LRT for DME: Laser-Ranibizumab-Triamcinolone for Diabetic Macular Edema

• Sponsor: Jaeb Center for Health Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT00444600
• Collaborator: National Eye Institute (NEI) (NIH), Allergan (Industry), Genentech, Inc. (Industry)
• Enrollment: 691
• Locations: 50
• Arms: 4
• Duration (Months): 83.1
• Patients Per Site: 13.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of the study is to find out which is a better treatment for diabetic macular edema (DME): laser alone, laser combined with an intravitreal injection of triamcinolone, laser combined with an intravitreal injection of ranibizumab, or intravitreal injection of ranibizumab alone. At the present time, it is not known whether intravitreal steroid or anti-vascular endothelial growth factor (anti-VEGF) injections, with or without laser treatment, are better than just laser by itself. It is possible that one or both of the types of injections, with or without laser treatment, will improve vision more often than will laser without injections. However, even if better vision outcomes are seen with injections, side effects may be more of a problem with the injections than with laser. Therefore, this study is conducted to find out whether the benefits of the injections will outweigh the risks.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Retinopathy; Diabetic Macular Edema	Drug: Triamcinolone Acetonide + laser; Drug: Ranibizumab + laser; Drug: Sham injection + laser; Drug: Ranibizumab + deferred laser	Phase 3

Detailed Description

Thus far the only demonstrated means to reduce the risk of vision loss from diabetic macular edema are laser photocoagulation, intensive glycemic control, and blood pressure control. Earlier studies have shown that photocoagulation, although effective in reducing the risk of moderate vision loss, can eventually result in retinal and retinal pigment epithelium atrophy resulting in loss of central vision, central scotomata, and decreased color vision. Consequently, many retinal specialists today tend to treat diabetic macular edema (DME) with lighter, less intense laser burns than was originally specified in the Early Treatment Diabetic Retinopathy Study (ETDRS). The additional unsatisfactory outcome from treatments with laser photocoagulation in a significant proportion of eyes with DME has prompted interest in other treatment modalities. One such treatment is pars plana vitrectomy. Studies suggest that vitreomacular traction may play a role in increased retinal vascular permeability, and that removal of the vitreous, or relief of mechanical traction with vitrectomy and membrane stripping may substantially improve macular edema and visual acuity. However, this treatment may be applicable only to a specific subset of eyes with a component of vitreomacular traction secondary to edema. Other treatment modalities such as pharmacologic therapy with oral protein kinase C inhibitors and intravitreal corticosteroids are under investigation.

The use of antibodies targeted at vascular endothelial growth factor (VEGF) is another treatment modality that needs to be further explored for its potential benefits. Increased VEGF levels have been demonstrated in the retina and vitreous of human eyes with diabetic retinopathy. VEGF, also knows as vascular permeability factor, has been shown to increase retinal vascular permeability in in vivo models. Therapy that inhibits VEGF, therefore, may represent a useful therapeutic modality which targets the underlying pathogenesis of diabetic macular edema. Ranibizumab is a promising anti-VEGF drug. Its efficacy and safety have been demonstrated in treatment of age-related macular degeneration. Reports of its use and that of other anti-VEGF drugs in DME have suggested sufficient benefit to warrant evaluation of efficacy and safety in a phase III trial. Corticosteroids, a class of substances with anti-inflammatory properties, have also been demonstrated to inhibit the expression of the VEGF gene. The Diabetic Retinopathy Clinical Research Network (DRCR.net) is currently conducting a phase III randomized clinical trial comparing focal photocoagulation to intravitreal corticosteroids (triamcinolone acetonide) for diabetic macular edema. However, even if triamcinolone or ranibizumab are proven to be efficacious, a major concern, based on clinical observations with intravitreal corticosteroids, is that DME will recur as the effect of the intravitreal drug wears off, necessitating repetitive injections long-term. Combining an intravitreal drug (triamcinolone or ranibizumab) with photocoagulation provides hope that one could get the short-term benefit of the intravitreal drug (decreased retinal thickening and decreased fluid leakage) and the long-term reduction in fluid leakage as a result of photocoagulation. In addition, it is possible that the worsening of macular edema immediately following focal photocoagulation, a known complication of this treatment, could be decreased if an intravitreal drug was present at the time of photocoagulation. This might result in an increased likelihood of vision improvement following photocoagulation and a decreased likelihood of vision loss.

This study is designed to determine if ranibizumab alone or ranibizumab added to laser photocoagulation is more efficacious than photocoagulation alone, and if so, to determine if combining ranibizumab with photocoagulation reduces the total number of injections needed to obtain these benefits. Furthermore, this study is designed to determine if combining photocoagulation with corticosteroids, the only other class of drugs currently being considered for treatment of DME, is efficacious in the population being enrolled.

Subjects will be randomly assigned to one of the following 4 groups:

1. Group A: Sham injection plus focal (macular) photocoagulation

2. Group B: 0.5 mg injection of intravitreal ranibizumab plus focal photocoagulation

3. Group C: 0.5 mg injection of intravitreal ranibizumab plus deferred focal photocoagulation

4. Group D: 4 mg intravitreal triamcinolone plus focal photocoagulation

In groups A, B and D, laser will be given 7-10 days after the initial injection at the time of the injection follow-up safety visit. During the first year, subjects are evaluated for retreatment every 4 weeks. The injection for group A is a sham and for groups B and C ranibizumab. For group D, a triamcinolone injection is given if one has not been given in the prior 15 weeks; otherwise a sham injection is given. For Groups A, B, and D, focal photocoagulation will be given 7 to 10 days later following each injection unless focal photocoagulation has been given in the past 15 weeks or no macular edema is present. In Years 2 and 3, subjects continue to be evaluated for retreatment every 4 weeks unless injections are discontinued due to failure. In that case, follow-up visits occur every 4 months and treatment is at investigator discretion.

Study Design

• Study Type: Interventional
• Actual Enrollment: 691 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination With Laser Photocoagulation for Diabetic Macular Edema
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Feb 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 0.5mg Ranibizumab plus laser	Drug: Ranibizumab + laser; 0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.; Other Names: Lucentis, anti-VEGF drug
Experimental: 0.5 mg Ranibizumab plus deferred laser	Drug: Ranibizumab + deferred laser; 0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.; Other Names: Lucentis, anti-VEGF drug
Experimental: 4 mg Triamcinolone plus laser	Drug: Triamcinolone Acetonide + laser; 4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.; Other Names: corticosteroid
Active Comparator: Sham plus laser	Drug: Sham injection + laser; Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.; Other Names: placebo

Outcome Measures

Primary Outcome Measures

1. Mean Change in Visual Acuity (Letters) From Baseline to 1 Year Adjusted for Baseline Visual Acuity [from baseline to 1 Year]

   Change in best correct visual acuity letter score from baseline to one year as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale 97, worst 0.

2. Distribution of Change in Visual Acuity (Letters) From Baseline to 1 Year [from baseline to 1 Year]

   Change in best correct visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method.

3. Change in Visual Acuity From Baseline to 1 Year Among Eyes That Were Pseudophakic at Baseline [from baseline to 1 Year]

4. Change in Visual Acuity From Baseline to 1 Year Among Eyes That Had Prior Treatment for Diabetic Macular Edema [from baseline to 1 Year]

5. Change in Visual Acuity From Baseline to 1 Year Grouped by Baseline Visual Acuity Letter Score [from baseline to 1 Year]

   Change in best correct visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale 97, worst 0.

6. Change in Visual Acuity From Baseline to 1 Year Grouped by Optical Coherence Tomography Central Subfield Thickness [from baseline to 1 Year]

   Change in best correct visual acuity letter score from baseline to one year as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale 97, worst 0.

7. Change in Visual Acuity From Baseline to 1 Year Grouped by Diabetic Retinopathy Severity [from baseline to 1 Year]

   Change in best correct visual acuity letter score from baseline to one year as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale 97, worst 0.

8. Change in Visual Acuity From Baseline to 1 Year Grouped by Diffuse vs. Focal Edema as Characterized by the Investigator [from baseline to 1 Year]

   Change in best correct visual acuity letter score from baseline to one year as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale 97, worst 0.

Secondary Outcome Measures

1. Change in Retinal Thickening of Central Subfield on Optical Coherence Tomography From Baseline to 1 Year [from baseline to 1 year]

   Negative change denotes an improvement.

2. Number of Injections in First Year [from baseline to 1 year]

   Maximum possible number of injections for each of the following groups: sham+prompt laser=13 sham injections;ranibizumab+prompt laser=13 ranibizumab injections; ranibizumab+deferred laser=13 ranibizumab injections; triamcinolone+prompt laser=4 triamcinolone injections and 9 sham injections.

3. Number of Laser Treatments Received Prior to the 1 Year Visit [1 Year]

   One eye in the sham+prompt laser group did not receive laser until post 1-year due to an adverse event unrelated to study treatment. One eye in the triamcinolone+prompt laser did not receive laser until after 1-year due to missing 2 consecutive visits at the time of required laser treatment.

4. Percentage of Eyes Receiving Laser at the 48 Week Visit (%) [1 Year]

5. Mean Optical Coherence Tomography Retinal Volume at 1 Year [1 Year]

6. Mean Change in Optical Coherence Tomography Retinal Volume From Baseline to 1 Year [from baseline to 1 Year]

Other Outcome Measures

1. Central Subfield Thickness < 250 With at Least a 25 Micron Decrease From Baseline to 1 Year [1 Year]

2. Distribution of Logarithmic Transformation of Optical Coherence Tomography (LogOCT) Improvement and Worsening [1 Year]

   Logarithmic transformation of optical coherence tomography central subfield thickness is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounding to the nearest hundredth. The change is the change in the log values.

3. Eyes With Alternative Treatments Prior to the 1-year Visit [1 Year]

   Each combination of treatment only counted once.

4. Change From Moderately Severe Non-proliferative Diabetic Retinopathy or Better From Baseline to 1-year [from baseline to 1 Year]

   113 eyes had missing or ungradable photos at 1 year. Criteria are based on the ETDRS fundus photographic risk factors for the progression of diabetic retinopathy. ETDRS report no. 12. Ophthalmology 1991; 98:823-833

5. Change From Severe Non-proliferative Diabetic Retinopathy or Worse From Baseline to 1-year [from baseline to 1 Year]

   Criteria are based on the ETDRS fundus photographic risk factors for the progression of diabetic retinopathy. ETDRS report no. 12. Ophthalmology 1991; 98:823-833, ETDRS Severity Scale = Diabetic retinopathy absent, minimal non-proliferative diabetic retinopathy (PDR), mild to moderately severe non-PDR, severe non-PDR, scars of full pr partial panretinal photocoagulation present PDR absent, mild to moderate PDR, high risk PDR, cannot grade, missing.

6. Cardiovascular Events According to Antiplatelet Trialists' Collaboration Through 1 Year [1 Year]

   Antiplatelet Trialists' Collaboration is a collaborative overview of randomised trials of antiplatelet therapy - I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. MBJ 1994; 308:81-106. Nonfatal cerebrovascular accident includes ischemic or hemorrhagic or unknown events. Vascular death includes death from any potential vascular or unknown cause.

7. Major Ocular Adverse Events During First Year of Follow-Up [1 Year]

Eligibility Criteria

Criteria

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

General Inclusion Criteria

To be eligible, the following inclusion criteria (1-5) must be met:

• Age >= 18 years

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

• At least one eye meets the study eye criteria

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

• Able and willing to provide informed consent

General Exclusion Criteria

A subject is not eligible if any of the following exclusion criteria are present:

• 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 drug.

• 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 growth factor (anti-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 first 12 months of the study.

Study Eye Inclusion Criteria

The subject must have one eye meeting all of the inclusion criteria and none of the exclusion criteria listed below. A subject may have two study eyes only if both are eligible at the time of randomization.

• Best corrected electronic Early Treatment Diabetic Retinopathy (E-ETDRS) visual acuity letter score <= 78 (i.e., 20/32 or worse) and >= 24 (i.e., 20/320 or better) within 8 days of randomization.

• On clinical exam, definite retinal thickening due to diabetic macular edema involving the center of the macula.

• Ocular coherence tomography (OCT) central subfield >=250 microns within 8 days of randomization.

• Media clarity, pupillary dilation, and subject cooperation sufficient for adequate fundus photographs.

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

Study Eye Exclusion Criteria

The following exclusions apply to the study eye only (i.e., they may be present for the nonstudy eye):

• 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, visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, nonretinal 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., vein 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 diabetic macular edema 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 panretinal (scatter) photocoagulation (PRP) within 4 months prior to randomization.

• Anticipated need for PRP in the 6 months following randomization.

• 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 (YAG) 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: history of angle-closure glaucoma is not an exclusion criterion).

• History of steroid-induced intraocular pressure (IOP) elevation that required IOP-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.

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	Retina Vitreous Consultants	Fort Lauderdale	Florida	United States	33334
9	Retina Consultants of Southwest Florida	Fort Myers	Florida	United States	33912
10	University of Florida College of Med., Department of Ophthalmology	Jacksonville	Florida	United States	32209
11	Central Florida Retina Institute	Lakeland	Florida	United States	33805
12	Southeast Retina Center, P.C.	Augusta	Georgia	United States	30909
13	Illinois Retina Associates	Joliet	Illinois	United States	60435
14	Raj K. Maturi, M.D., P.C.	Indianapolis	Indiana	United States	46280
15	John-Kenyon American Eye Institute	New Albany	Indiana	United States	47150
16	Medical Associates Clinic, P.C.	Dubuque	Iowa	United States	52002
17	Retina and Vitreous Associates of Kentucky	Lexington	Kentucky	United States	40509-1802
18	Paducah Retinal Center	Paducah	Kentucky	United States	42001
19	Elman Retina Group, P.A.	Baltimore	Maryland	United States	21237
20	Wilmer Eye Institute at Johns Hopkins	Baltimore	Maryland	United States	21287-9277
21	Retina Consultants of Delmarva, P.A.	Salisbury	Maryland	United States	21801
22	Ophthalmic Consultants of Boston	Boston	Massachusetts	United States	02114
23	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
24	Retina Center, PA	Minneapolis	Minnesota	United States	55404
25	Eyesight Ophthalmic Services, PA	Portsmouth	New Hampshire	United States	03801
26	The New York Eye and Ear Infirmary/Faculty Eye Practice	New York	New York	United States	10003
27	Retina-Vitreous Surgeons of Central New York, PC	Syracuse	New York	United States	13224
28	University of North Carolina, Dept of Ophthalmology	Chapel Hill	North Carolina	United States	27599-7040
29	Charlotte Eye, Ear, Nose and Throat Assoc., PA	Charlotte	North Carolina	United States	28210
30	Wake Forest University Eye Center	Winston-Salem	North Carolina	United States	27157
31	Retina Associates of Cleveland, Inc.	Beachwood	Ohio	United States	44122
32	Case Western Reserve University	Cleveland	Ohio	United States	44106
33	Retina Northwest, PC	Portland	Oregon	United States	97210
34	Casey Eye Institute	Portland	Oregon	United States	97239
35	Penn State College of Medicine	Hershey	Pennsylvania	United States	17033
36	University of Pennsylvania Scheie Eye Institute	Philadelphia	Pennsylvania	United States	19104
37	Retina Consultants	Providence	Rhode Island	United States	02903
38	Palmetto Retina Center	Columbia	South Carolina	United States	29169
39	Carolina Retina Center	Columbia	South Carolina	United States	29223
40	Southeastern Retina Associates, PC	Kingsport	Tennessee	United States	37660
41	Southeastern Retina Associates, P.C.	Knoxville	Tennessee	United States	37909
42	West Texas Retina Consultants P.A.	Abilene	Texas	United States	79605
43	Retina Research Center	Austin	Texas	United States	78705
44	Texas Retina Associates	Dallas	Texas	United States	75231
45	Retina and Vitreous of Texas	Houston	Texas	United States	77025
46	Vitreoretinal Consultants	Houston	Texas	United States	77030
47	Texas Retina Associates	Lubbock	Texas	United States	79424
48	University of Washington Medical Center	Seattle	Washington	United States	98195
49	University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service	Madison	Wisconsin	United States	53705
50	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

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

Investigators

• Study Chair: Michael J. Elman, M.D., Elman Retina Group, PA

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• DRCR Retina Network

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, Ayala AR, Bressler NM, Melia M, Qin H, Ferris FL 3rd, Flaxel CJ, Friedman SM, Glassman AR, Jampol LM, Rauser ME; Diabetic Retinopathy Clinical Research Network. Persistent Macular Thickening After Ranibizumab Treatment for Diabetic Macular Edema With Vision Impairment. JAMA Ophthalmol. 2016 Mar;134(3):278-85. doi: 10.1001/jamaophthalmol.2015.5346.
• 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, Odia I, Glassman AR, Danis RP, Grover S, Hampton GR, Jampol LM, Maguire MG, Melia M. CHANGES IN DIABETIC RETINOPATHY SEVERITY WHEN TREATING DIABETIC MACULAR EDEMA WITH RANIBIZUMAB: DRCR.net Protocol I 5-Year Report. Retina. 2018 Oct;38(10):1896-1904. doi: 10.1097/IAE.0000000000002302.
• 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.
• Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, Glassman AR, Scott IU, Stockdale CR, Sun JK; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):609-14. doi: 10.1016/j.ophtha.2010.12.033.
• 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: NCT00444600
• Other Study ID Numbers: NEI-133; U10EY018817-03; U10EY014229-07; U10EY014231-09
• First Posted: Mar 8, 2007
• Last Update Posted: Oct 7, 2019
• Last Verified: Sep 1, 2019

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

Study Results

Participant Flow

Recruitment Details	Fifty two academic and community based sites across the United States recruited 691 study participants from March 2007 to December 2008.
Pre-assignment Detail	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+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Period Title: Overall Study
STARTED	293	187	188	186
COMPLETED	274	171	178	176
NOT COMPLETED	19	16	10	10

Baseline Characteristics

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser	Total
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.	Total of all reporting groups
Overall Participants	293	187	188	186	854
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	63	62	64	62	63
Sex: Female, Male (Count of Participants)
Female	123 42%	85 45.5%	78 41.5%	86 46.2%	372 43.6%
Male	170 58%	102 54.5%	110 58.5%	100 53.8%	482 56.4%
Race/Ethnicity, Customized (Number) [Number]
White	202 68.9%	131 70.1%	134 71.3%	134 72%	601 70.4%
African American	51 17.4%	30 16%	25 13.3%	32 17.2%	138 16.2%
Hispanic or Latino	34 11.6%	21 11.2%	25 13.3%	15 8.1%	95 11.1%
Asian	4 1.4%	1 0.5%	2 1.1%	4 2.2%	11 1.3%
Native Hawaiian/Other Pacific Islander	0 0%	1 0.5%	0 0%	0 0%	1 0.1%
More than one race	1 0.3%	1 0.5%	1 0.5%	0 0%	3 0.4%
Unknown/not reported	1 0.3%	2 1.1%	1 0.5%	1 0.5%	5 0.6%
Visual Acuity Letter Score (approximate Snellen equivalent) by randomization strata (Eyes) [Number]
≥66 (better than 20/50)	146	95	95	93	429
≤65 (20/50 or worse)	147	92	93	93	425
Classification of diabetic macular edema (Eyes) [Number]
Predominantly focal	78	60	68	53	259
Neither predominantly focal or diffuse	71	46	41	48	206
Predominantly diffuse	144	81	79	85	389
Number of study eyes (Number) [Number]
1 study eye	130 44.4%	131 70.1%	132 70.2%	135 72.6%	528 61.8%
2 study eyes	163 55.6%	56 29.9%	56 29.8%	51 27.4%	326 38.2%
Diabetes Type (Number) [Number]
Type 1	25 8.5%	11 5.9%	15 8%	14 7.5%	65 7.6%
Type 2	260 88.7%	172 92%	170 90.4%	166 89.2%	768 89.9%
Uncertain	8 2.7%	4 2.1%	3 1.6%	6 3.2%	21 2.5%
Duration of diabetes (Years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Years]	16	18	17	17	16
HbA1c (Percentage) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Percentage]	7.3	7.3	7.5	7.4	7.3
Prior cardiovascular event (Number) [Number]
Yes	93 31.7%	66 35.3%	61 32.4%	61 32.8%	281 32.9%
No	200 68.3%	121 64.7%	127 67.6%	125 67.2%	573 67.1%
Hypertension (Number) [Number]
Yes	240 81.9%	154 82.4%	156 83%	148 79.6%	698 81.7%
No	53 18.1%	33 17.6%	32 17%	38 20.4%	156 18.3%
Prior Panretinal Photocoagulation (Eyes) [Number]
Yes	48	36	31	37	152
No	245	151	157	149	702
Prior treatment for diabetic macular edema (Eyes) [Number]
No	105	74	74	61	314
Yes	188	113	114	125	540
Prior laser for diabetic macular edema (Eyes) [Number]
Yes	173	101	101	114	489
No	120	86	87	72	365
Prior IVT for diabetic macular edema (Eyes) [Number]
Yes	39	22	36	31	128
No	254	165	152	155	726
Prior vitrectomy for diabetic macular edema (Eyes) [Number]
Yes	15	7	5	12	39
No	278	180	183	174	815
Prior peribulbar triamcinolone for diabetic macular edema (Eyes) [Number]
Yes	12	9	5	5	31
No	281	178	183	181	823
Prior anti-VEGF for diabetic macular edema (Eyes) [Number]
Yes	24	24	21	20	89
No	269	163	167	166	765
Intraocular pressure (mmHg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mmHg]	16	16	16	16	16
Currently on intraocular pressure lowering medicine for glaucoma or ocular hypertension (Eyes) [Number]
Yes	5	6	4	2	17
No	288	181	184	184	837
Lens status (Eyes) [Number]
Phakic	192	131	134	124	581
Anterior Chamber Intraocular Lense	3	1	1	0	5
Posterior Chamber Intraocular Lense	98	55	53	62	268
E-ETDRS Visual Acuity Letter Score (Letter Score) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [Letter Score]	65	66	66	66	66
Central subfield thickness on optical coherence tomography (microns) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [microns]	407	371	382	374	381
Retinal volume on optical coherence tomography (microns) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [microns]	8.7	8.4	8.4	8.5	8.5
Optical coherence tomography cystoid abnormality (Eyes) [Number]
No evidence	19	13	12	8	52
Questionable or definite	274	171	174	177	796
Cannot grade or missing	0	3	2	1	6
Optical coherence tomography subretinal fluid present (Eyes) [Number]
No evidence	222	149	140	146	657
Questionable or definite	70	36	45	38	189
Cannot grade	1	2	3	2	8
ETDRS retinopathy severity level (ETDRS description) (Eyes) [Number]
Diabetic retinopathy absent	5	4	3	1	13
Minimal non-proliferative DR	2	2	3	3	10
Mild to moderately severe non-proliferative DR	171	103	107	95	476
Severe non-proliferative DR	22	16	11	15	64
Scars of full or partial PRP present;PDR absent	38	30	30	29	127
Mild to moderate proliferative DR	33	24	22	34	113
High risk proliferative DR	7	4	1	3	15
Cannot grade	10	1	2	4	17
Missing	5	3	9	2	19

Outcome Measures

1. Secondary Outcome

Title	Change in Retinal Thickening of Central Subfield on Optical Coherence Tomography From Baseline to 1 Year
Description	Negative change denotes an improvement.
Time Frame	from baseline to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	271	171	175	173
Measure Eyes	271	171	175	173
Mean (Standard Deviation) [microns]	-102 (151)	-131 (129)	-137 (136)	-127 (140)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	Difference in central subfield thickness mean change from sham+prompt laser
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	Adjusted for baseline retinal thickness and visual acuity and correlation between two study eyes.
Method of Estimation	Estimation Parameter	Difference in mean change
	Estimated Value	-55
	Confidence Interval	(2-Sided) 95%; -78 to -32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	Difference in optical coherence tomography central subfield thickness mean change from sham+prompt laser
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	Adjusted for baseline retinal thickness and visual acuity and correlation between two study eyes.
Method of Estimation	Estimation Parameter	Difference in mean change
	Estimated Value	-49
	Confidence Interval	(2-Sided) 95%; -72 to -26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments	Difference in optical coherence tomography central subfield thickness mean change from sham+prompt laser
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence interval is adjusted for multiple comparisons
	Method	ANCOVA
	Comments	Adjusted for baseline retinal thickness and visual acuity and correlation between two study eyes.
Method of Estimation	Estimation Parameter	Difference in mean change
	Estimated Value	-52
	Confidence Interval	(2-Sided) 95%; -75 to -29
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Injections in First Year
Description	Maximum possible number of injections for each of the following groups: sham+prompt laser=13 sham injections;ranibizumab+prompt laser=13 ranibizumab injections; ranibizumab+deferred laser=13 ranibizumab injections; triamcinolone+prompt laser=4 triamcinolone injections and 9 sham injections.
Time Frame	from baseline to 1 year

Outcome Measure Data

Analysis Population Description

Sham+prompt laser group listed median excludes 56 eyes among 163 participants with 2 study eyes that were unmasked at baseline because the participant's other eye was in the ranibizumab+deferred laser group, precluding sham injections for the study eye assigned to sham+prompt laser.

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	274	171	178	176
Measure Eyes	274	171	178	176
Median (Inter-Quartile Range) [Injections]	11	8	9	3

3. Primary Outcome

Title	Mean Change in Visual Acuity (Letters) From Baseline to 1 Year Adjusted for Baseline Visual Acuity
Description	Change in best correct visual acuity letter score from baseline to one year as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale 97, worst 0.
Time Frame	from baseline to 1 Year

Outcome Measure Data

Analysis Population Description

For eyes without any 1-year data the last observation carried forward method was used to impute data for the primary analysis. followed intention to treat principle.

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
Measure Eyes	293	187	188	186
Mean (Standard Deviation) [Letters]	3 (13)	9 (11)	9 (12)	4 (13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	Adjusted for baseline visual acuity and correlation between 2 study eyes.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.8
	Confidence Interval	(2-Sided) 95%; 3.2 to 8.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	Adjusted for baseline visual acuity and correlation between 2 study eyes.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.0
	Confidence Interval	(2-Sided) 95%; 3.4 to 8.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments	Adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	Adjusted for baseline visual acuity and correlation between 2 study eyes.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 95%; -1.5 to 3.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Distribution of Change in Visual Acuity (Letters) From Baseline to 1 Year
Description	Change in best correct visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method.
Time Frame	from baseline to 1 Year

Outcome Measure Data

Analysis Population Description

For eyes without any 1-year data the last observation carried forward method was used to impute data for the primary analysis.

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
Measure Eyes	293	187	188	186
≥15 letter improvement	43	57	52	39
14-10 letter improvement	38	38	36	22
9-5 letter improvement	67	34	54	32
Same ±4 letters	86	38	35	54
5-9 letters worse	20	14	5	12
10-14 letters worse	16	3	2	12
≥15 letters worse	23	3	4	15

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	Difference in proportion with ≥10 letter improvement for sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	23
	Confidence Interval	(2-Sided) 95%; 13 to 34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	Difference in proportion with ≥10 letter improvement from sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	19
	Confidence Interval	(2-Sided) 95%; 9 to 29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments	Difference in proportion with ≥10 letter improvement from sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	6
	Confidence Interval	(2-Sided) 95%; -4 to 16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	Relative risk for ≥10 letter improvement comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.84
	Confidence Interval	(2-Sided) 95%; 1.40 to 2.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	Relative risk for ≥10 letter improvement comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.68
	Confidence Interval	(2-Sided) 95%; 1.27 to 2.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments	Relative risk for ≥10 letter improvement comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.16
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Eyes were analyzed.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	Difference in proportion with ≥10 letter worsening from sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	-10
	Confidence Interval	(2-Sided) 95%; -16 to -5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	Difference in proportion with ≥10 letter worsening from sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	-10
	Confidence Interval	(2-Sided) 95%; -16 to -4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments	Difference in proportion with ≥10 letter worsening from sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	1
	Confidence Interval	(2-Sided) 95%; -7 to 9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	Relative risk for ≥10 letter worsening comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; 0.09 to 0.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	Relative risk for ≥10 letter worsening comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.24
	Confidence Interval	(2-Sided) 95%; 0.08 to 0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments	Relative risk for ≥10 letter worsening comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.75
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.62 to 1.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	Difference in proportion with ≥15 letter improvement from sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	16
	Confidence Interval	(2-Sided) 95%; 6 to 26
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	Difference in proportion with ≥15 letter improvement from sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	13
	Confidence Interval	(2-Sided) 95%; 4 to 22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments	Difference in proportion with ≥15 letter improvement from sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	6
	Confidence Interval	(2-Sided) 95%; -2 to 15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	Relative risk for ≥15 letter improvement comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	2.09
	Confidence Interval	(2-Sided) 95%; 1.35 to 3.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	Relative risk for ≥15 letter improvement comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.89
	Confidence Interval	(2-Sided) 95%; 1.25 to 2.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments	Relative risk for ≥15 letter improvement comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.07
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 95%; 0.90 to 2.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	Difference in proportion with ≥15 letter worsening from sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	-6
	Confidence Interval	(2-Sided) 95%; -11 to -2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 20

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	Difference in proportion with ≥15 letter worsening from sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	-6
	Confidence Interval	(2-Sided) 95%; -10 to -1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 21

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments	Difference in proportion with ≥15 letter worsening from sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; -6 to 6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 22

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	Relative risk for ≥15 letter worsening comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.21
	Confidence Interval	(2-Sided) 95%; 0.05 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 23

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	Relative risk for ≥15 letter worsening comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; 0.08 to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 24

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments	Relative risk for ≥15 letter worsening comparison with sham+prompt laser at 1 year
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.95
	Comments
	Method	Log-Binomial Regression
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.47 to 2.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Other Pre-specified Outcome

Title	Central Subfield Thickness < 250 With at Least a 25 Micron Decrease From Baseline to 1 Year
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	271	171	175	173
Measure Eyes	271	171	175	173
Number [Eyes]	72	91	74	82

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	Relative risk for comparison with sham+prompt laser
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	Regression, Logistic
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	2.00
	Confidence Interval	(2-Sided) 95%; 1.52 to 2.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	Relative risk for comparison with sham+prompt laser
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	Confidence intervals adjusted for multiple comparisons
	Method	Regression, Logistic
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.55
	Confidence Interval	(2-Sided) 95%; 1.13 to 2.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments	Relative risk for comparison with sham+prompt laser
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence intervals adjusted for multiple comparisons.
	Method	Regression, Logistic
	Comments	Adjusted for correlation between 2 study eyes and multiple comparisons.
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.76
	Confidence Interval	() 95%; 1.31 to 2.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Other Pre-specified Outcome

Title	Distribution of Logarithmic Transformation of Optical Coherence Tomography (LogOCT) Improvement and Worsening
Description	Logarithmic transformation of optical coherence tomography central subfield thickness is calculated by taking the log base 10 of the ratio of the central subfield thickness divided by 200 and rounding to the nearest hundredth. The change is the change in the log values.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	271	171	175	173
Measure Eyes	271	171	175	173
≥2 step improvement	81	72	71	65
≥2 step worsening	6	1	0	4

7. Primary Outcome

Title	Change in Visual Acuity From Baseline to 1 Year Among Eyes That Were Pseudophakic at Baseline
Time Frame	from baseline to 1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
Measure Eyes	293	187	188	186
Not pseudophakic at baseline	2 (13)	9 (10)	10 (14)	2 (14)
Pseudophakic at baseline	4 (14)	8 (12)	7 (9)	8 (9)

8. Primary Outcome

Title	Change in Visual Acuity From Baseline to 1 Year Among Eyes That Had Prior Treatment for Diabetic Macular Edema
Time Frame	from baseline to 1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
No	2 (14)	9 (12)	11 (13)	3 (13)
Yes	3 (13)	9 (10)	8 (12)	5 (13)

9. Primary Outcome

Title	Change in Visual Acuity From Baseline to 1 Year Grouped by Baseline Visual Acuity Letter Score
Description	Change in best correct visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale 97, worst 0.
Time Frame	from baseline to 1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
≥66 (better than 20/50)	1 (12)	6 (10)	5 (13)	1 (11)
≤65 (20/50 or worse)	5 (14)	12 (11)	13 (10)	7 (14)

10. Primary Outcome

Title	Change in Visual Acuity From Baseline to 1 Year Grouped by Optical Coherence Tomography Central Subfield Thickness
Description	Change in best correct visual acuity letter score from baseline to one year as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale 97, worst 0.
Time Frame	from baseline to 1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
Measure Eyes	293	187	188	186
<400 microns	3 (11)	7 (11)	7 (12)	3 (12)
≥400 microns	3 (15)	11 (10)	11 (13)	6 (14)

11. Primary Outcome

Title	Change in Visual Acuity From Baseline to 1 Year Grouped by Diabetic Retinopathy Severity
Description	Change in best correct visual acuity letter score from baseline to one year as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale 97, worst 0.
Time Frame	from baseline to 1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
Measure eyes	293	187	188	186
Moderately severe non-proliferative DR or better	3 (13)	10 (11)	9 (12)	3 (14)
Severe non-proliferative DR or worse	2 (15)	8 (10)	9 (13)	5 (12)

12. Primary Outcome

Title	Change in Visual Acuity From Baseline to 1 Year Grouped by Diffuse vs. Focal Edema as Characterized by the Investigator
Description	Change in best correct visual acuity letter score from baseline to one year as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. A positive change denotes an improvement. Best value on the scale 97, worst 0.
Time Frame	from baseline to 1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
Measure Eyes	293	187	188	186
Typical/predominantly focal	3 (13)	8 (11)	8 (13)	3 (11)
Neither predominantly focal nor diffuse	2 (14)	10 (9)	8 (15)	3 (13)
Typical/predominantly diffuse	3 (13)	9 (12)	10 (10)	5 (14)

13. Secondary Outcome

Title	Number of Laser Treatments Received Prior to the 1 Year Visit
Description	One eye in the sham+prompt laser group did not receive laser until post 1-year due to an adverse event unrelated to study treatment. One eye in the triamcinolone+prompt laser did not receive laser until after 1-year due to missing 2 consecutive visits at the time of required laser treatment.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

Number who completed the 1-year visit.

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	274	171	178	176
Measure Eyes	274	171	178	176
0	1	0	124	1
1	35	53	36	46
2	75	54	17	53
3	107	46	1	49
4	56	18	0	27

14. Other Pre-specified Outcome

Title	Eyes With Alternative Treatments Prior to the 1-year Visit
Description	Each combination of treatment only counted once.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
Measure Eyes	293	187	188	186
Intravitreal bevacizumab	3	0	0	1
Intravitreal triamcinolone acetonide	5	0	0	0
Vitrectomy	2	0	0	0
Intravitreal bevacizumab+triamcinolone acetonide	4	0	0	0
Total number of eyes with alternative treatments	14	1	0	1
Total number of treatments applied	25	1	0	1
Total per protocol treatments applied	5	1	0	1
Total deviations from protocol treatments applied	9	0	0	0

15. Other Pre-specified Outcome

Title	Change From Moderately Severe Non-proliferative Diabetic Retinopathy or Better From Baseline to 1-year
Description	113 eyes had missing or ungradable photos at 1 year. Criteria are based on the ETDRS fundus photographic risk factors for the progression of diabetic retinopathy. ETDRS report no. 12. Ophthalmology 1991; 98:823-833
Time Frame	from baseline to 1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham	Ranibizumab	Triamcinolone
Arm/Group Description
Measure Participants	150	182	80
Measure Eyes	150	182	80
Improved by 2 or more levels	6	46	20
Worsened by 2 or more levels	11	5	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	P value for comparison with sham
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	GEE repeated measures
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	P value for comparison with sham
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.17
	Comments
	Method	GEE repeated measures
	Comments

16. Other Pre-specified Outcome

Title	Change From Severe Non-proliferative Diabetic Retinopathy or Worse From Baseline to 1-year
Description	Criteria are based on the ETDRS fundus photographic risk factors for the progression of diabetic retinopathy. ETDRS report no. 12. Ophthalmology 1991; 98:823-833, ETDRS Severity Scale = Diabetic retinopathy absent, minimal non-proliferative diabetic retinopathy (PDR), mild to moderately severe non-PDR, severe non-PDR, scars of full pr partial panretinal photocoagulation present PDR absent, mild to moderate PDR, high risk PDR, cannot grade, missing.
Time Frame	from baseline to 1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham	Ranibizumab	Triamcinolone
Arm/Group Description
Measure Participants	83	121	70
Measure Eyes	83	121	70
Improved by 2 or more levels	10	18	6
Worsened by 2 or more levels	7	1	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	P value for comparison with sham
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	GEE repeated measures
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	P value for comparison with sham
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.17
	Comments
	Method	GEE repeated measures
	Comments

17. Secondary Outcome

Title	Percentage of Eyes Receiving Laser at the 48 Week Visit (%)
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	274	171	178	176
Measure Eyes	274	171	178	176
Number [Eyes]	26	16	8	21

18. Other Pre-specified Outcome

Title	Cardiovascular Events According to Antiplatelet Trialists' Collaboration Through 1 Year
Description	Antiplatelet Trialists' Collaboration is a collaborative overview of randomised trials of antiplatelet therapy - I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. MBJ 1994; 308:81-106. Nonfatal cerebrovascular accident includes ischemic or hemorrhagic or unknown events. Vascular death includes death from any potential vascular or unknown cause.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

Study participants with 2 study eyes are assigned to the non-sham group. Multiple events within a study participant are only counted once per event.

Arm/Group Title	Sham	Ranibizumab	Triamcinolone
Arm/Group Description
Measure Participants	130	375	186
Nonfatal myocardial infarction	3 1%	1 0.5%	2 1.1%
Nonfatal cerebrovascular accident	5 1.7%	3 1.6%	1 0.5%
Vascular death	4 1.4%	7 3.7%	2 1.1%
Any ATC cardiovascular event	10 3.4%	11 5.9%	5 2.7%

19. Secondary Outcome

Title	Mean Optical Coherence Tomography Retinal Volume at 1 Year
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
Measure Eyes	293	187	188	186
Mean (Standard Deviation) [mm^3]	8.1 (1.4)	7.3 (1.0)	7.4 (1.2)	7.5 (1.3)

20. Secondary Outcome

Title	Mean Change in Optical Coherence Tomography Retinal Volume From Baseline to 1 Year
Time Frame	from baseline to 1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
Measure Eyes	293	187	188	186
Mean (Standard Deviation) [mm^3]	-1.0 (1.4)	-1.4 (1.4)	-1.5 (1.5)	-1.4 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Prompt Laser
	Comments	Difference in mean change from sham+prompt laser
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	Adjusted for baseline optical coherence tomography (OCT) retinal volume, OCT retinal thickness and visual acuity and correlation between 2 study eyes.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.73
	Confidence Interval	(2-Sided) 95%; -1.01 to -0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 0.5 mg Ranibizumab+Deferred Laser
	Comments	Difference in mean change from sham+prompt laser
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence intervals adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	Adjusted for baseline optical coherence tomography (OCT) retinal volume, OCT retinal thickness and visual acuity and correlation between 2 study eyes.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.68
	Confidence Interval	(2-Sided) 95%; -0.96 to -0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Sham+Prompt Laser, 4 mg Triamcinolone+Prompt Laser
	Comments	Difference in mean change from sham+prompt laser
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Confidence intervals are adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	Adjusted for baseline optical coherence tomography (OCT) retinal volume, OCT retinal thickness and visual acuity and correlation between 2 study eyes.
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 95%; -0.91 to -0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Other Pre-specified Outcome

Title	Major Ocular Adverse Events During First Year of Follow-Up
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sham+Prompt Laser	0.5 mg Ranibizumab+Prompt Laser	0.5 mg Ranibizumab+Deferred Laser	4 mg Triamcinolone+Prompt Laser
Arm/Group Description	Sham injection at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization plus focal photocoagulation 1 week post-injection. Injections are repeated every 4 weeks with focal photocoagulation given post-injection every 16 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT.	0.5 mg intravitreal ranibizumab at randomization, repeated every 4 weeks. Retreatment starting at 16 weeks depends on visual acuity and OCT. If improvement has not occured from injections alone, laser can be given starting at the 24 week visit.	4 mg intravitreal triamcinolone at randomization plus focal photocoagulation 1 week post-injection, repeated every 16 weeks with sham injections at 4-week intervals in-between. Retreatment starting at 16 weeks depends on visual acuity and OCT.
Measure Participants	293	187	188	186
Measure Eyes	293	187	188	186
Endophthalmitis	1	1	1	0
Pseudoendophthalmitis	1	0	0	1
Ocular vascular event	1	1	0	2
Retinal detachment	0	0	1	0
Vitrectomy	7	0	3	0
Vitreous hemorrhage	15	3	4	2
Increase in intraocular pressure >=10 mmHg	16	10	5	70
Intraocular pressure >=30 mmHg	3	2	4	46
Initiation of intraocular lowering medication	23	12	7	79
Glaucoma surgery	0	0	0	0
Cataract surgery	11	6	8	19

Adverse Events

Time Frame	1 Year
Adverse Event Reporting Description	All ocular adverse events are listed under treatment group drug. Participants with a systemic adverse event with two study eyes are listed under the sham/ranibizumab or triamcinolone combination.
Arm/Group Title	Sham + Prompt Laser		Ranibizumab + Prompt Laser		Ranibizumab + Deferred Laser		Triamcinolone + Prompt Laser		Sham + Ranibizumab + Laser		Sham + Ranibizumab + Deferred Laser		Sham + Triamcinolone + Laser
Arm/Group Description	Laser was given within 3 to 10 days after sham injections, Laser = Focal/grid photocoagulation		0.5 mg intravitreal ranibizumab plus prompt (within 3-10 days after injection) focal/grid photocoagulation		0.5 mg intravitreal ranibizumab with deferred (24 weeks) focal/grid photocoagulation		4 mg intravitreal triamcinolone plus prompt (within 3-10 days after injection) focal/grid photocoagulation		Participants in this group had 2 study eyes, the right eye was assigned randomly with equal probability to one of the four groups (Sham + prompt laser, ranibizumab + prompt laser, ranibizumab + deferred laser, triamcinolone + prompt laser). If the right eye was assigned to a treatment group other than the sham + prompt laser group, then the left eye was assigned to the sham + prompt laser group. If the right eye was assigned to the sham prompt + prompt laser group, then the left eye was assigned randomly to one of the other three groups.		Participants in this group had 2 study eyes, the right eye was assigned randomly with equal probability to one of the four groups (Sham + prompt laser, ranibizumab + prompt laser, ranibizumab + deferred laser, triamcinolone + prompt laser). If the right eye was assigned to a treatment group other than the sham + prompt laser group, then the left eye was assigned to the sham + prompt laser group. If the right eye was assigned to the sham prompt + prompt laser group, then the left eye was assigned randomly to one of the other three groups.		Participants in this group had 2 study eyes, the right eye was assigned randomly with equal probability to one of the four groups (Sham + prompt laser, ranibizumab + prompt laser, ranibizumab + deferred laser, triamcinolone + prompt laser). If the right eye was assigned to a treatment group other than the sham + prompt laser group, then the left eye was assigned to the sham + prompt laser group. If the right eye was assigned to the sham prompt + prompt laser group, then the left eye was assigned randomly to one of the other three groups.
All Cause Mortality
	Sham + Prompt Laser		Ranibizumab + Prompt Laser		Ranibizumab + Deferred Laser		Triamcinolone + Prompt Laser		Sham + Ranibizumab + Laser		Sham + Ranibizumab + Deferred Laser		Sham + Triamcinolone + Laser
	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 + Prompt Laser		Ranibizumab + Prompt Laser		Ranibizumab + Deferred Laser		Triamcinolone + Prompt Laser		Sham + Ranibizumab + Laser		Sham + Ranibizumab + Deferred Laser		Sham + Triamcinolone + Laser
	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	53/130 (40.8%)		46/131 (35.1%)		41/132 (31.1%)		57/135 (42.2%)		21/56 (37.5%)		20/56 (35.7%)		12/51 (23.5%)
Cardiac disorders
Arrhythmia	1/130 (0.8%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Cardiac failure	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Cardiac failure congestive	2/130 (1.5%)		8/131 (6.1%)		0/132 (0%)		4/135 (3%)		4/56 (7.1%)		3/56 (5.4%)		0/51 (0%)
Cardio-respiratory arrest	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		1/56 (1.8%)		0/56 (0%)		0/51 (0%)
Cardiomegaly	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		2/56 (3.6%)		0/51 (0%)
Heart rate increased	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Heart rate irregular	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Left ventricular hypertrophy	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Myocardial infacrtion	3/130 (2.3%)		0/131 (0%)		1/132 (0.8%)		2/135 (1.5%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Tachycardia	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Transient ischaemic attack	2/130 (1.5%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Bradycardia	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Supraventricular tachycardia	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Arteriosclerosis coronary artery	1/130 (0.8%)		0/131 (0%)		1/132 (0.8%)		2/135 (1.5%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Endocrine disorders
Diabetes mellitus	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		1/56 (1.8%)		0/56 (0%)		0/51 (0%)
Diabetes mellitus inadequate control	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		1/51 (2%)
Diabetic ketoacidosis	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		1/56 (1.8%)		1/56 (1.8%)		0/51 (0%)
Eye disorders
Cataract	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Endophthalmitis	2/130 (1.5%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Intraocular pressure increased	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Retinal vein occlusion	0/130 (0%)		0/131 (0%)		0/132 (0%)		2/135 (1.5%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Glaucoma	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Iris neovascularisation	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Gastrointestinal disorders
Food poisoning	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		1/56 (1.8%)		0/56 (0%)		0/51 (0%)
Gastroenteritis	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		1/51 (2%)
Gastroesophageal reflux disease	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Impaired gastric emptying	0/130 (0%)		0/131 (0%)		2/132 (1.5%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Diverticulitis	2/130 (1.5%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Gastric bypass	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		1/56 (1.8%)		0/56 (0%)		0/51 (0%)
Gastrointestinal haemorrhage	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Vomiting	0/130 (0%)		0/131 (0%)		0/132 (0%)		2/135 (1.5%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
General disorders
Abdominal pain	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Anemia	0/130 (0%)		1/131 (0.8%)		1/132 (0.8%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Angina pectoris	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Blood potassium increased	1/130 (0.8%)		0/131 (0%)		2/132 (1.5%)		2/135 (1.5%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Cellulitis	0/130 (0%)		2/131 (1.5%)		0/132 (0%)		2/135 (1.5%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Chest pain	5/130 (3.8%)		0/131 (0%)		3/132 (2.3%)		2/135 (1.5%)		2/56 (3.6%)		0/56 (0%)		0/51 (0%)
Convulsion	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		1/56 (1.8%)		0/56 (0%)		0/51 (0%)
Death	2/130 (1.5%)		1/131 (0.8%)		2/132 (1.5%)		2/135 (1.5%)		1/56 (1.8%)		1/56 (1.8%)		0/51 (0%)
Dehydration	2/130 (1.5%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Dysarthria	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		1/51 (2%)
Dyspnoea	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Goitre	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Haematochezia	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Hernia	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		1/51 (2%)
Hyperglycaemia	1/130 (0.8%)		0/131 (0%)		2/132 (1.5%)		0/135 (0%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Oedema peripheral	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		2/135 (1.5%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Pain in extremity	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		1/51 (2%)
Post procedural complications	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Presyncope	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		1/56 (1.8%)		0/56 (0%)		0/51 (0%)
Pulmonary oedema	0/130 (0%)		1/131 (0.8%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Rhabdomyolysis	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Syncope	0/130 (0%)		2/131 (1.5%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Vertigo	2/130 (1.5%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Arthralgia	1/130 (0.8%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Atrial fibrillation	0/130 (0%)		1/131 (0.8%)		2/132 (1.5%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Anxiety	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Blood glucose decreased	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Cholecystitis acute	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Contusion	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		1/56 (1.8%)		0/56 (0%)		0/51 (0%)
Gout	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Hemiparesis	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Hypersensitivity	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Lymphoedema	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Nausea	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Migraine	0/130 (0%)		2/131 (1.5%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Salivary gland disorder	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
hypoglycaemia	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		1/56 (1.8%)		0/56 (0%)		2/51 (3.9%)
Anaemia of Chronic disease	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Joint Injury	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Skin Ulcer	1/130 (0.8%)		0/131 (0%)		1/132 (0.8%)		1/135 (0.7%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Infections and infestations
Infection	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Localised infection	0/130 (0%)		0/131 (0%)		2/132 (1.5%)		3/135 (2.2%)		2/56 (3.6%)		0/56 (0%)		0/51 (0%)
Musculoskeletal and connective tissue disorders
Facial bones fracture	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Fracture	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		1/56 (1.8%)		0/56 (0%)		1/51 (2%)
Multiple fractures	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Osteomyelitis	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Hip fracture	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Intervertebral disc protrusion	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Abdominal neoplasm	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Prostate cancer	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Throat cancer	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Boneneoplasm malignant	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Nervous system disorders
Neuropathy	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Renal and urinary disorders
Renal failure	1/130 (0.8%)		3/131 (2.3%)		1/132 (0.8%)		1/135 (0.7%)		0/56 (0%)		2/56 (3.6%)		1/51 (2%)
Renal failure chronic	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Renal failure acute	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Urinary tract infection	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Reproductive system and breast disorders
Breast cancer	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Respiratory, thoracic and mediastinal disorders
Bronchitis	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		1/56 (1.8%)		0/56 (0%)		0/51 (0%)
Influenza	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Pneumonia	2/130 (1.5%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Lung cancer metastatic	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Skin and subcutaneous tissue disorders
Skin Ulcer	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Surgical and medical procedures
Arterial bypass operation	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Coronary arterial stent insertion	0/130 (0%)		1/131 (0.8%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Hysterectomy	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Knee operation	0/130 (0%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		1/51 (2%)
Leg amputation	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Shoulder operation	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Stent placement	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		1/56 (1.8%)		1/51 (2%)
Biopsy thyroid gland	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Vascular disorders
Arteriosclerosis coronary artery	1/130 (0.8%)		0/131 (0%)		1/132 (0.8%)		2/135 (1.5%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
cerebrovascular accident	1/130 (0.8%)		0/131 (0%)		2/132 (1.5%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Coronary artery disease	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		1/135 (0.7%)		1/56 (1.8%)		0/56 (0%)		0/51 (0%)
Hypertension	1/130 (0.8%)		0/131 (0%)		2/132 (1.5%)		3/135 (2.2%)		0/56 (0%)		0/56 (0%)		1/51 (2%)
Hypotension	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Ischaemic stroke	3/130 (2.3%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		1/56 (1.8%)		0/51 (0%)
Peripheral vascular disorder	0/130 (0%)		1/131 (0.8%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Arterial occlusive disease	0/130 (0%)		0/131 (0%)		1/132 (0.8%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Embolism	1/130 (0.8%)		0/131 (0%)		0/132 (0%)		0/135 (0%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Pulmonary embolism	0/130 (0%)		0/131 (0%)		0/132 (0%)		1/135 (0.7%)		0/56 (0%)		0/56 (0%)		0/51 (0%)
Other (Not Including Serious) Adverse Events
	Sham + Prompt Laser		Ranibizumab + Prompt Laser		Ranibizumab + Deferred Laser		Triamcinolone + Prompt Laser		Sham + Ranibizumab + Laser		Sham + Ranibizumab + Deferred Laser		Sham + Triamcinolone + Laser
	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	139/139 (100%)		97/97 (100%)		105/105 (100%)		145/145 (100%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Eye disorders
Cataract	12/139 (8.6%)		9/97 (9.3%)		10/105 (9.5%)		31/145 (21.4%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Cataract subcapsular	7/139 (5%)		5/97 (5.2%)		4/105 (3.8%)		23/145 (15.9%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Eye pain	22/139 (15.8%)		23/97 (23.7%)		20/105 (19%)		12/145 (8.3%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Myodesopsia	8/139 (5.8%)		4/97 (4.1%)		10/105 (9.5%)		19/145 (13.1%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Vitreous floaters	9/139 (6.5%)		13/97 (13.4%)		11/105 (10.5%)		23/145 (15.9%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Conjunctival haemorrhage	4/139 (2.9%)		21/97 (21.6%)		25/105 (23.8%)		17/145 (11.7%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Eye Irritation	9/139 (6.5%)		8/97 (8.2%)		11/105 (10.5%)		10/145 (6.9%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Intraocular pressure increased	7/139 (5%)		4/97 (4.1%)		7/105 (6.7%)		55/145 (37.9%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Lacrimation increased	9/139 (6.5%)		6/97 (6.2%)		16/105 (15.2%)		5/145 (3.4%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Maculopathy	24/139 (17.3%)		12/97 (12.4%)		14/105 (13.3%)		9/145 (6.2%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Ocular Hyperaemia	6/139 (4.3%)		10/97 (10.3%)		5/105 (4.8%)		4/145 (2.8%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Vision Blurred	39/139 (28.1%)		16/97 (16.5%)		20/105 (19%)		32/145 (22.1%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Visual Acuity Reduced	13/139 (9.4%)		6/97 (6.2%)		8/105 (7.6%)		11/145 (7.6%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Visual Disturbance	13/139 (9.4%)		7/97 (7.2%)		5/105 (4.8%)		13/145 (9%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Vitreous haemorrhage	15/139 (10.8%)		3/97 (3.1%)		4/105 (3.8%)		2/145 (1.4%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
General disorders
Influenza	10/139 (7.2%)		6/97 (6.2%)		6/105 (5.7%)		11/145 (7.6%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Nasopharyngitis	10/139 (7.2%)		10/97 (10.3%)		10/105 (9.5%)		14/145 (9.7%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract infection	8/139 (5.8%)		12/97 (12.4%)		7/105 (6.7%)		6/145 (4.1%)		0/0 (NaN)		0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.