AB: Anti-VEGF vs. Prompt Vitrectomy for VH From PDR

• Sponsor: Jaeb Center for Health Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT02858076
• Collaborator: National Institutes of Health (NIH) (NIH), Regeneron Pharmaceuticals (Industry), National Eye Institute (NEI) (NIH)
• Enrollment: 205
• Locations: 62
• Arms: 2
• Actual Duration (Months): 38
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Although vitreous hemorrhage (VH) from proliferative diabetic retinopathy (PDR) can cause acute and dramatic vision loss for patients with diabetes, there is no current, evidence-based clinical guidance as to what treatment method is most likely to provide the best visual outcomes once intervention is desired. Intravitreous anti-vascular endothelial growth factor (anti-VEGF) therapy alone or vitrectomy combined with intraoperative PRP each provide the opportunity to stabilize or regress retinal neovascularization. However, clinical trials are lacking to elucidate the relative time frame of visual recovery or final visual outcome in prompt vitrectomy compared with initial anti-VEGF treatment. The Diabetic Retinopathy Clinical Research Network Protocol N demonstrated short-term trends consistent with a possible beneficial effect of anti-VEGF treatment in eyes with VH from PDR, including greater visual acuity improvement and reduced rates of recurrent VH as compared with saline injection. It is possible that a study with a longer duration of follow-up with structured anti-VEGF retreatment would demonstrate even greater effectiveness of anti-VEGF for VH to avoid vitrectomy and its attendant adverse events while also improving visual acuity. On the other hand, advances in surgical techniques leading to faster operative times, quicker patient recovery, and reduced complication rates may make prompt vitrectomy a more attractive alternative since it results in the immediate ability to clear hemorrhage and to perform PRP if desired, often as part of one procedure. This proposed study will evaluate the safety and efficacy of two treatment approaches for eyes with VH from PDR: prompt vitrectomy + PRP and intravitreous aflibercept injections.

Condition or Disease	Intervention/Treatment	Phase
Proliferative Diabetic Retinopathy; Vitreous Hemorrhage	Drug: 2-mg Intravitreous Aflibercept Injection; Procedure: Prompt Vitrectomy Plus Panretinal Photocoagulation	Phase 2/Phase 3

Detailed Description

A participant could have only one eye enrolled in the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 205 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage From Proliferative Diabetic Retinopathy
• Actual Study Start Date: Nov 1, 2016
• Actual Primary Completion Date: Jan 1, 2020
• Actual Study Completion Date: Jan 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Intravitreous 2 mg aflibercept injections Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met.	Drug: 2-mg Intravitreous Aflibercept Injection; Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.; Other Names: Eylea Vascular endothelial growth factor Trap-Eye
Active Comparator: Prompt vitrectomy plus panretinal photocoagulation For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage.	Procedure: Prompt Vitrectomy Plus Panretinal Photocoagulation; Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser; Other Names: PRP

Outcome Measures

Primary Outcome Measures

1. E-ETDRS Visual Acuity Letter Score (Area Under the Curve From Baseline) [24 weeks]

   The area under the curve (units = letters·weeks) was divided by 24 weeks (units = weeks) to obtain an average change in letter score (units = letters) over the 24-weekr follow-up. Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent of <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

Secondary Outcome Measures

1. E-ETDRS Visual Acuity Letter Score [4 Weeks]

   Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

2. E-ETDRS Visual Acuity Letter Score [12 Weeks]

   Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

3. E-ETDRS Visual Acuity Letter Score [24 Weeks]

   Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

4. E-ETDRS Visual Acuity Letter Score [1-Year from participant randomization]

   Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

5. E-ETDRS Visual Acuity Letter Score [2 Years]

   Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

6. E-ETDRS Visual Acuity Letter Score (Area Under the Curve From Baseline) [2-Years]

   Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity. The area under the curve (units = letters·years) was divided by 2 years (units = years) to obtain an average change in letter score (units = letters) over the 2-year follow-up. Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent of <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

7. Snellen Equivalent Range (Visual Acuity Score) [4 weeks]

   Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

8. Snellen Equivalent Range (Visual Acuity Score) [12 weeks]

   Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

9. Snellen Equivalent Range (Visual Acuity Score) [24 weeks]

   Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

10. Snellen Equivalent Range (Visual Acuity Score) [1 year]

    Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.

11. Snellen Equivalent Range (Visual Acuity Score) [2 years]

    Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity..

12. Recurrent Vitreous Hemorrhage [At any time through 2 years]

    Assessed by the investigator and defined as presence of vitreous hemorrhage after a period of absence. Excludes eyes in which vitreous hemorrhage could not be assessed during follow-up.

13. Retinal Neovascularization on Clinical Exam [24 weeks]

    Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined.

14. Retinal Neovascularization on Clinical Exam [1 year]

    Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined

15. Retinal Neovascularization on Clinical Exam [2 years]

    Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Age >= 18 years Participants <18 years old are not being included because proliferative diabetic retinopathy is so rare in this age group that the diagnosis may be questionable.

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

Any one of the following will be considered to be sufficient evidence that diabetes is present:

• Current regular use of insulin for the treatment of diabetes

• Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes

• Documented diabetes by American Diabetes Association and/or World Health Organization criteria 4. Able and willing to provide informed consent. 5. Patient is willing and able to undergo vitrectomy within next 2 weeks and the vitrectomy can be scheduled within that time frame.

1. Vitreous hemorrhage causing vision impairment, presumed to be from proliferative diabetic retinopathy, for which intervention is deemed necessary.

• Note: Prior panretinal photocoagulation is neither a requirement nor an exclusion.

• Subhyaloid hemorrhage alone does not make an eye eligible; however, presence of subhyaloid hemorrhage in addition to the criteria above will not preclude participation provided the investigator is comfortable with either treatment regimen.

1. Immediate vitrectomy not required (investigator and participant are willing to wait at least 4 months to see if hemorrhage clears sufficiently with anti-vascular endothelial growth factor without having to proceed to vitrectomy).

2. Visual acuity letter score ≤78 (approximate Snellen equivalent 20/32) and at least light perception.

3. Investigators should use particular caution when considering enrollment of an eye with visual acuity letter score 69 to 78 (approximate Snellen equivalent 20/32 to 20/40) to ensure that the need for vitrectomy and its potential benefits outweigh the potential risks.

Exclusion Criteria:

• A potential participant is not eligible if any of the following exclusion criteria are present:

1. History of chronic renal failure requiring dialysis (including placement of fistula if performed in preparation for dialysis) or kidney transplant.

2. 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).

3. Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months.

4. A condition that, in the opinion of the investigator, would preclude participant undergoing elective vitrectomy surgery if indicated during the study.

5. Participation in an investigational trial within 30 days of randomization that involved treatment with any drug that has not received regulatory approval for the indication being studied.

• Note: participants cannot receive another investigational drug while participating in the study.

1. Known allergy to any component of the study drug or any drug used in the injection prep (including povidone iodine).

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

3. If blood pressure is brought below 180/110 by anti-hypertensive treatment, potential participant can become eligible.

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

• These drugs cannot be used during the study.

1. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next two years.

• Women who are potential participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed.

1. Potential participant is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the two years.

2. Evidence of traction detachment involving or threatening the macula.

• If the density of the hemorrhage precludes a visual assessment on clinical exam to confirm eligibility, then it is recommended that assessment be performed with ultrasound as standard care.

1. Evidence of rhegmatogenous retinal detachment.

• If the density of the hemorrhage precludes a visual assessment on clinical exam to confirm eligibility, then it is recommended that assessment be performed with ultrasound as standard care.

1. Evidence of neovascular glaucoma (iris or angle neovascularization is not an exclusion).

2. Known diabetic macular edema (DME), defined as either

3. Optical coherence tomography central subfield thickness (microns):

4. Zeiss Cirrus: ≥290 in women; ≥305 in men

5. Heidelberg Spectralis: ≥305 in women; ≥320 in men OR

6. Diabetic macular edema on clinical exam that the investigator believes currently requires treatment.

7. History of intravitreous anti-vascular endothelial growth factor treatment within 2 months prior to current vitreous hemorrhage onset or after onset.

8. History of intraocular corticosteroid treatment within 4 months prior to current vitreous hemorrhage onset or after onset.

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

10. History of vitrectomy.

11. History of YAG capsulotomy performed within 2 months prior to randomization.

12. Aphakia.

13. Uncontrolled glaucoma (in investigator's judgment).

14. Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Retinal Diagnostic Center	Campbell	California	United States	95008
2	Macula & Retina Institute	Glendale	California	United States	91203
3	Atlantis Eye Care	Huntington Beach	California	United States	92647
4	Loma Linda University Health Care, Department of Ophthalmology	Loma Linda	California	United States	92354
5	Shashi D Ganti, MD PC	Porterville	California	United States	93257
6	Florida Retina Consultants	Lakeland	Florida	United States	33805
7	Southeast Eye Institute, P.A. dba Eye Associates of Pinellas	Pinellas Park	Florida	United States	33782
8	Retina Associates of Sarasota	Sarasota	Florida	United States	34233
9	Retina Associates of Florida, P.A.	Tampa	Florida	United States	33609
10	Emory Eye Center	Atlanta	Georgia	United States	30322
11	Southeast Retina Center, P.C.	Augusta	Georgia	United States	30909
12	Marietta Eye Clinic	Marietta	Georgia	United States	30060
13	Thomas Eye Group	Sandy Springs	Georgia	United States	30328
14	Gailey Eye Clinic	Bloomington	Illinois	United States	61704
15	Northwestern Medical Faculty Foundation	Chicago	Illinois	United States	60611
16	University of Illinois at Chicago Medical Center	Chicago	Illinois	United States	60612
17	Carle Foundation Hospital	Urbana	Illinois	United States	61801
18	Raj K. Maturi, MD, PC	Indianapolis	Indiana	United States	42690
19	John-Kenyon American Eye Institute	New Albany	Indiana	United States	47150
20	Retina Associates, P.A.	Shawnee Mission	Kansas	United States	66204
21	Paducah Retinal Center	Paducah	Kentucky	United States	42001
22	Eye Associates of Northeast Louisiana dba Haik Humble Eye Center	West Monroe	Louisiana	United States	71291
23	Elman Retina Group, P.A.	Baltimore	Maryland	United States	21237
24	Wilmer Eye Institute at Johns Hopkins	Baltimore	Maryland	United States	21287
25	Valley Eye Physicians and Surgeons	Ayer	Massachusetts	United States	01432
26	Joslin Diabetes Center	Boston	Massachusetts	United States	02215
27	Kellogg Eye Center, University of Michigan	Ann Arbor	Michigan	United States	48105
28	Henry Ford Health System, Dept of Ophthalmology and Eye Care Services	Detroit	Michigan	United States	48202
29	Retina Specialists of Michigan	Grand Rapids	Michigan	United States	49546
30	Retina Center, PA	Minneapolis	Minnesota	United States	55404
31	Mayo Clinic Department of Ophthalmology	Rochester	Minnesota	United States	55905
32	Mid-America Retina Consultants, P.A.	Kansas City	Missouri	United States	64111
33	The Retina Institute	Saint Louis	Missouri	United States	63128
34	The New York Eye and Ear Infirmary/Faculty Eye Practice	New York	New York	United States	10003
35	MaculaCare	New York	New York	United States	10021
36	Weill Cornell Medical College	New York	New York	United States	10021
37	Retina-Vitreous Surgeons of Central New York, PC	Syracuse	New York	United States	13224
38	Kittner Eye Center	Chapel Hill	North Carolina	United States	27517
39	Charlotte Eye, Ear, Nose and Throat Assoc., PA	Charlotte	North Carolina	United States	28210
40	Retina Associates of Cleveland, Inc.	Beachwood	Ohio	United States	44122
41	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
42	Retina Vitreous Center	Edmond	Oklahoma	United States	73013
43	Dean A. McGee Eye Institute	Oklahoma City	Oklahoma	United States	73104
44	Oregon Retina, LLP	Eugene	Oregon	United States	97401
45	Retina Northwest, PC	Portland	Oregon	United States	97221
46	Casey Eye Institute	Portland	Oregon	United States	97239
47	Retina Vitreous Consultants	Monroeville	Pennsylvania	United States	15146
48	Palmetto Retina Center	West Columbia	South Carolina	United States	29169
49	Southeastern Retina Associates	Chattanooga	Tennessee	United States	37421
50	Southeastern Retina Associates, P.C.	Knoxville	Tennessee	United States	37909
51	Southwest Retina Specialists	Amarillo	Texas	United States	79106
52	Retina Research Center	Austin	Texas	United States	78705
53	Retina and Vitreous of Texas	Houston	Texas	United States	77025
54	Baylor Eye Physicians and Surgeons	Houston	Texas	United States	77030
55	Texas Retina Associates	Lubbock	Texas	United States	79424
56	Valley Retina Institute	McAllen	Texas	United States	78503
57	Medical Center Ophthalmology Associates	San Antonio	Texas	United States	78240
58	Retinal Consultants of San Antonio	San Antonio	Texas	United States	78240
59	Spokane Eye Clinic	Spokane	Washington	United States	99204
60	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
61	UBC/VCHA Eye Care Centre	Vancouver	British Columbia	Canada	V5Z 3N9
62	University Health Network - Toronto Western Hospital	Toronto	Ontario	Canada	M5T 2S8

Sponsors and Collaborators

• Jaeb Center for Health Research
• National Institutes of Health (NIH)
• Regeneron Pharmaceuticals
• National Eye Institute (NEI)

Investigators

• Study Chair: Andrew Antoszyk, MD, Charlotte Eye, Ear, Nose and Throat Assoc., PA

Study Documents (Full-Text)

• Study Protocol - Jul 28, 2016
• Statistical Analysis Plan - Apr 27, 2020
• Informed Consent Form - Jun 24, 2016

More Information

Publications

None provided.

• Responsible Party: Jaeb Center for Health Research
• ClinicalTrials.gov Identifier: NCT02858076
• Other Study ID Numbers: DRCR.net Protocol AB; EY14231; EY23207; EY18817
• First Posted: Aug 8, 2016
• Last Update Posted: Apr 20, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by Jaeb Center for Health Research: Anti-VEGF; Vitrectomy
• Additional relevant MeSH terms: Retinal Diseases; Diabetic Retinopathy; Vitreous Hemorrhage; Hemorrhage; Aflibercept; Endothelial Growth Factors

Study Results

Participant Flow

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Vitrectomy With Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2 mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of vascular endothelial growth factor (VEGF) as well as to placental growth factor.	For the prompt vitrectomy with panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Vitrectomy with Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Period Title: Overall Study
STARTED	100	105
COMPLETED	90	87
NOT COMPLETED	10	18

Baseline Characteristics

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation	Total
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser	Total of all reporting groups
Overall Participants	100	105	205
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56 (12)	57 (11)	57 (11)
Sex: Female, Male (Count of Participants)
Female	47 47%	43 41%	90 43.9%
Male	53 53%	62 59%	115 56.1%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	43 43%	41 39%	84 41%
Non-Hispanic White	36 36%	47 44.8%	83 40.5%
Non-Hispanic Black/African American	16 16%	11 10.5%	27 13.2%
Asian	2 2%	5 4.8%	7 3.4%
American Indian/Alaska Native	1 1%	0 0%	1 0.5%
More than one race	1 1%	0 0%	1 0.5%
Unknown or not reported	1 1%	1 1%	2 1%
Region of Enrollment (participants) [Number]
United States	100 100%	105 100%	205 100%
Diabetes Type (Count of Participants)
Type 1	17 17%	19 18.1%	36 17.6%
Type 2	83 83%	86 81.9%	169 82.4%
Duration of Diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	19 (10)	21 (11)	20 (11)
Insulin Used (Count of Participants)
Yes	78 78%	78 74.3%	156 76.1%
No	22 22%	27 25.7%	49 23.9%
Hemoglobin A1c (Hemoglobin A1c percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Hemoglobin A1c percentage]	8.7 (2.2)	8.3 (1.9)	8.5 (2.0)
Mean Arterial Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	102 (12)	102 (12)	102 (12)
Prior Myocardial Infarction (Count of Participants)
Count of Participants [Participants]	7 7%	15 14.3%	22 10.7%
Prior Stroke (Count of Participants)
Count of Participants [Participants]	5 5%	8 7.6%	13 6.3%
Kidney Disease (Count of Participants)
Count of Participants [Participants]	20 20%	18 17.1%	38 18.5%
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	31 (7)	32 (7)	31 (7)
Daily Cigarette Smoking (Count of Participants)
Never	60 60%	72 68.6%	132 64.4%
Prior	27 27%	25 23.8%	52 25.4%
Current	13 13%	8 7.6%	21 10.2%
Prior Treatment for Diabetic Macular Edema (Eyes) [Number]
Number [Eyes]	29	37	66
Prior anti-vascular endothelial growth factor for diabetic macular edema (Eyes) [Number]
Number [Eyes]	23	28	51
Prior anti-vascular endothelial growth factor for diabetic retinopathy (Eyes) [Number]
Number [Eyes]	23	22	45
Prior panretinal photocoagulation (Eyes) [Number]
Number [Eyes]	42	58	100
Approximate Duration of Vitreous Hemorrhage (Eyes) [Number]
Less than 1 Month	60	57	117
1 to 3 Months	27	27	54
4 to 6 Months	8	6	14
7 to 12 Months	1	6	7
More than 12 Months	4	9	13
Lens Status on Clinical Exam (Eyes) [Number]
Phakic (natural lens)	75	81	156
Prosthetic intraocular lens	25	24	49
E-ETDRS visual acuity letter score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	35.6 (28.1)	33.5 (28.8)	34.5 (28.4)
Traction Retinal Detachment, Macula Not Threatened (Eyes) [Number]
Number [Eyes]	5	3	8
Intraocular Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	16 (4)	15 (3)	15 (4)
Prior focal/grid laser for Diabetic Macular Edema (Eyes) [Number]
Number [Eyes]	15	16	31

Outcome Measures

1. Primary Outcome

Title	E-ETDRS Visual Acuity Letter Score (Area Under the Curve From Baseline)
Description	The area under the curve (units = letters·weeks) was divided by 24 weeks (units = weeks) to obtain an average change in letter score (units = letters) over the 24-weekr follow-up. Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent of <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	97	98
Mean (Standard Deviation) [units on a scale]	59.3 (21.9)	63.0 (21.7)

2. Secondary Outcome

Title	E-ETDRS Visual Acuity Letter Score
Description	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
Time Frame	4 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Vitrectomy With Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2 mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of vascular endothelial growth factor (VEGF) as well as to placental growth factor.	For the prompt vitrectomy with panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Vitrectomy with Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	95	99
Mean (Standard Deviation) [units on a scale]	52.6 (29.4)	62.3 (26.8)

3. Secondary Outcome

Title	E-ETDRS Visual Acuity Letter Score
Description	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
Time Frame	12 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	97	102
Mean (Standard Deviation) [units on a scale]	63.7 (25.0)	67.3 (24.7)

4. Secondary Outcome

Title	E-ETDRS Visual Acuity Letter Score
Description	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
Time Frame	24 Weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	97	98
Mean (Standard Deviation) [units on a scale]	69.4 (23.8)	69.0 (23.1)

5. Secondary Outcome

Title	E-ETDRS Visual Acuity Letter Score
Description	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
Time Frame	1-Year from participant randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	95	98
Mean (Standard Deviation) [units on a scale]	70.5 (20.3)	72.7 (20.3)

6. Secondary Outcome

Title	E-ETDRS Visual Acuity Letter Score
Description	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
Time Frame	2 Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	90	87
Mean (Standard Deviation) [units on a scale]	73.7 (16.4)	71.0 (24.0)

7. Secondary Outcome

Title	E-ETDRS Visual Acuity Letter Score (Area Under the Curve From Baseline)
Description	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity. The area under the curve (units = letters·years) was divided by 2 years (units = years) to obtain an average change in letter score (units = letters) over the 2-year follow-up. Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent of <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
Time Frame	2-Years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	90	87
Mean (Standard Deviation) [units on a scale]	68.7 (15.0)	70.0 (18.8)

8. Secondary Outcome

Title	Snellen Equivalent Range (Visual Acuity Score)
Description	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	95	99
20/32 or better (>=74)	24 24%	49 46.7%
20/200 or worse (<=38)	26 26%	18 17.1%

9. Secondary Outcome

Title	Snellen Equivalent Range (Visual Acuity Score)
Description	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	97	102
20/32 or better (>=74	45 45%	58 55.2%
20/200 or worse (<=38)	16 16%	12 11.4%

10. Secondary Outcome

Title	Snellen Equivalent Range (Visual Acuity Score)
Description	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	97	98
20/32 or better (>=74	61 61%	59 56.2%
20/200 or worse (<=38)	10 10%	10 9.5%

11. Secondary Outcome

Title	Snellen Equivalent Range (Visual Acuity Score)
Description	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	95	98
20/32 or better (>=74	55 55%	65 61.9%
20/200 or worse (<=38)	8 8%	8 7.6%

12. Secondary Outcome

Title	Snellen Equivalent Range (Visual Acuity Score)
Description	Best-corrected visual acuity following protocol-defined refraction. Visual Acuity was measured with the Electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity test on a scale from 100 letters (Snellen equivalent of 20/10) to 0 letters (Snellen equivalent <20/800). Higher scores indicate better visual acuity and lower scores indicate worse visual acuity..
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	90	87
20/32 or better (>=74	56 56%	59 56.2%
20/200 or worse (<=38)	3 3%	10 9.5%

13. Secondary Outcome

Title	Recurrent Vitreous Hemorrhage
Description	Assessed by the investigator and defined as presence of vitreous hemorrhage after a period of absence. Excludes eyes in which vitreous hemorrhage could not be assessed during follow-up.
Time Frame	At any time through 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	97	104
Count of Participants [Participants]	48 48%	16 15.2%

14. Secondary Outcome

Title	Retinal Neovascularization on Clinical Exam
Description	Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined.
Time Frame	24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	85	92
Count of Participants [Participants]	25 25%	3 2.9%

15. Secondary Outcome

Title	Retinal Neovascularization on Clinical Exam
Description	Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	89	95
Count of Participants [Participants]	15 15%	2 1.9%

16. Secondary Outcome

Title	Retinal Neovascularization on Clinical Exam
Description	Defined as neovascularization of the disc or elsewhere. Excludes eyes in which retinal neovascularization could not be determined
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravitreous 2 mg Aflibercept Injections	Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.	For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
Measure Participants	88	83
Count of Participants [Participants]	20 20%	2 1.9%

Adverse Events

Time Frame	2 Years
Arm/Group Title	Intravitreous 2 mg Aflibercept Injections		Prompt Vitrectomy Plus Panretinal Photocoagulation
Arm/Group Description	Initial injection must be given on the day of randomization. Follow-up injections will be performed as often as every 4 weeks unless criteria for deferral are met. 2-mg Intravitreous Aflibercept Injection: Soluble decoy receptor fusion protein that has a high binding affinity to all isoforms of VEGF as well as to placental growth factor.		For the prompt vitrectomy + panretinal photocoagulation group, the vitrectomy must be scheduled to be performed within 2 weeks of randomization. Vitrectomy will be performed according to the investigator's usual routine, including pre-operative care, surgical procedure, and post-operative care, although anti-VEGF may not be given post-operatively unless there is recurrent hemorrhage. Prompt Vitrectomy Plus Panretinal Photocoagulation: Surgical removal of the vitreous gel and associated hemorrhage, concurrent delivery of panretinal endolaser
All Cause Mortality
	Intravitreous 2 mg Aflibercept Injections		Prompt Vitrectomy Plus Panretinal Photocoagulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/100 (6%)		3/105 (2.9%)
Serious Adverse Events
	Intravitreous 2 mg Aflibercept Injections		Prompt Vitrectomy Plus Panretinal Photocoagulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/100 (44%)		45/105 (42.9%)
Blood and lymphatic system disorders
Anemia	1/100 (1%)	1	0/105 (0%)	0
Lymphangitis	0/100 (0%)	0	1/105 (1%)	1
Neutropenia	1/100 (1%)	1	0/105 (0%)	0
Cardiac disorders
Acute coronary syndrome	1/100 (1%)	1	1/105 (1%)	1
Bicuspid aortic valve	0/100 (0%)	0	1/105 (1%)	1
Cardiac arrest	3/100 (3%)	3	0/105 (0%)	0
Congestive heart failure	4/100 (4%)	6	4/105 (3.8%)	5
Coronary artery disease	1/100 (1%)	1	2/105 (1.9%)	2
Heart failure	1/100 (1%)	1	2/105 (1.9%)	2
Mitral valve disorders	0/100 (0%)	0	1/105 (1%)	1
Mitral valve stenosis	0/100 (0%)	0	1/105 (1%)	1
Myocardial infarction	2/100 (2%)	2	1/105 (1%)	1
Unstable angina	1/100 (1%)	1	0/105 (0%)	0
Endocrine disorders
Diabetes	0/100 (0%)	0	1/105 (1%)	1
Diabetic ketoacidosis	4/100 (4%)	7	2/105 (1.9%)	3
Hyperglycemia	1/100 (1%)	1	0/105 (0%)	0
Hyperglycemic hyperosmolar nonketotic syndrome	1/100 (1%)	1	0/105 (0%)	0
Hypoglycemia	1/100 (1%)	1	1/105 (1%)	1
Loss of control of blood sugar	0/100 (0%)	0	1/105 (1%)	1
Eye disorders
Endophthalmitis	1/100 (1%)	1	2/105 (1.9%)	2
Exposure keratoconjunctivitis	0/100 (0%)	0	1/105 (1%)	1
Ischemia retinal	0/100 (0%)	0	1/105 (1%)	1
Ocular fundus arteriosclerosis	0/100 (0%)	0	1/105 (1%)	1
Rhegmatogenous retinal detachment	2/100 (2%)	3	0/105 (0%)	0
Traction retinal detachment	1/100 (1%)	1	0/105 (0%)	0
Visual acuity decreased	1/100 (1%)	1	0/105 (0%)	0
Vitreous hemorrhage	2/100 (2%)	2	0/105 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/100 (1%)	1	0/105 (0%)	0
Appendicitis	1/100 (1%)	1	0/105 (0%)	0
Bowel obstruction	0/100 (0%)	0	1/105 (1%)	1
Gastritis	1/100 (1%)	1	0/105 (0%)	0
Gastroenteritis	3/100 (3%)	4	0/105 (0%)	0
Gastroparesis	1/100 (1%)	4	0/105 (0%)	0
Hyperemesis	0/100 (0%)	0	1/105 (1%)	1
Pancreatitis	1/100 (1%)	1	0/105 (0%)	0
Vomiting	1/100 (1%)	1	1/105 (1%)	1
General disorders
Chest pain	0/100 (0%)	0	1/105 (1%)	1
Death	2/100 (2%)	2	1/105 (1%)	1
Gait disturbance	1/100 (1%)	1	0/105 (0%)	0
Leg edema	1/100 (1%)	1	1/105 (1%)	1
Peripheral edema	1/100 (1%)	1	0/105 (0%)	0
Hepatobiliary disorders
Acute cholecystitis	0/100 (0%)	0	1/105 (1%)	1
Immune system disorders
Anaphylaxis	1/100 (1%)	1	0/105 (0%)	0
Infections and infestations
Abscess NOS	0/100 (0%)	0	2/105 (1.9%)	2
Bacteremia	0/100 (0%)	0	1/105 (1%)	1
Foot infection	6/100 (6%)	6	1/105 (1%)	1
Infection	1/100 (1%)	1	1/105 (1%)	1
Influenza	1/100 (1%)	1	1/105 (1%)	1
MRSA	1/100 (1%)	1	1/105 (1%)	1
Sepsis	5/100 (5%)	6	0/105 (0%)	0
Injury, poisoning and procedural complications
Fall	1/100 (1%)	1	1/105 (1%)	1
Head injury	1/100 (1%)	1	0/105 (0%)	0
Investigations
Heart rate low	0/100 (0%)	0	2/105 (1.9%)	2
Troponin increased	1/100 (1%)	1	0/105 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/100 (1%)	1	1/105 (1%)	1
Fluid overload - fluid volume increased	0/100 (0%)	0	1/105 (1%)	1
Hyperkalemia	0/100 (0%)	0	1/105 (1%)	1
Hypokalemia	0/100 (0%)	0	1/105 (1%)	1
Hyponatremia	0/100 (0%)	0	1/105 (1%)	1
Type II diabetes mellitus	0/100 (0%)	0	1/105 (1%)	1
Water retention	1/100 (1%)	1	0/105 (0%)	0
Musculoskeletal and connective tissue disorders
Back discomfort	1/100 (1%)	1	0/105 (0%)	0
Broken bones	1/100 (1%)	1	0/105 (0%)	0
Femur fracture	1/100 (1%)	1	0/105 (0%)	0
Fractured collar bone	0/100 (0%)	0	1/105 (1%)	1
Fractured ribs	0/100 (0%)	0	1/105 (1%)	1
Hip fracture	2/100 (2%)	2	1/105 (1%)	1
Osteomyelitis	3/100 (3%)	6	0/105 (0%)	0
Pulled hamstring	1/100 (1%)	1	0/105 (0%)	0
Nervous system disorders
Coma	1/100 (1%)	1	0/105 (0%)	0
Dizziness	0/100 (0%)	0	1/105 (1%)	1
Syncope	0/100 (0%)	0	1/105 (1%)	1
Viral meningitis	0/100 (0%)	0	1/105 (1%)	1
Psychiatric disorders
Anxiety	1/100 (1%)	1	0/105 (0%)	0
Drug abuse	1/100 (1%)	1	0/105 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/100 (1%)	1	2/105 (1.9%)	3
Acute renal failure	0/100 (0%)	0	1/105 (1%)	1
Chronic kidney disease	1/100 (1%)	1	1/105 (1%)	1
Chronic renal failure worsened	0/100 (0%)	0	1/105 (1%)	2
End stage renal disease (ESRD)	1/100 (1%)	1	1/105 (1%)	1
Kidney failure	7/100 (7%)	7	1/105 (1%)	2
Kidney infection	1/100 (1%)	1	0/105 (0%)	0
Kidney stones	0/100 (0%)	0	1/105 (1%)	1
Nephrotic syndrome	1/100 (1%)	1	0/105 (0%)	0
Renal failure	2/100 (2%)	2	0/105 (0%)	0
Urinary tract infection	1/100 (1%)	1	0/105 (0%)	0
Reproductive system and breast disorders
Testicular torsion	0/100 (0%)	0	1/105 (1%)	1
Respiratory, thoracic and mediastinal disorders
Acute bronchitis	1/100 (1%)	1	0/105 (0%)	0
Acute respiratory failure	2/100 (2%)	2	1/105 (1%)	1
Cardiopulmonary arrest	1/100 (1%)	1	0/105 (0%)	0
Dyspnea	1/100 (1%)	1	1/105 (1%)	1
Exacerbation of asthma	0/100 (0%)	0	1/105 (1%)	2
Hypoxemia	0/100 (0%)	0	1/105 (1%)	1
Pleural effusion	1/100 (1%)	1	1/105 (1%)	1
Pneumonia	3/100 (3%)	3	4/105 (3.8%)	5
Pulmonary embolism	1/100 (1%)	1	0/105 (0%)	0
Respiratory distress	0/100 (0%)	0	1/105 (1%)	1
Shortness of breath	2/100 (2%)	3	0/105 (0%)	0
Skin and subcutaneous tissue disorders
Cellulitis	1/100 (1%)	1	1/105 (1%)	1
Cellulitis of arm	1/100 (1%)	2	0/105 (0%)	0
Cellulitis of foot	0/100 (0%)	0	1/105 (1%)	1
Cellulitis of leg	1/100 (1%)	1	0/105 (0%)	0
Cellulitis of toe	1/100 (1%)	1	0/105 (0%)	0
Diabetic foot ulcer	1/100 (1%)	1	1/105 (1%)	1
Foot ulcer	0/100 (0%)	0	1/105 (1%)	1
Surgical and medical procedures
Back surgery	0/100 (0%)	0	1/105 (1%)	1
Bypass surgery	0/100 (0%)	0	1/105 (1%)	1
Coronary artery bypass graft	1/100 (1%)	1	0/105 (0%)	0
Foot surgery	2/100 (2%)	2	0/105 (0%)	0
Implantable defibrillator insertion	1/100 (1%)	1	0/105 (0%)	0
Knee surgery NOS	0/100 (0%)	0	1/105 (1%)	1
Metatarsal excision	1/100 (1%)	1	0/105 (0%)	0
Stent placement	0/100 (0%)	0	2/105 (1.9%)	2
Surgery	0/100 (0%)	0	1/105 (1%)	1
Toe amputation	0/100 (0%)	0	1/105 (1%)	1
Vascular disorders
Deep vein thrombosis	0/100 (0%)	0	1/105 (1%)	1
Embolism - blood clot	2/100 (2%)	2	0/105 (0%)	0
Hypertension	0/100 (0%)	0	2/105 (1.9%)	2
Hypertension worsened	3/100 (3%)	4	2/105 (1.9%)	2
Hypotension	2/100 (2%)	3	1/105 (1%)	1
Intraventricular hemorrhage	0/100 (0%)	0	1/105 (1%)	1
Ischemia - systemic	0/100 (0%)	0	1/105 (1%)	1
Peripheral vascular disease	1/100 (1%)	1	0/105 (0%)	0
Stroke	0/100 (0%)	0	1/105 (1%)	1
Stroke (cerebrovascular accident)	0/100 (0%)	0	1/105 (1%)	1
Stroke - Ischemic	1/100 (1%)	1	0/105 (0%)	0
Transient ischemic attacks	0/100 (0%)	0	1/105 (1%)	1
Other (Not Including Serious) Adverse Events
	Intravitreous 2 mg Aflibercept Injections		Prompt Vitrectomy Plus Panretinal Photocoagulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	97/100 (97%)		98/105 (93.3%)
Blood and lymphatic system disorders
Anemia	4/100 (4%)	4	7/105 (6.7%)	8
Anemia of chronic disease	1/100 (1%)	1	1/105 (1%)	1
Anemia, unspecified	1/100 (1%)	1	0/105 (0%)	0
Leukocytosis	1/100 (1%)	1	1/105 (1%)	1
Thrombocytopenia	0/100 (0%)	0	1/105 (1%)	1
Cardiac disorders
Arteriosclerotic heart disease	1/100 (1%)	1	0/105 (0%)	0
Atrial fibrillation	0/100 (0%)	0	3/105 (2.9%)	3
Cardiomegaly	0/100 (0%)	0	1/105 (1%)	1
Congestive heart failure	2/100 (2%)	2	1/105 (1%)	1
Coronary artery disease	2/100 (2%)	2	0/105 (0%)	0
Ischemic cardiomyopathy	1/100 (1%)	1	0/105 (0%)	0
Left ventricular hypertrophy	1/100 (1%)	1	0/105 (0%)	0
Myocardial disorder	0/100 (0%)	0	1/105 (1%)	1
Myocardial infarction	0/100 (0%)	0	1/105 (1%)	1
Pericardial effusion	1/100 (1%)	1	0/105 (0%)	0
Pulmonary valve regurgitation	1/100 (1%)	1	0/105 (0%)	0
Tachycardia	0/100 (0%)	0	1/105 (1%)	1
Tricuspid regurgitation	1/100 (1%)	1	0/105 (0%)	0
Congenital, familial and genetic disorders
Anomaly heart	1/100 (1%)	1	0/105 (0%)	0
Ear and labyrinth disorders
Ear infection	0/100 (0%)	0	2/105 (1.9%)	2
Hearing loss	0/100 (0%)	0	1/105 (1%)	1
Otitis externa	0/100 (0%)	0	1/105 (1%)	1
Otitis media acute	1/100 (1%)	1	1/105 (1%)	1
Tinnitus	0/100 (0%)	0	1/105 (1%)	1
Tympanic membrane perforation	1/100 (1%)	1	0/105 (0%)	0
Endocrine disorders
Diabetes	1/100 (1%)	1	1/105 (1%)	1
Diabetes mellitus poor control	1/100 (1%)	1	1/105 (1%)	1
Hyperglycemia	1/100 (1%)	1	2/105 (1.9%)	2
Hyperparathyroidism	0/100 (0%)	0	1/105 (1%)	1
Hypoglycemia	5/100 (5%)	6	3/105 (2.9%)	3
Hypothyroidism	0/100 (0%)	0	2/105 (1.9%)	2
Loss of control of blood sugar	1/100 (1%)	1	3/105 (2.9%)	3
Worsening of diabetes	3/100 (3%)	3	2/105 (1.9%)	2
Eye disorders
Allergic conjunctivitis	0/100 (0%)	0	1/105 (1%)	1
Amaurosis fugax	1/100 (1%)	1	0/105 (0%)	0
Anterior chamber angle neovascularisation	3/100 (3%)	3	1/105 (1%)	1
Anterior chamber cell	4/100 (4%)	4	3/105 (2.9%)	4
Anterior chamber flare	2/100 (2%)	2	2/105 (1.9%)	2
Atrophy of macula	0/100 (0%)	0	1/105 (1%)	1
Band keratopathy	0/100 (0%)	0	1/105 (1%)	1
Blepharitis (eyelid irritation)	1/100 (1%)	1	2/105 (1.9%)	2
Blurred vision	9/100 (9%)	10	3/105 (2.9%)	3
Blurry vision	10/100 (10%)	11	3/105 (2.9%)	3
Cataract	14/100 (14%)	14	20/105 (19%)	23
Cataract cortical	5/100 (5%)	5	1/105 (1%)	2
Cataract fragments in eye postoperative	0/100 (0%)	0	1/105 (1%)	1
Cataract subcapsular	1/100 (1%)	1	1/105 (1%)	1
Chalazion	0/100 (0%)	0	1/105 (1%)	1
Choroidal detachment	0/100 (0%)	0	2/105 (1.9%)	2
Cloudy vision	0/100 (0%)	0	4/105 (3.8%)	4
Conjunctival cyst	0/100 (0%)	0	1/105 (1%)	1
Conjunctival hyperemia	0/100 (0%)	0	1/105 (1%)	2
Corneal abrasion	3/100 (3%)	3	2/105 (1.9%)	2
Corneal defect	1/100 (1%)	1	1/105 (1%)	1
Corneal disorder (NOS)	0/100 (0%)	0	1/105 (1%)	1
Corneal edema	0/100 (0%)	0	5/105 (4.8%)	5
Corneal endothelial disorder	1/100 (1%)	1	0/105 (0%)	0
Corneal erosion	0/100 (0%)	0	1/105 (1%)	1
Corneal guttata	0/100 (0%)	0	1/105 (1%)	1
Corneal haze	0/100 (0%)	0	1/105 (1%)	1
Corneal irritation	0/100 (0%)	0	2/105 (1.9%)	2
Corneal scar	0/100 (0%)	0	1/105 (1%)	1
Corneal ulcer	0/100 (0%)	0	2/105 (1.9%)	2
Cortical spoking	7/100 (7%)	7	2/105 (1.9%)	2
Cupping of optic nerve	0/100 (0%)	0	1/105 (1%)	1
Decrease in depth perception	1/100 (1%)	1	0/105 (0%)	0
Detachment of retinal pigment epithelium	0/100 (0%)	0	1/105 (1%)	1
Diabetic macular edema	10/100 (10%)	11	9/105 (8.6%)	11
Diplopia	0/100 (0%)	0	1/105 (1%)	1
Disc neovascularization	7/100 (7%)	7	0/105 (0%)	0
Double vision	2/100 (2%)	2	2/105 (1.9%)	2
Dry eye	6/100 (6%)	6	7/105 (6.7%)	7
Dry eye syndrome	1/100 (1%)	1	1/105 (1%)	1
Epiretinal membrane	12/100 (12%)	13	13/105 (12.4%)	13
Exposure keratoconjunctivitis	0/100 (0%)	0	1/105 (1%)	1
Eye ache	1/100 (1%)	1	1/105 (1%)	1
Eye irritation	2/100 (2%)	2	5/105 (4.8%)	5
Eye itching	3/100 (3%)	5	7/105 (6.7%)	7
Eye pain	11/100 (11%)	14	6/105 (5.7%)	7
Eye strain	1/100 (1%)	1	0/105 (0%)	0
Eye tearing	2/100 (2%)	2	1/105 (1%)	1
Eyelid edema	0/100 (0%)	0	1/105 (1%)	1
Eyelid pain	1/100 (1%)	1	0/105 (0%)	0
Eyelid twitching	0/100 (0%)	0	1/105 (1%)	1
Filmy vision	1/100 (1%)	1	0/105 (0%)	0
Flame-shaped hemorrhage	1/100 (1%)	1	0/105 (0%)	0
Floaters	24/100 (24%)	30	11/105 (10.5%)	11
Folds in Descemet's membrane	0/100 (0%)	0	1/105 (1%)	1
Foreign body in conjunctival sac	0/100 (0%)	0	2/105 (1.9%)	2
Foreign body sensation in eyes	2/100 (2%)	2	4/105 (3.8%)	4
Glare	0/100 (0%)	0	1/105 (1%)	1
Glaucoma	2/100 (2%)	2	4/105 (3.8%)	5
Hazy vision	4/100 (4%)	4	1/105 (1%)	1
Hordeolum	1/100 (1%)	1	0/105 (0%)	0
Hypertensive retinopathy	1/100 (1%)	1	1/105 (1%)	1
Hyphema	0/100 (0%)	0	4/105 (3.8%)	5
Hypotony of eye	0/100 (0%)	0	1/105 (1%)	1
Intraretinal microvascular abnormalities	2/100 (2%)	4	0/105 (0%)	0
Iris neovascularization	2/100 (2%)	2	2/105 (1.9%)	2
Iritis (anterior uveitis, iridocyclitis)	1/100 (1%)	2	1/105 (1%)	1
Ischemia retinal	0/100 (0%)	0	1/105 (1%)	1
Keratopathy NOS	0/100 (0%)	0	1/105 (1%)	1
Lattice degeneration of retina	1/100 (1%)	1	0/105 (0%)	0
Macular atrophy	1/100 (1%)	1	0/105 (0%)	0
Macular dystrophy	0/100 (0%)	0	1/105 (1%)	1
Macular edema	0/100 (0%)	0	1/105 (1%)	1
Macular hole	2/100 (2%)	2	0/105 (0%)	0
Macular puckering	1/100 (1%)	1	2/105 (1.9%)	2
Macular scar	0/100 (0%)	0	1/105 (1%)	1
Meibomian gland obstruction	0/100 (0%)	0	1/105 (1%)	1
Neovascular glaucoma	1/100 (1%)	1	2/105 (1.9%)	2
Neurosensory detachment	0/100 (0%)	0	1/105 (1%)	1
Nuclear sclerosis	15/100 (15%)	16	10/105 (9.5%)	10
Ocular discomfort	2/100 (2%)	2	0/105 (0%)	0
Ocular hypertension	3/100 (3%)	3	3/105 (2.9%)	3
Optic nerve pallor	2/100 (2%)	2	0/105 (0%)	0
Photophobia	3/100 (3%)	3	1/105 (1%)	1
Photopsia	1/100 (1%)	1	1/105 (1%)	1
Posterior capsule opacification	10/100 (10%)	11	11/105 (10.5%)	12
Posterior subcapsular cataract	16/100 (16%)	19	16/105 (15.2%)	19
Posterior vitreous detachment	2/100 (2%)	2	0/105 (0%)	0
Preretinal fibrosis	2/100 (2%)	2	0/105 (0%)	0
Preretinal hemorrhage	3/100 (3%)	3	0/105 (0%)	0
Proliferative vitreoretinopathy	1/100 (1%)	1	0/105 (0%)	0
Ptosis	0/100 (0%)	0	2/105 (1.9%)	2
Punctate epithelial erosion	3/100 (3%)	3	0/105 (0%)	0
Red eye	1/100 (1%)	2	0/105 (0%)	0
Retinal cyst	0/100 (0%)	0	1/105 (1%)	1
Retinal edema	1/100 (1%)	1	2/105 (1.9%)	2
Retinal exudates	4/100 (4%)	5	3/105 (2.9%)	3
Retinal hemorrhage	1/100 (1%)	1	0/105 (0%)	0
Retinal macroaneurysm	1/100 (1%)	1	0/105 (0%)	0
Retinal neovascularization	7/100 (7%)	9	3/105 (2.9%)	3
Retinal tear	7/100 (7%)	7	5/105 (4.8%)	5
Retinal vessel avulsion	2/100 (2%)	2	0/105 (0%)	0
Rhegmatogenous retinal detachment	2/100 (2%)	2	2/105 (1.9%)	2
Rubeosis iridis	0/100 (0%)	0	3/105 (2.9%)	3
Secondary cataract	1/100 (1%)	1	0/105 (0%)	0
Senile nuclear sclerosis	0/100 (0%)	0	1/105 (1%)	1
Sensation of pressure in eye	0/100 (0%)	0	1/105 (1%)	1
Sensitivity to light (photophobia)	2/100 (2%)	2	4/105 (3.8%)	4
Soreness in eyes	3/100 (3%)	5	0/105 (0%)	0
Stye	0/100 (0%)	0	1/105 (1%)	1
Subconjunctival hemorrhage	3/100 (3%)	3	4/105 (3.8%)	4
Subconjunctival/conjunctival hemorrhage	0/100 (0%)	0	1/105 (1%)	1
Subretinal fibrosis	0/100 (0%)	0	1/105 (1%)	1
Subretinal hemorrhage	1/100 (1%)	1	0/105 (0%)	0
Superficial punctate keratitis	3/100 (3%)	3	2/105 (1.9%)	2
Swollen eyelid	1/100 (1%)	1	0/105 (0%)	0
Swollen eyes	2/100 (2%)	2	0/105 (0%)	0
Synechiae	1/100 (1%)	1	0/105 (0%)	0
Traction retinal detachment	20/100 (20%)	23	2/105 (1.9%)	3
Varying retinal vessel calibre	1/100 (1%)	1	0/105 (0%)	0
Vision decreased	11/100 (11%)	11	5/105 (4.8%)	6
Vision peripheral decreased	0/100 (0%)	0	1/105 (1%)	1
Visual acuity decreased	3/100 (3%)	4	1/105 (1%)	1
Visual disturbances	2/100 (2%)	2	1/105 (1%)	1
Visual flashes	3/100 (3%)	5	5/105 (4.8%)	5
Vitreoretinal traction syndrome	1/100 (1%)	1	0/105 (0%)	0
Vitreous debris	3/100 (3%)	3	0/105 (0%)	0
Vitreous disorder NOS	1/100 (1%)	1	0/105 (0%)	0
Vitreous floater	2/100 (2%)	2	0/105 (0%)	0
Vitreous hemorrhage	52/100 (52%)	75	24/105 (22.9%)	31
Vitreous membranes and strands	0/100 (0%)	0	1/105 (1%)	1
Vitreous opacities	1/100 (1%)	1	0/105 (0%)	0
Vitreous opacity	1/100 (1%)	1	0/105 (0%)	0
Watering eyes	1/100 (1%)	1	2/105 (1.9%)	2
Gastrointestinal disorders
Abdominal pain	3/100 (3%)	3	3/105 (2.9%)	4
Acid reflux (oesophageal)	2/100 (2%)	2	0/105 (0%)	0
Barrett's esophagus	1/100 (1%)	1	0/105 (0%)	0
Bloody stool	0/100 (0%)	0	1/105 (1%)	1
Chipped tooth	2/100 (2%)	2	0/105 (0%)	0
Constipation	3/100 (3%)	3	4/105 (3.8%)	4
Diarrhea	6/100 (6%)	8	1/105 (1%)	1
Distention	1/100 (1%)	1	0/105 (0%)	0
Duodenitis	1/100 (1%)	1	0/105 (0%)	0
External hemorrhoids	0/100 (0%)	0	1/105 (1%)	1
Food poisoning	0/100 (0%)	0	1/105 (1%)	1
Gastric ulcer	0/100 (0%)	0	1/105 (1%)	1
Gastritis	1/100 (1%)	1	0/105 (0%)	0
Gastroenteritis	2/100 (2%)	2	0/105 (0%)	0
Gastroesophageal reflux	2/100 (2%)	2	2/105 (1.9%)	2
Gastroparesis	1/100 (1%)	1	0/105 (0%)	0
Nausea	5/100 (5%)	5	7/105 (6.7%)	7
Pancreatitis	1/100 (1%)	1	0/105 (0%)	0
Peritonitis	1/100 (1%)	1	0/105 (0%)	0
Stomach pain	1/100 (1%)	2	0/105 (0%)	0
Stomach virus	2/100 (2%)	2	2/105 (1.9%)	2
Tooth abscess	1/100 (1%)	3	0/105 (0%)	0
Tooth infection	0/100 (0%)	0	1/105 (1%)	1
Toothache	1/100 (1%)	1	0/105 (0%)	0
Upset stomach	1/100 (1%)	1	0/105 (0%)	0
Vomiting	6/100 (6%)	8	2/105 (1.9%)	2
General disorders
Anasarca	1/100 (1%)	1	0/105 (0%)	0
Chest pain	4/100 (4%)	4	1/105 (1%)	1
Chronic pain	0/100 (0%)	0	1/105 (1%)	1
Cyst	1/100 (1%)	1	1/105 (1%)	1
Dialysis access malfunction	1/100 (1%)	1	1/105 (1%)	1
Fever	1/100 (1%)	1	2/105 (1.9%)	2
General Swelling	1/100 (1%)	1	1/105 (1%)	1
Leg edema	4/100 (4%)	4	1/105 (1%)	1
Localized superficial swelling, mass, or lump	0/100 (0%)	0	1/105 (1%)	1
Pain NOS	0/100 (0%)	0	1/105 (1%)	1
Pedal edema	1/100 (1%)	1	0/105 (0%)	0
Swelling of feet	2/100 (2%)	2	1/105 (1%)	1
Hepatobiliary disorders
Acute cholecystitis	0/100 (0%)	0	1/105 (1%)	1
Gallstones	1/100 (1%)	1	1/105 (1%)	1
Hepatopathy	1/100 (1%)	1	0/105 (0%)	0
Liver enlargement	1/100 (1%)	1	0/105 (0%)	0
Immune system disorders
Allergic reaction	2/100 (2%)	2	0/105 (0%)	0
Hives	1/100 (1%)	1	0/105 (0%)	0
Seasonal allergy	3/100 (3%)	3	1/105 (1%)	1
Specific allergy (drug)	0/100 (0%)	0	1/105 (1%)	1
Infections and infestations
Abscess NOS	0/100 (0%)	0	1/105 (1%)	1
Acute pharyngitis	1/100 (1%)	1	0/105 (0%)	0
Bacteremia	1/100 (1%)	1	0/105 (0%)	0
Diverticulitis	1/100 (1%)	1	0/105 (0%)	0
Foot infection	1/100 (1%)	1	2/105 (1.9%)	2
Fungal infection of nail	1/100 (1%)	1	0/105 (0%)	0
Fungal skin infection	0/100 (0%)	0	2/105 (1.9%)	2
Gum infection	1/100 (1%)	1	0/105 (0%)	0
Infected toe	0/100 (0%)	0	1/105 (1%)	1
Infection	0/100 (0%)	0	2/105 (1.9%)	3
Influenza	10/100 (10%)	10	10/105 (9.5%)	10
Lyme disease	0/100 (0%)	0	1/105 (1%)	1
MRSA	2/100 (2%)	2	0/105 (0%)	0
Sepsis	0/100 (0%)	0	2/105 (1.9%)	2
Streptococcal infection NOS	0/100 (0%)	0	1/105 (1%)	1
Thrush	1/100 (1%)	1	0/105 (0%)	0
Viral syndrome	0/100 (0%)	0	1/105 (1%)	1
Yeast infection	1/100 (1%)	1	0/105 (0%)	0
Injury, poisoning and procedural complications
Back injury	1/100 (1%)	1	0/105 (0%)	0
Bee sting	0/100 (0%)	0	1/105 (1%)	1
Black eye	0/100 (0%)	0	1/105 (1%)	1
Bug bite	1/100 (1%)	1	0/105 (0%)	0
Burn	0/100 (0%)	0	1/105 (1%)	1
Eye injury	1/100 (1%)	1	0/105 (0%)	0
Fall	8/100 (8%)	9	3/105 (2.9%)	3
Foot injury	2/100 (2%)	2	0/105 (0%)	0
Head injury	0/100 (0%)	0	1/105 (1%)	1
Knee injury	1/100 (1%)	1	1/105 (1%)	2
Laceration of leg	0/100 (0%)	0	1/105 (1%)	1
Phlebitis - Injury	1/100 (1%)	1	0/105 (0%)	0
Wound	2/100 (2%)	2	0/105 (0%)	0
Investigations
Blood sugar decreased	1/100 (1%)	1	1/105 (1%)	1
Hormonal imbalance	0/100 (0%)	0	1/105 (1%)	1
Intraocular pressure increased	7/100 (7%)	7	9/105 (8.6%)	10
Laboratory test abnormal	1/100 (1%)	1	1/105 (1%)	2
Oxygen saturation low	0/100 (0%)	0	1/105 (1%)	1
Potassium high	0/100 (0%)	0	1/105 (1%)	1
Metabolism and nutrition disorders
Abnormal weight gain	0/100 (0%)	0	1/105 (1%)	1
Dehydration	2/100 (2%)	2	0/105 (0%)	0
Fluid overload - fluid volume increased	2/100 (2%)	3	0/105 (0%)	0
Hypercholesterolemia	4/100 (4%)	4	3/105 (2.9%)	3
Hyperkalemia	3/100 (3%)	3	1/105 (1%)	1
Hyperlipidemia	1/100 (1%)	1	1/105 (1%)	1
Hyperphosphatemia	2/100 (2%)	2	0/105 (0%)	0
Hypertriglyceridemia	1/100 (1%)	1	1/105 (1%)	1
Hyperuricemia	0/100 (0%)	0	1/105 (1%)	1
Hypoalbuminemia	1/100 (1%)	1	0/105 (0%)	0
Hypokalemia	0/100 (0%)	0	1/105 (1%)	1
Hyponatremia	0/100 (0%)	0	1/105 (1%)	1
Iron deficiency	1/100 (1%)	1	0/105 (0%)	0
Magnesium deficiency	0/100 (0%)	0	1/105 (1%)	1
Malnutrition	0/100 (0%)	0	1/105 (1%)	1
Morbid obesity	0/100 (0%)	0	1/105 (1%)	1
Vitamin B12 deficiency	1/100 (1%)	1	0/105 (0%)	0
Vitamin B6 deficiency	1/100 (1%)	1	0/105 (0%)	0
Vitamin D deficiency	1/100 (1%)	1	0/105 (0%)	0
Water retention	1/100 (1%)	1	0/105 (0%)	0
Musculoskeletal and connective tissue disorders
Ankle fracture	1/100 (1%)	1	1/105 (1%)	1
Arthritis NOS	2/100 (2%)	2	0/105 (0%)	0
Back discomfort	1/100 (1%)	1	0/105 (0%)	0
Back pain	5/100 (5%)	5	2/105 (1.9%)	2
Back strain	0/100 (0%)	0	2/105 (1.9%)	2
Bone spur	1/100 (1%)	1	0/105 (0%)	0
Broken bones	0/100 (0%)	0	1/105 (1%)	1
Broken foot	0/100 (0%)	0	1/105 (1%)	1
Bunion	0/100 (0%)	0	1/105 (1%)	1
Charcot arthropathy	0/100 (0%)	0	1/105 (1%)	1
Degenerative disc disease	0/100 (0%)	0	1/105 (1%)	1
Dislocated shoulder	0/100 (0%)	0	1/105 (1%)	1
Foot fracture	0/100 (0%)	0	1/105 (1%)	1
Foot pain	1/100 (1%)	2	0/105 (0%)	0
Fractured ribs	1/100 (1%)	1	0/105 (0%)	0
Frozen shoulder	0/100 (0%)	0	1/105 (1%)	1
Generalized muscle weakness	1/100 (1%)	1	1/105 (1%)	1
Gout	1/100 (1%)	1	3/105 (2.9%)	3
Hand pain	0/100 (0%)	0	1/105 (1%)	1
Hip fracture	0/100 (0%)	0	1/105 (1%)	1
Intervertebral disc bulging	1/100 (1%)	1	0/105 (0%)	0
Knee pain	4/100 (4%)	4	1/105 (1%)	1
Leg pain	2/100 (2%)	2	1/105 (1%)	1
Muscle cramps	2/100 (2%)	3	0/105 (0%)	0
Muscle pain	3/100 (3%)	3	2/105 (1.9%)	2
Muscle spasms	0/100 (0%)	0	1/105 (1%)	1
Neck pain	1/100 (1%)	1	0/105 (0%)	0
Osteomyelitis	2/100 (2%)	2	1/105 (1%)	1
Pain in arm	1/100 (1%)	1	0/105 (0%)	0
Pain in hip	1/100 (1%)	1	1/105 (1%)	1
Scoliosis	1/100 (1%)	1	0/105 (0%)	0
Shoulder pain	2/100 (2%)	2	2/105 (1.9%)	2
Sprained ankle	1/100 (1%)	1	0/105 (0%)	0
Sprains and strains of ribs	1/100 (1%)	1	1/105 (1%)	1
Wrist fracture	1/100 (1%)	1	1/105 (1%)	1
Wrist pain	1/100 (1%)	1	0/105 (0%)	0
Nervous system disorders
Bell's palsy	0/100 (0%)	0	1/105 (1%)	1
Carpal tunnel syndrome	0/100 (0%)	0	2/105 (1.9%)	2
Concussion	0/100 (0%)	0	1/105 (1%)	1
Diabetic neuropathy	1/100 (1%)	1	0/105 (0%)	0
Dizziness	4/100 (4%)	4	2/105 (1.9%)	2
Head pain	2/100 (2%)	2	0/105 (0%)	0
Head pressure	1/100 (1%)	1	0/105 (0%)	0
Headache	9/100 (9%)	9	7/105 (6.7%)	7
Migraine headache	3/100 (3%)	4	0/105 (0%)	0
Neuropathy	4/100 (4%)	4	0/105 (0%)	0
Numbness in hand	0/100 (0%)	0	1/105 (1%)	1
Paralysis	0/100 (0%)	0	1/105 (1%)	1
Restless leg syndrome	1/100 (1%)	1	0/105 (0%)	0
Sciatica	2/100 (2%)	2	0/105 (0%)	0
Seizures	1/100 (1%)	1	0/105 (0%)	0
Syncope	1/100 (1%)	1	0/105 (0%)	0
VIth nerve palsy	0/100 (0%)	0	2/105 (1.9%)	2
Vertigo	1/100 (1%)	1	4/105 (3.8%)	4
Product Issues
Deposit on the surface of intraocular lens	1/100 (1%)	1	0/105 (0%)	0
Psychiatric disorders
Adjustment disorder NOS	1/100 (1%)	1	0/105 (0%)	0
Anxiety	3/100 (3%)	3	1/105 (1%)	1
Depression	2/100 (2%)	2	3/105 (2.9%)	3
Insomnia	0/100 (0%)	0	1/105 (1%)	1
Post-traumatic stress disorder	1/100 (1%)	1	0/105 (0%)	0
Renal and urinary disorders
Acute kidney injury	2/100 (2%)	2	1/105 (1%)	1
Acute renal failure	1/100 (1%)	1	0/105 (0%)	0
Bladder infection	1/100 (1%)	1	1/105 (1%)	1
Chronic kidney disease	2/100 (2%)	4	7/105 (6.7%)	7
Chronic renal failure worsened	1/100 (1%)	1	2/105 (1.9%)	2
End stage renal disease (ESRD)	1/100 (1%)	1	0/105 (0%)	0
Hydronephrosis	0/100 (0%)	0	1/105 (1%)	1
Kidney failure	1/100 (1%)	1	2/105 (1.9%)	2
Kidney function abnormal	2/100 (2%)	2	0/105 (0%)	0
Kidney infection	2/100 (2%)	2	1/105 (1%)	1
Kidney stones	3/100 (3%)	3	0/105 (0%)	0
Nocturia	1/100 (1%)	1	0/105 (0%)	0
Proteinuria	1/100 (1%)	1	0/105 (0%)	0
Pyelonephritis	0/100 (0%)	0	1/105 (1%)	1
Renal failure	0/100 (0%)	0	1/105 (1%)	1
Renal insufficiency	0/100 (0%)	0	1/105 (1%)	1
Uremia	1/100 (1%)	1	0/105 (0%)	0
Urinary hesitancy	0/100 (0%)	0	1/105 (1%)	1
Urinary incontinence	0/100 (0%)	0	1/105 (1%)	1
Urinary tract infection	8/100 (8%)	13	7/105 (6.7%)	9
Reproductive system and breast disorders
Enlarged prostate	1/100 (1%)	1	0/105 (0%)	0
Erectile dysfunction	2/100 (2%)	2	1/105 (1%)	1
Hydrocele	0/100 (0%)	0	1/105 (1%)	1
Uterine bleeding	1/100 (1%)	1	0/105 (0%)	0
Uterine fibroid	1/100 (1%)	1	0/105 (0%)	0
Vulvodynia	0/100 (0%)	0	1/105 (1%)	1
Respiratory, thoracic and mediastinal disorders
Acute bronchitis	3/100 (3%)	3	0/105 (0%)	0
Acute sinusitis	1/100 (1%)	1	1/105 (1%)	1
Allergic rhinitis	3/100 (3%)	3	1/105 (1%)	1
Asthma	1/100 (1%)	1	0/105 (0%)	0
Bronchitis	6/100 (6%)	6	1/105 (1%)	1
Bronchospasm	1/100 (1%)	1	0/105 (0%)	0
Chest congestion	0/100 (0%)	0	1/105 (1%)	1
Cold	13/100 (13%)	17	7/105 (6.7%)	9
Cough	1/100 (1%)	1	2/105 (1.9%)	2
Dyspnea	0/100 (0%)	0	1/105 (1%)	1
Epistaxis	0/100 (0%)	0	1/105 (1%)	1
Hypoxemia	1/100 (1%)	1	0/105 (0%)	0
Nasal congestion	1/100 (1%)	1	0/105 (0%)	0
Pleural effusion	0/100 (0%)	0	1/105 (1%)	1
Pneumonia	1/100 (1%)	1	2/105 (1.9%)	2
Pulmonary edema	2/100 (2%)	2	0/105 (0%)	0
Shortness of breath	9/100 (9%)	9	4/105 (3.8%)	4
Sinus infection	4/100 (4%)	4	1/105 (1%)	1
Sinusitis	1/100 (1%)	1	3/105 (2.9%)	3
Sleep apnea	0/100 (0%)	0	1/105 (1%)	1
Upper respiratory infection	3/100 (3%)	4	3/105 (2.9%)	4
Wheezing	0/100 (0%)	0	1/105 (1%)	1
Skin and subcutaneous tissue disorders
Blister of foot and toe(s), without mention of infection	2/100 (2%)	2	1/105 (1%)	1
Bruise	0/100 (0%)	0	1/105 (1%)	1
Cellulitis	1/100 (1%)	1	1/105 (1%)	1
Cellulitis of foot	1/100 (1%)	1	1/105 (1%)	1
Cellulitis of toe	1/100 (1%)	1	0/105 (0%)	0
Decubitus ulcer	0/100 (0%)	0	1/105 (1%)	1
Dermatochalasis	0/100 (0%)	0	2/105 (1.9%)	2
Diabetic foot ulcer	2/100 (2%)	2	1/105 (1%)	2
Diabetic ulcer	1/100 (1%)	1	0/105 (0%)	0
Epidermal cyst	1/100 (1%)	1	0/105 (0%)	0
Erythematous conditions	1/100 (1%)	1	0/105 (0%)	0
Foot ulcer	2/100 (2%)	3	3/105 (2.9%)	5
Fungal infection of nail	0/100 (0%)	0	1/105 (1%)	1
Itching	1/100 (1%)	1	0/105 (0%)	0
Mole of skin	1/100 (1%)	1	0/105 (0%)	0
Rash	2/100 (2%)	2	1/105 (1%)	1
Sebaceous cyst	1/100 (1%)	1	0/105 (0%)	0
Skin abrasion	1/100 (1%)	1	0/105 (0%)	0
Skin cancer	0/100 (0%)	0	1/105 (1%)	1
Skin infection	3/100 (3%)	3	0/105 (0%)	0
Skin lesion	0/100 (0%)	0	1/105 (1%)	1
Swelling of face	1/100 (1%)	1	0/105 (0%)	0
Surgical and medical procedures
Benign tumor excision	1/100 (1%)	1	1/105 (1%)	1
Carpal tunnel release	1/100 (1%)	1	0/105 (0%)	0
Cataract extraction	2/100 (2%)	2	1/105 (1%)	1
Coronary stent placement	0/100 (0%)	0	1/105 (1%)	1
Foot surgery	0/100 (0%)	0	1/105 (1%)	1
Implantable defibrillator insertion	0/100 (0%)	0	1/105 (1%)	1
Sinus operation	1/100 (1%)	1	0/105 (0%)	0
Skin graft	1/100 (1%)	18	0/105 (0%)	0
Surgery	2/100 (2%)	2	2/105 (1.9%)	2
Toe amputation	0/100 (0%)	0	3/105 (2.9%)	3
Tooth extraction	3/100 (3%)	3	3/105 (2.9%)	3
Vitrectomy	1/100 (1%)	1	0/105 (0%)	0
Wrist surgery	0/100 (0%)	0	1/105 (1%)	1
Vascular disorders
Arteriovenous graft site hemorrhage	0/100 (0%)	0	1/105 (1%)	1
Benign essential hypertension	1/100 (1%)	1	0/105 (0%)	0
Deep vein thrombosis	1/100 (1%)	1	0/105 (0%)	0
Hypertension	4/100 (4%)	4	4/105 (3.8%)	4
Hypertension worsened	6/100 (6%)	7	3/105 (2.9%)	3
Hypertensive crisis	2/100 (2%)	2	1/105 (1%)	1
Hypotension	3/100 (3%)	3	1/105 (1%)	1
Iliac artery blockage	0/100 (0%)	0	1/105 (1%)	1
Peripheral arterial disease	0/100 (0%)	0	1/105 (1%)	1
Stroke	1/100 (1%)	1	0/105 (0%)	0
Venous malformation NOS	1/100 (1%)	1	1/105 (1%)	1

Limitations/Caveats

[Not Specified]

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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.