLETED	118	103	105
NOT COMPLETED	5	10	4

Baseline Characteristics

Arm/Group Title	Sham Injection	0.5mg Ranibizumab	4-mg Triamcinolone Acetonided	Total
Arm/Group Description	Sham injection at baseline and 4 weeks	Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks	4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks	Total of all reporting groups
Overall Participants	123	113	109	345
Age, Customized (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	54	57	58	56
Sex: Female, Male (Count of Participants)
Female	44 35.8%	48 42.5%	44 40.4%	136 39.4%
Male	79 64.2%	65 57.5%	65 59.6%	209 60.6%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	1 0.8%	0 0%	1 0.9%	2 0.6%
Asian	3 2.4%	1 0.9%	2 1.8%	6 1.7%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.9%	0 0%	1 0.3%
Black or African American	11 8.9%	15 13.3%	18 16.5%	44 12.8%
White	76 61.8%	72 63.7%	61 56%	209 60.6%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 0.8%	1 0.9%	0 0%	2 0.6%
Hispanic or Latino	31 25.2%	23 20.4%	27 24.8%	81 23.5%
Optical coherence tomography subretinal fluid present (questionable or definite) (Eyes) [Number]
Yes	30	31	32	93
No	93	82	77	252
Classification of diabetic macular edema on clinical exam (Eyes) [Number]
Predominantly Focal'	37	19	27	83
Neither perdominantly focal or diffuse	18	25	14	57
Predominantly diffuse	68	69	68	205
Intraocular Pressure (mmHg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mmHg]	15	16	15	15
Diabetes Type (Number) [Number]
Type 1	20 16.3%	13 11.5%	12 11%	45 13%
Type 2	101 82.1%	93 82.3%	95 87.2%	289 83.8%
Uncertain	2 1.6%	7 6.2%	2 1.8%	11 3.2%
Duration of diabetes (Years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Years]	15	15	15	15
Hemoglobin A1c (Percentage) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Percentage]	7.9	8.1	8.1	8.0
Prior Cardiovascular event (Number) [Number]
Yes	21 17.1%	35 31%	28 25.7%	84 24.3%
No	102 82.9%	78 69%	81 74.3%	261 75.7%
Hypertension (Number) [Number]
Yes	97 78.9%	88 77.9%	82 75.2%	267 77.4%
No	26 21.1%	25 22.1%	27 24.8%	78 22.6%
Number of study eyes (Number) [Number]
1 study eye	97 78.9%	100 88.5%	96 88.1%	293 84.9%
2 study eyes	26 21.1%	13 11.5%	13 11.9%	52 15.1%
Prior Panretinal scatter photocoagulation (Eyes) [Number]
Yes	16	20	19	55
No	107	93	90	290
prior treatment for diabetic macular edema (Eyes) [Number]
Yes	80	75	72	227
No	43	38	37	118
Prior laser for diabetic macular edema (Eyes) [Number]
Yes	40	33	36	109
No	83	80	73	236
Prior intravitreal triamcinolone for diabetic macular edema (Eyes) [Number]
Yes	1	9	3	13
No	122	104	106	332
Prior vitrectomy for diabetic macular edema (Eyes) [Number]
Yes	2	0	0	2
No	121	113	109	343
Prior peribulbar triamcinolone for diabetic macular edema (Eyes) [Number]
Yes	1	0	1	2
No	122	113	108	343
prior anti- vascular endothelial growth factor for diabetic macular edema (Eyes) [Number]
Yes	6	1	3	10
No	117	112	106	335
Currently on intraocular pressure lowering medication for glaucoma or ocular hypertension (Eyes) [Number]
Yes	0	3	0	3
No	123	110	109	342
Lens status (clinical examination) (Eyes) [Number]
Phakic	111	91	99	301
Pseudophakic	12	22	10	44
Baseline visual acuity by randomization strata (Letter Score) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Letter Score]	67	68	67	67
Central subfield thickness on optical coherence tomography (Microns) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Microns]	355	352	359	355
Retinal volume on optical coherence tomography (cubic millimetre) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cubic millimetre]	9.4	9.2	9.1	9.2
Optical coherence tomography cystoid abnormality (questionable or definite) (Eyes) [Number]
Yes	108	96	96	300
No	15	17	13	45
Early Treatment Diabetic Retinopath Study Retinopathy severity level from photograph grading (Eyes) [Number]
Level 35, 43 (Mild/Moderate NPDR)	6	5	6	17
Level 47 (Moderately severe NPDR)	26	15	10	51
Level 53 (Severe NPDR)	5	6	5	16
Level 60 (Prior PRP without active neovascularizat	2	4	3	9
Level 61 (Mild/Moderate PDR)	48	36	38	122
Level 71, 75 (High-risk PDR)	32	43	43	118
cannot grade	4	4	4	12

Outcome Measures

1. Primary Outcome

Title	Change in Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score From Baseline to 14 Weeks
Description	Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.
Time Frame	baseline to 14 weeks

Outcome Measure Data

Analysis Population Description

Participants with 2 study eyes enrolled each eye in a different arm. Each arm includes no more than 1 study eye for a given participant, and thus the numbers of eyes is equal to the number of participants in each arm. Analysis followed intention to treat principle; eyes without 14-week data, the Last Observation Carried Forward method was used.

Arm/Group Title	Sham Injection	0.5mg Ranibizumab	4-mg Triamcinolone Acetonided
Arm/Group Description	Sham injection at baseline and 4 weeks	Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks	4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks
Measure Participants	123	113	109
Mean (Standard Deviation) [Letter Score]	-4 (14)	1 (11)	2 (11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, 0.5mg Ranibizumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	adjusted for baseline visual acuity, number of planned panretinal photocoagulation sittings, and correlation between two study eyes
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.6
	Confidence Interval	(2-Sided) 95%; 2.2 to 9.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	adjusted for multiple comparison

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, 4-mg Triamcinolone Acetonided
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	adjusted for baseline visual acuity, number of planned panretinal photocoagulation sittings, and correlation between two study eyes
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.7
	Confidence Interval	(2-Sided) 95%; 3.2 to 10.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	adjusted for multiple comparisons

2. Secondary Outcome

Title	Additional Treatments for Diabetic Macular Edema
Description	Each combination of treatment is only counted once per treatment eye. Participants could have 2 study eyes, with random assignments to different treatments.
Time Frame	14 weeks to 56-weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham Injection	0.5mg Ranibizumab	4-mg Triamcinolone Acetonided
Arm/Group Description	Sham injection at baseline and 4 weeks	Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks	4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks
Measure Participants	123	113	109
Bevacizumab	14	12	9
Ranibizumab	1	0	3
Triamcinolone	3	8	2
Pegaptanib	0	0	3
Laser	31	10	21
Vitrectomy	2	1	0
Bevacizumab plus Triamcinolone	2	0	2
Ranibizumab plus Triamcinolone	0	1	0
Bevacizumab plus laser	8	5	0
Ranibizumab plus laser	0	3	0
Triamcinolone plus laser	7	4	5
Pegaptanib plus laser	1	0	0
Triamcinolone plus vitrectomy	0	1	0
Pegaptanib plus vitrectomy	0	1	0
Triamcinolone plus laser plus vitrectomy	0	1	0
Bevacizumab plus triamcinolone plus laser	2	1	0

3. Secondary Outcome

Title	Change in Optical Coherence Tomography Central Subfield Thickness
Time Frame	Baseline to 14 weeks

Outcome Measure Data

Analysis Population Description

Participants with two study eyes enrolled each eye in a different treatment group. Therefore, each treatment group/arm includes no more than one study eye for a given participant, and thus the numbers of eyes is equal to the number of participants in each arm.

Arm/Group Title	Sham Injection	0.5mg Ranibizumab	4-mg Triamcinolone Acetonided
Arm/Group Description	Sham injection at baseline and 4 weeks	Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks	4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks
Measure Participants	123	113	109
Median (Inter-Quartile Range) [Microns]	362	312	265

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, 0.5mg Ranibizumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.01
	Comments	Adjusted for baseline optical coherence tomography retinal thickness and visual acuity, number of planned panretinal photocoagulation sittings, and correlation between 2 study eyes
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-35
	Confidence Interval	(2-Sided) 95%; -64 to -6
	Parameter Dispersion	Type: Value:
	Estimation Comments	adjusted for multiple comparisons

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, 4-mg Triamcinolone Acetonided
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	adjusted for baseline optical coherence tomography retinal thickness and visual acuity, number of planned panretinal photocoagulation sittings, and correlation between 2 study eyes
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-100
	Confidence Interval	(2-Sided) 95%; -128 to -71
	Parameter Dispersion	Type: Value:
	Estimation Comments	adjusted for multiple comparisons

4. Secondary Outcome

Title	Total Optical Coherence Tomography Retinal Volume
Description	Missing/ungradable as follows: Sham = 49, Ranibizumab = 37, Triamcinolone = 39. Visits occured between 70 days and 153 days from randomization adjusted for baseline optical coherence tomography (OCT) retinal volume, OCT retinal thickness and visual acuity, number of planned panretinal photocoagulation sittings, and correlation between 2 study eyes. Confidence intervals are adjusted for multiple comparisons.
Time Frame	Baseline to 14-weeks

Outcome Measure Data

Analysis Population Description

Participants with 2 study eyes enrolled each eye in a different arm. Therefore, each arm includes no more than 1 eye for a given participant, and thus the numbers of eyes is equal to number of participants.

Arm/Group Title	Sham Injection	0.5mg Ranibizumab	4-mg Triamcinolone Acetonided
Arm/Group Description	Sham injection at baseline and 4 weeks	Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks	4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks
Measure Participants	69	66	66
Mean (Standard Deviation) [mm^3]	9.7 (1.8)	9.3 (1.9)	7.9 (1.0)

5. Secondary Outcome

Title	Change in Visual Acuity From Baseline
Description	Visual Acuity was measured with the Electronic Early Treatment Study (E-ETDRS) visual acuity test. Unit of measure is based on the E-ETDRS letter score scale, 0-97, where 0 = worst and 97 = best.
Time Frame	baseline to 56-weeks

Outcome Measure Data

Analysis Population Description

Participants with two study eyes enrolled each eye in a different treatment group. Therefore, each treatment group/arm includes no more than one study eye for a given participant, and thus the numbers of eyes is equal to the number of participants in each arm.

Arm/Group Title	Sham Injection	0.5mg Ranibizumab	4-mg Triamcinolone Acetonided
Arm/Group Description	Sham injection at baseline and 4 weeks	Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks	4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks
Measure Participants	111	95	93
Mean (Standard Deviation) [Letter Score]	-6 (17)	-4 (21)	-5 (16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, 0.5mg Ranibizumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments	Adjusted for baseline visual acuity, number of planned panretinal photocoagulation sittings, and correlation between 2 study eyes
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 95%; -3.7 to 7.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	adjusted for multiple comparisons

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, 4-mg Triamcinolone Acetonided
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments	Adjusted for baseline visual acuity, number of planned panretinal photocoagulation sittings, and correlation between 2 study eyes
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 95%; -4.4 to 6.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	adjusted for multiple comparisons

6. Secondary Outcome

Title	Eyes With Anti-vascular Endothelial Growth Factor Treatment for Diabetic Macular Edema
Time Frame	14 weeks to 56-weeks

Outcome Measure Data

Analysis Population Description

Participants with two study eyes enrolled each eye in a different treatment group. Therefore, each treatment group/arm includes no more than one study eye for a given participant, and thus the numbers of eyes is equal to the number of participants in each arm.

Arm/Group Title	Sham Injection	0.5mg Ranibizumab	4-mg Triamcinolone Acetonided
Arm/Group Description	Sham injection at baseline and 4 weeks	Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks	4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks
Measure Participants	123	113	109
Number [Eyes]	28	23	17

7. Secondary Outcome

Title	Number of Eyes With Additional Number of Treatments for Diabetic Macular Edema
Description	Treatments include any type or combination of treatment for diabetic macular edema. Eyes were only counted once, when receiving a combination of treatments.
Time Frame	14 weeks to 56-weeks

Outcome Measure Data

Analysis Population Description

Participants with two study eyes enrolled each eye in a different treatment group. Therefore, each treatment group/arm includes no more than one study eye for a given participant, and thus the numbers of eyes is equal to the number of participants in each arm.

Arm/Group Title	Sham Injection	0.5mg Ranibizumab	4-mg Triamcinolone Acetonided
Arm/Group Description	Sham injection at baseline and 4 weeks	Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks	4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks
Measure Participants	123	113	109
Number [Eyes]	71	48	45

8. Secondary Outcome

Title	Change in Optical Coherence Tomography Retinal Volume
Description	Missing or un-gradable data as follows for the sham plus focal/grid/panretinal photocoagulation laser, triamcinolone plus focal/grid panretinal photocoagulation laser, and Ranibizumab groups were 49, 37, and 39, respectively
Time Frame	Baseline to 14 weeks

Outcome Measure Data

Analysis Population Description

Participants with two study eyes enrolled each eye in a different treatment group. Therefore, each treatment group/arm includes no more than one study eye for a given participant, and thus the numbers of eyes is equal to the number of participants in each arm.

Arm/Group Title	Sham Injection	0.5mg Ranibizumab	4-mg Triamcinolone Acetonided
Arm/Group Description	Sham injection at baseline and 4 weeks	Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks	4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks
Measure Participants	69	66	66
Mean (Standard Deviation) [mm^3]	0.1 (1.1)	-0.4 (1.3)	-1.3 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham Injection
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	adjusted for baseline retinal volume, optical coherence tomography retinal thickness and visual acuity, number of planned panretinal photocoagulation sittings, and correlation between 2 study eyes
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.6
	Confidence Interval	(2-Sided) 95%; -1.0 to -0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	adjusted for multiple comparisons

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham Injection, 4-mg Triamcinolone Acetonided
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	adjusted for baseline retinal volume, optical coherence tomography retinal thickness and visual acuity, number of planned panretinal photocoagulation sittings, and correlation between 2 study eyes
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -2.1 to -1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	adjusted for multiple comparisons

Adverse Events

Time Frame	Through 14-week Primary outcome visit
Adverse Event Reporting Description	Data from 1 clinical site where a majority of eyes were judged not to meet the Optical Coherence Tomography eligibility criterion of central subfield >=250 microns when graded manually at a central reading center (14 eyes of 10 subjects) are excluded from all analysis except for safety data.
Arm/Group Title	Sham Injection		0.5mg Ranibizumab		4-mg Triamcinolone Acetonided
Arm/Group Description	Sham injection at baseline and 4 weeks		Intravitreal injections of 0.5mg Ranibizumab at baseline and at 4 weeks		4-mg Triamcinolone Acetonide at baseline and sham injection at 4 weeks
All Cause Mortality
	Sham Injection		0.5mg Ranibizumab		4-mg Triamcinolone Acetonided
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Sham Injection		0.5mg Ranibizumab		4-mg Triamcinolone Acetonided
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/133 (8.3%)		15/116 (12.9%)		12/115 (10.4%)
Cardiac disorders
Angina pectoris	0/133 (0%)		0/116 (0%)		1/115 (0.9%)
Coronary artery disease	0/133 (0%)		1/116 (0.9%)		1/115 (0.9%)
Heart rate decreased	0/133 (0%)		1/116 (0.9%)		0/115 (0%)
Ischaemic cardiomyopathy	0/133 (0%)		1/116 (0.9%)		0/115 (0%)
Myocardial infarction	1/133 (0.8%)		0/116 (0%)		0/115 (0%)
Transient ischaemic attach	1/133 (0.8%)		0/116 (0%)		1/115 (0.9%)
Endocrine disorders
Renal failure	1/133 (0.8%)		0/116 (0%)		0/115 (0%)
Eye disorders
Endophthalmitis	0/133 (0%)		1/116 (0.9%)		0/115 (0%)
Retinal detachment	1/133 (0.8%)		0/116 (0%)		0/115 (0%)
Vitreous haemorrhage	1/133 (0.8%)		0/116 (0%)		0/115 (0%)
Gastrointestinal disorders
Cholelithiasis	0/133 (0%)		0/116 (0%)		1/115 (0.9%)
Diabetic gastroparesis	1/133 (0.8%)		0/116 (0%)		0/115 (0%)
General disorders
Abdominal pain	0/133 (0%)		0/116 (0%)		1/115 (0.9%)
Cellulitis	0/133 (0%)		1/116 (0.9%)		0/115 (0%)
Cerebrovascular accident	1/133 (0.8%)		1/116 (0.9%)		1/115 (0.9%)
Chest pain	0/133 (0%)		1/116 (0.9%)		0/115 (0%)
Convulsion	0/133 (0%)		0/116 (0%)		1/115 (0.9%)
Death	1/133 (0.8%)		1/116 (0.9%)		1/115 (0.9%)
Diabetes mellitus	1/133 (0.8%)		1/116 (0.9%)		0/115 (0%)
Hypertension	1/133 (0.8%)		0/116 (0%)		0/115 (0%)
Ischaemic stroke	0/133 (0%)		0/116 (0%)		1/115 (0.9%)
Nausea	0/133 (0%)		0/116 (0%)		1/115 (0.9%)
Vomiting	0/133 (0%)		0/116 (0%)		1/115 (0.9%)
Infections and infestations
Localised infection	1/133 (0.8%)		1/116 (0.9%)		1/115 (0.9%)
Osteomyelitis	0/133 (0%)		1/116 (0.9%)		0/115 (0%)
Pneumonia	0/133 (0%)		1/116 (0.9%)		0/115 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	0/133 (0%)		1/116 (0.9%)		0/115 (0%)
Surgical and medical procedures
Cholecystectomy	0/133 (0%)		1/116 (0.9%)		0/115 (0%)
Coronary arterial stant insertion	0/133 (0%)		1/116 (0.9%)		0/115 (0%)
Other (Not Including Serious) Adverse Events
	Sham Injection		0.5mg Ranibizumab		4-mg Triamcinolone Acetonided
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	57/133 (42.9%)		50/116 (43.1%)		66/115 (57.4%)
Eye disorders
Conjunctival haemorrhage	2/133 (1.5%)		11/116 (9.5%)		8/115 (7%)
Eye pain	11/133 (8.3%)		7/116 (6%)		6/115 (5.2%)
Intraocular pressure increase	1/133 (0.8%)		0/116 (0%)		11/115 (9.6%)
Myodesopsia	5/133 (3.8%)		7/116 (6%)		10/115 (8.7%)
Vision Blurred	13/133 (9.8%)		8/116 (6.9%)		9/115 (7.8%)
Vitreous floaters	3/133 (2.3%)		4/116 (3.4%)		10/115 (8.7%)
Vitreous haemorrhage	15/133 (11.3%)		6/116 (5.2%)		7/115 (6.1%)
General disorders
headache	7/133 (5.3%)		7/116 (6%)		5/115 (4.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.