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Anti-VEGF Treatment for Prevention of PDR/DME

Sponsor
Jaeb Center for Health Research (Other)
Overall Status
Completed
CT.gov ID
NCT02634333
Collaborator
Regeneron Pharmaceuticals (Industry), Juvenile Diabetes Research Foundation (Other), National Eye Institute (NEI) (NIH), National Institutes of Health (NIH) (NIH)
399
Enrollment
85
Locations
2
Arms
76.3
Actual Duration (Months)
4.7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Multiple studies have implicated vascular endothelial growth factor VEGF as a major causative factor in human eye diseases characterized by neovascularization including proliferative diabetic retinopathy (PDR) and vascular permeability including diabetic macular edema (DME). While there is strong evidence that PDR outcomes are markedly reduced in eyes that are treated with monthly anti-VEGF therapy (A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus: RIDE/RISE) and moderately reduced in eyes that received fairly frequent dosing during the 1st year of treatment (Diabetic Retinopathy Clinical Research Network protocol I), it is unknown whether or not an earlier but less frequent dosing regimen would result in similar, favorable anatomic outcomes, and whether favorable anatomic outcomes subsequently would result in favorable visual acuity outcomes.

If this study demonstrates that intravitreous aflibercept treatment is effective and safe for reducing the onset of PDR or center involved- DME (CI-DME) in eyes that are at high risk for these complications, a new strategy to prevent vision threatening complications of diabetes will be available for patients. The application of intravitreous aflibercept earlier in the course of disease (i.e., at the time when an eye has baseline severe non-proliferative diabetic retinopathy) could help to reduce future potential treatment burden in patients, at the same time resulting in similar or better long-term visual outcomes, if PDR and DME are prevented.

The primary objectives of this protocol are to 1) determine the efficacy and safety of intravitreous aflibercept injections versus sham injections (observation) for prevention of PDR or CI-DME in eyes at high risk for development of these complications and 2) compare long-term visual outcomes in eyes that receive anti-VEGF therapy early in the course of disease with those that are observed initially, and treated only if high-risk PDR or CI-DME with vision loss develops.

Secondary objectives include:

  • Comparing other visual acuity outcomes between treatment groups, such as proportion of eyes with at least 10 or at least 15 letter loss from baseline, or gain or loss of at least 5 letters at the consecutive study visit just before and at the 2- or 4-year visit

  • Comparing optical coherence tomography (OCT) outcomes, such as mean change in OCT central subfield thickness and volume from baseline

  • Comparing proportion of eyes with at least 2 and 3-step worsening or improvement of diabetic retinopathy severity level (scale for individual eyes) by central reading center from baseline

  • Comparing associated treatment and follow-up exam costs between treatment groups

  • Comparing safety outcomes between treatment groups

Condition or Disease Intervention/Treatment Phase
  • Procedure: Prompt Sham
  • Drug: Prompt aflibercept
  • Procedure: Deferred laser
  • Drug: Deferred aflibercept
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
399 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Outcomes Assessor)
Primary Purpose:
Prevention
Official Title:
Intravitreous Anti-Vascular Endothelial Growth Factor Treatment for Prevention of Vision Threatening Diabetic Retinopathy in Eyes at High Risk
Actual Study Start Date :
Jan 1, 2016
Actual Primary Completion Date :
May 1, 2020
Actual Study Completion Date :
May 11, 2022

Arms and Interventions

Arm Intervention/Treatment
Sham Comparator: Observation (Prompt Sham)

Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.

Procedure: Prompt Sham
A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.

Procedure: Deferred laser
Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
Other Names:
  • focal/grid photocoagulation
  • panretinal photocoagulation

    • Drug: Deferred aflibercept
    Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
    Other Names:
  • intravitreal anti-vascular endothelial growth factor
  • Eylea

    		•
    Experimental: Prompt aflibercept

    Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met.

    Drug: Prompt aflibercept
    Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter.
    Other Names:
  • intravitreal anti-vascular endothelial growth factor
  • Eylea

    • Procedure: Deferred laser
    Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met
    Other Names:
  • focal/grid photocoagulation
  • panretinal photocoagulation

    • Drug: Deferred aflibercept
    Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
    Other Names:
  • intravitreal anti-vascular endothelial growth factor
  • Eylea

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Development of PDR and/or DME (Whichever Came First) [2 years]

      CI-DME = center-involved diabetic macular edema, PDR = proliferative diabetic macular edema. First development of criteria meeting end point. Eyes that met any criteria are then censored from contributing to the next criteria. Eyes that did not meet the outcome were censored at the time of the last completed visit. Each outcome appears only once under "First PDR and/or DME criteria met." Outcomes appear under "Development of PDR" if PDR developed at any time in the study (regardless of if or when DME developed) and outcomes appear under "Development of DME" if DME developed at any time in the study (regardless of if or when PDR developed)

    Secondary Outcome Measures

    1. Change in Visual Acuity From Baseline [2 years]

      Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart.

    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

    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:

    1. Current regular use of insulin for the treatment of diabetes

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

    3. Documented diabetes by American Diabetes Association and/or World Health Organization criteria

    4. Able and willing to provide informed consent.

    Meets all of the following ocular criteria in at least one eye:

    1. Best corrected Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity letter score ≥79 (approximate Snellen equivalent 20/25 or better)

    2. Severe non-proliferative diabetic retinopathy (NPDR) (based on the 4:2:1 rule) evident on clinical examination and on digital imaging as judged by the investigator. Reading center grading of less than ETDRS level 43 or greater than 53 is an exclusion.

    Severe NPDR is defined as:

    1. All 4 midperipheral quadrants show severe hemorrhages or microaneurysms (at least as great as Standard photograph 2A, approximately 20 dot and blot hemorrhages), or

    2. At least 2 fields of definite venous beading in the midperipheral quadrants or at least 1 field at least as severe as Standard photograph 6A, or

    3. At least 1 field of moderate intraretinal microvascular abnormalities (IRMA) in the midperipheral quadrants, at least as severe as Standard photograph 8A

    4. No evidence of neovascularization on clinical exam including active neovascularization of the iris (small iris tufts are not an exclusion) or angle neovascularization (if the angle is assessed).

    5. No evidence of neovascularization (NV) on fluorescein angiography within the 7-modified ETDRS fields, confirmed by the central Reading Center prior to randomization.

    • The widest method of imaging available at the site must be used to document whether there is NV present in the periphery; however, presence of NV outside of the 7-modified ETDRS fields on ultrawide field imaging will not be an exclusion provided treatment is not planned.

    1. No center-involved diabetic macular edema (CI-DME) on clinical exam and optical coherence tomography (OCT) central subfield thickness must be below the following gender and OCT-machine specific thresholds:

    2. Zeiss Cirrus: 290 µm in women and 305 µm in men

    3. Heidelberg Spectralis: 305 µm in women and 320 µm in men

    4. Investigator and potential participant are comfortable withholding treatment for DME until there is at least a 10% increase in OCT central subfield thickness with confirmed visual acuity loss (10 letter loss at a single visit or 5 to 9 at two consecutive visits).

    5. Prompt panretinal photocoagulation (PRP) or anti-vascular endothelial growth factor (anti-VEGF) treatment not required AND investigator and potential participant are willing to wait for development of high-risk characteristics (defined in protocol) to treat PDR.

    6. Media clarity, pupillary dilation, and study participant cooperation sufficient to obtain adequate fundus photographs, fluorescein angiogram, and OCT.

    • Investigator must verify accuracy of OCT scan by ensuring it is centered and of adequate quality (including segmentation line placement)
    Exclusion Criteria:

    1. History of chronic renal failure requiring 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. Participation in an investigational trial that involved treatment within 30 days of randomization with any drug that has not received regulatory approval for the indication being studied.

    • Note: study participants cannot participate in another investigational trial that involves treatment with an 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 prep).

    2. Known allergy to fluorescein dye.

    3. Blood pressure > 180/110 (systolic above 180 or diastolic above 110). • If blood pressure is brought below 180/110 by anti-hypertensive treatment, individual can become eligible.

    4. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization.

    • These drugs should not be used during the study.

    1. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 2 years.

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

    1. Individual is expecting to move out of the area of the clinical center to an area not covered by another Diabetic Retinopathy Clinical Research Network certified clinical center during the next 2 years.
    Individual has any of the following ocular characteristics in the eye(s) being evaluated:

    1. Exam or photographic evidence of vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.

    2. History of prior vitreous hemorrhage or preretinal hemorrhage presumed to be from PDR.

    3. History of prior PRP (defined as ≥100 burns outside of the posterior pole).

    4. An ocular condition is present (other than diabetic retinopathy) that, in the opinion of the investigator, might alter visual acuity during the course of the study (e.g., retinal vein or artery occlusion, uveitis or other ocular inflammatory disease, vitreomacular traction, etc.).

    5. History of DME or diabetic retinopathy treatment with laser or intraocular injections of medication within the prior 12 months and no more than 4 prior intraocular injections at any time in the past.

    • Enrollment will be limited to a maximum of 25% of the planned sample size with any history of treatment for DME and/or diabetic retinopathy. Once this number of eyes has been enrolled, any history of treatment for DME and/or diabetic retinopathy will be an exclusion criterion.

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

    2. Any history of vitrectomy.

    3. History of yttrium aluminum garnet capsulotomy performed within 2 months prior to randomization.

    4. Aphakia.

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

    6. Evidence of uncontrolled glaucoma.

    • Intraocular pressure must be <30, with no more than one topical glaucoma medication, and no documented glaucomatous field loss for the eye to be eligible.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Arizona Retina and Vitreous Consultants Phoenix Arizona United States 85021
    2 University of Arizona Medical Center/Department of Ophthalmology Tucson Arizona United States 85711
    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 East Bay Retina Consultants, Inc. Oakland California United States 94609
    6 Southern California Desert Retina Consultants, MC Palm Desert California United States 92211
    7 Shashi D Ganti, MD PC Porterville California United States 93257
    8 Retina Consultants of Southern California Redlands California United States 92374
    9 U.C. Davis Eye Center Sacramento California United States 95817
    10 California Retina Consultants Santa Barbara California United States 93103
    11 Retinal Consultants of Southern California Medical Group, Inc. Westlake Village California United States 91361
    12 New England Retina Associates Hamden Connecticut United States 06518
    13 Retina Group of Florida Fort Lauderdale Florida United States 33308
    14 National Ophthalmic Research Institute Fort Myers Florida United States 33912
    15 University of Florida College of Med., Department of Ophthalmology, Jacksonville Health Science Cent Jacksonville Florida United States 32209
    16 Florida Retina Institute-Jacksonville Jacksonville Florida United States 32216
    17 Florida Retina Consultants Lakeland Florida United States 33805
    18 Bascom Palmer Eye Institute Miami Florida United States 33136
    19 Magruder Eye Institute Orlando Florida United States 32803
    20 Florida Retina Institute Orlando Florida United States 32806
    21 Southeast Eye Institute, P.A. dba Eye Associates of Pinellas Pinellas Park Florida United States 33782
    22 Fort Lauderdale Eye Institute Plantation Florida United States 33324
    23 Sarasota Retina Institute Sarasota Florida United States 34239
    24 Retina Associates of Florida, P.A. Tampa Florida United States 33609
    25 Emory Eye Center Atlanta Georgia United States 30322
    26 Southeast Retina Center, P.C. Augusta Georgia United States 30909
    27 Marietta Eye Clinic Marietta Georgia United States 30060
    28 Thomas Eye Group Sandy Springs Georgia United States 30328
    29 Gailey Eye Clinic Bloomington Illinois United States 61704
    30 Northwestern Medical Faculty Foundation Chicago Illinois United States 60611
    31 University of Illinois at Chicago Medical Center Chicago Illinois United States 60612
    32 Springfield Clinic, LLP Springfield Illinois United States 62703
    33 Raj K. Maturi, M.D., P.C. Indianapolis Indiana United States 46290
    34 Medical Associates Clinic, P.C. Dubuque Iowa United States 52002
    35 Wolfe Eye Clinic West Des Moines Iowa United States 50266
    36 Retina Associates, P.A. Shawnee Mission Kansas United States 66204
    37 Paducah Retinal Center Paducah Kentucky United States 42001
    38 Eye Associates of Northeast Louisiana dba Haik Humble Eye Center West Monroe Louisiana United States 71291
    39 Elman Retina Group, P.A. Baltimore Maryland United States 21237
    40 Wilmer Eye Institute at Johns Hopkins Baltimore Maryland United States 21287
    41 Mid Atlantic Retina Specialists Hagerstown Maryland United States 21740
    42 Valley Eye Physicians and Surgeons Ayer Massachusetts United States 01432
    43 Joslin Diabetes Center Boston Massachusetts United States 02215
    44 Henry Ford Health System, Dept of Ophthalmology and Eye Care Services Detroit Michigan United States 48202
    45 Vitreo-Retinal Associates Grand Rapids Michigan United States 49546
    46 Retina Center, PA Minneapolis Minnesota United States 55404
    47 Mid-America Retina Consultants, P.A. Kansas City Missouri United States 64111
    48 Retinal and Ophthalmic Consultants, PC Northfield New Jersey United States 08225
    49 Eye Associates of New Mexico Albuquerque New Mexico United States 87109
    50 The New York Eye and Ear Infirmary/Faculty Eye Practice New York New York United States 10003
    51 MaculaCare New York New York United States 10021
    52 University of Rochester Rochester New York United States 14642
    53 Retina-Vitreous Surgeons of Central New York, PC Syracuse New York United States 13224
    54 Western Carolina Clinical Research, LLC Asheville North Carolina United States 28803
    55 Kittner Eye Center Chapel Hill North Carolina United States 27517
    56 Charlotte Eye, Ear, Nose and Throat Assoc., PA Charlotte North Carolina United States 28210
    57 Retina Associates of Cleveland, Inc. Beachwood Ohio United States 44122
    58 University Hospitals Cleveland Medical Center Cleveland Ohio United States 44106
    59 Oregon Retina, LLP Eugene Oregon United States 97401
    60 Retina Northwest, PC Portland Oregon United States 97210
    61 Casey Eye Institute Portland Oregon United States 97239
    62 Retina Vitreous Consultants Monroeville Pennsylvania United States 15146
    63 University of Pennsylvania Scheie Eye Institute Philadelphia Pennsylvania United States 19104
    64 Carolina Retina Center Columbia South Carolina United States 29223
    65 Palmetto Retina Center West Columbia South Carolina United States 29169
    66 Southeastern Retina Associates Chattanooga Tennessee United States 37421
    67 Southeastern Retina Associates, P.C. Knoxville Tennessee United States 37909
    68 Southwest Retina Specialists Amarillo Texas United States 79106
    69 Austin Retina Associates Austin Texas United States 78705
    70 Retina Research Center Austin Texas United States 78705
    71 Robert E. Torti, MD, PA dba Retina Specialists DeSoto Texas United States 75115
    72 Retina Center of Texas Grapevine Texas United States 76051
    73 Retina and Vitreous of Texas Houston Texas United States 77025
    74 Baylor Eye Physicians and Surgeons Houston Texas United States 77030
    75 Retina Consultants of Houston, PA Houston Texas United States 77030
    76 Texas Retina Associates Lubbock Texas United States 79424
    77 Valley Retina Institute McAllen Texas United States 78503
    78 Retinal Consultants of San Antonio San Antonio Texas United States 78240
    79 Retina Institute of Virginia Richmond Virginia United States 23235
    80 Virginia Commonwealth University, Dept. of Ophthalmology Richmond Virginia United States 23298
    81 University of Wisconsin-Madison, Dept of Ophthalmology/Retina Service Madison Wisconsin United States 53705
    82 UBC/VCHA Eye Care Centre Vancouver British Columbia Canada V5Z 3N9
    83 Nova Scotia District Health Authority Halifax Nova Scotia Canada B3H 2Y9
    84 Toronto Retina Institute (TRI) North York Ontario Canada M3C 0G9
    85 University Health Network - Toronto Western Hospital Toronto Ontario Canada M5T 2S8

    Sponsors and Collaborators

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

    Investigators

    • Study Chair: Jennifer K. Sun, MD, MPH, Joslin Diabetes Center

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Jaeb Center for Health Research
    ClinicalTrials.gov Identifier:
    NCT02634333
    Other Study ID Numbers:
    • DRCR.net Protocol W
    • EY14231
    • EY23207
    • EY18817
    First Posted:
    Dec 18, 2015
    Last Update Posted:
    Aug 17, 2022
    Last Verified:
    Aug 1, 2022
    Keywords provided by Jaeb Center for Health Research
    anti-vascular endothelial growth factor
    nonproliferative diabetic retinopathy
    Additional relevant MeSH terms:
    Macular Edema
    Retinal Diseases
    Diabetic Retinopathy
    Aflibercept
    Endothelial Growth Factors
    Mitogens

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Aflibercept Sham
    Arm/Group Description Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met. Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria. Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met. Prompt Sham: A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
    Period Title: Overall Study
    STARTED 200 199
    COMPLETED 160 167
    NOT COMPLETED 40 32

    Baseline Characteristics

    Arm/Group Title Aflibercept Sham Total
    Arm/Group Description Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met. Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria. Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met. Prompt Sham: A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria. Total of all reporting groups
    Overall Participants 200 199 399
    Overall Eyes 200 199 399
    Age (years) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [years]
    57
    56
    57
    Sex/Gender, Customized (Eyes) [Number]
    Female
    83
    86
    139
    Male
    117
    113
    189
    Race/Ethnicity, Customized (Eyes) [Number]
    White
    92
    86
    178
    Hispanic or Latino
    62
    67
    129
    Black or African American
    29
    32
    61
    Asian
    10
    9
    19
    More than one race
    3
    1
    4
    Unknown
    2
    3
    5
    American Indian or Alaskan native
    1
    0
    1
    Native Hawaiian or other Pacific Islander
    1
    1
    2
    Diabetes Type (Eyes) [Number]
    Type 1
    12
    23
    35
    Type 2
    188
    176
    364
    Duration of Diabetes (years) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [years]
    17
    16
    16
    Hemoglobin A1c (Percent) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [Percent]
    8.6
    8.3
    8.4
    Mean arterial blood pressure (mmHg) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [mmHg]
    100
    98
    99
    Body mass index (kg/m^2) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [kg/m^2]
    31
    31
    31
    Prior myocardial infarction (Participant) [Number]
    Number [Participant]
    16
    19
    35
    Prior stroke (Participant) [Number]
    Number [Participant]
    13
    11
    21
    Pre-existing renal disease (Participant) [Number]
    Number [Participant]
    6
    6
    11
    Visual acuity (letter score) [Mean (Inter-Quartile Range) ]
    Mean (Inter-Quartile Range) [letter score]
    88
    88
    88
    Optical coherence tomography central subfield thickness (Microns) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [Microns]
    283
    283
    283
    Diabetic retinopathy severity scale level (Eyes) [Number]
    Moderate NPDR (level 43)
    33
    35
    68
    Moderately severe NPDR (level 47A)
    65
    61
    126
    Moderately severe NPDR (level 47B-D)
    54
    55
    109
    Severe NPDR (level 53)
    48
    48
    96
    Intraocular pressure (mmHg) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [mmHg]
    15
    15
    15
    Lens status (Eyes) [Number]
    Posterior chamber Intraocular lens
    34
    32
    66
    Phakic
    166
    167
    333
    Non-central diabetic macular edema (Eyes) [Number]
    Number [Eyes]
    75
    83
    158
    Prior anti-vascular endothelial growth factor therapy for diabetic macular edema (Eyes) [Number]
    Number [Eyes]
    8
    5
    13
    Prior focal or grid laser for diabetic macular edema (Eyes) [Number]
    Number [Eyes]
    12
    19
    31

    Outcome Measures

    1. Primary Outcome
    Title Development of PDR and/or DME (Whichever Came First)
    Description CI-DME = center-involved diabetic macular edema, PDR = proliferative diabetic macular edema. First development of criteria meeting end point. Eyes that met any criteria are then censored from contributing to the next criteria. Eyes that did not meet the outcome were censored at the time of the last completed visit. Each outcome appears only once under "First PDR and/or DME criteria met." Outcomes appear under "Development of PDR" if PDR developed at any time in the study (regardless of if or when DME developed) and outcomes appear under "Development of DME" if DME developed at any time in the study (regardless of if or when PDR developed)
    Time Frame 2 years

    Outcome Measure Data

    Analysis Population Description
    Units are in eyes. A participant could have 2 study eyes. For participants with two study eyes the participant was randomly assigned to receive sham in the eye with worse diabetic retinopathy and aflibercept in the other, or aflibercept in the eye with the worse diabetic retinopathy and sham in the other.
    Arm/Group Title Aflibercept Sham
    Arm/Group Description Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met. Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria. Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met. Prompt Sham: A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
    Measure Participants 200 199
    Measure Eyes 200 199
    Number [Eyes]
    27
    75
    2. Secondary Outcome
    Title Change in Visual Acuity From Baseline
    Description Visual acuity is measured as a continuous integer letter score from 0 to 100, with higher numbers indicating better visual acuity. A letter score of 85 is approximately 20/20 and a letter score of 70 is approximately 20/40, the legal unrestricted driving limit in most states. A 5-letter change for an individual is approximately equal to a 1-line change on a vision chart.
    Time Frame 2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Aflibercept Sham
    Arm/Group Description Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met. Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria. Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met. Prompt Sham: A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria.
    Measure Participants 160 166
    Measure Eyes 160 166
    Mean (Standard Deviation) [Letter Score]
    -0.9
    (5.8)
    -2.0
    (6.1)

    Adverse Events

    Time Frame 2 Years
    Adverse Event Reporting Description To get the total number of participant/eyes in each treatment group add the unilateral and bilateral participants together: Unilateral Aflibercept = 129 Total aflibercept = unilateral aflibercept + bilateral = 129 + 71 = 200 Unilateral sham = 128 total sham = unilateral sham + bilateral = 128 + 71 = 199
    Arm/Group Title Aflibercept Sham Bilateral Participants
    Arm/Group Description Aflibercept injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. More frequent aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met. Prompt aflibercept: Intravitreal injection of 2.0mg aflibercept is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria. Sham injection in study eye at randomization and at visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred aflibercept may be given if center-involved diabetic macular edema or proliferative diabetic retinopathy develops and deferred laser may subsequently be added to intravitreal aflibercept if certain criteria are met. Prompt Sham: A sham injection (syringe without a needle pressed against the injection site) is performed on the day of randomization and visits at 1, 2, and 4 months and then every 4 months thereafter. Deferred laser: Laser (either focal/grid laser for diabetic macular edema or panretinal photocoagulation for proliferative diabetic retinopathy) is added following initiation of anti-vascular endothelial growth factor injections for center-involved diabetic macular edema or proliferative diabetic retinopathy only if certain criteria are met Deferred aflibercept: Intravitreal injection of 2.0mg aflibercept performed once proliferative diabetic retinopathy or center-involved diabetic macular edema develops and then up to every 4 weeks using defined treatment criteria. Participants with one eye enrolled in each arm of the study.
    All Cause Mortality
    Aflibercept Sham Bilateral Participants
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 9/129 (7%) 10/128 (7.8%) 5/71 (7%)
    Serious Adverse Events
    Aflibercept Sham Bilateral Participants
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 52/129 (40.3%) 50/128 (39.1%) 24/71 (33.8%)
    Blood and lymphatic system disorders
    Anemia 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Cardiac disorders
    AFib 1/129 (0.8%) 2 0/128 (0%) 0 1/71 (1.4%) 1
    Atrial fibrillation 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Cardiac arrest 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Cardiac arrhythmia 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Cardiogenic shock 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Cardiomyopathy 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Congestive heart failure 6/129 (4.7%) 8 6/128 (4.7%) 8 2/71 (2.8%) 5
    Coronary artery disease 2/129 (1.6%) 2 2/128 (1.6%) 2 1/71 (1.4%) 1
    Coronary artery occlusion 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Endocarditis 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Heart failure 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Hypertensive heart disease 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Myocardial infarction 4/129 (3.1%) 5 6/128 (4.7%) 6 3/71 (4.2%) 3
    Non ST segment elevation myocardial infarction 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Pericardial effusion 1/129 (0.8%) 2 0/128 (0%) 0 0/71 (0%) 0
    Pulmonary incompetence 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Tachycardia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Endocrine disorders
    Diabetic ketoacidosis 1/129 (0.8%) 1 0/128 (0%) 0 2/71 (2.8%) 2
    Hyperglycemia 1/129 (0.8%) 1 2/128 (1.6%) 2 2/71 (2.8%) 2
    Hyperglycemic hyperosmolar nonketotic syndrome 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Eye disorders
    Endophthalmitis 2/129 (1.6%) 2 0/128 (0%) 0 1/71 (1.4%) 1
    Rhegmatogenous retinal detachment 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Gastrointestinal disorders
    Achalasia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Appendicitis 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Colitis collagenous 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Colon cancer 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Gastric ulcer 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Gastritis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Gastroenteritis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Gastrointestinal bleed 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Gastroparesis 1/129 (0.8%) 3 1/128 (0.8%) 2 0/71 (0%) 0
    Pancreatitis 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Rectal bleeding 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    esophagus ulcer 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    General disorders
    Chest pain 1/129 (0.8%) 1 0/128 (0%) 0 2/71 (2.8%) 2
    Death 2/129 (1.6%) 2 2/128 (1.6%) 2 2/71 (2.8%) 2
    Fatigue 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    General Swelling 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Multi-organ failure 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Swelling of feet 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Hepatobiliary disorders
    Acute cholecystitis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Liver cirrhosis 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Immune system disorders
    Allergic reaction 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Infections and infestations
    Abscess NOS 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Bacteremia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    COVID-19 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Diverticulitis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Foot infection 2/129 (1.6%) 2 1/128 (0.8%) 1 0/71 (0%) 0
    Helicobacter pylori infection 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Infection 1/129 (0.8%) 2 1/128 (0.8%) 1 1/71 (1.4%) 1
    Infection (chronic) of amputation stump 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Influenza 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    MRSA 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Pseudomonas infection 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Sepsis 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Septic shock 0/129 (0%) 0 2/128 (1.6%) 2 1/71 (1.4%) 1
    Septicemia 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Staphylococcal infection NOS 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Injury, poisoning and procedural complications
    Burn 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Fall 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Gun shot wound 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Leg injury 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Wound 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Investigations
    Decreased hemoglobin 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Metabolism and nutrition disorders
    Acidosis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Dehydration 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Feeding intolerance 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Hyperkalemia 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Hypokalemia 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Musculoskeletal and connective tissue disorders
    Ankle fracture 2/129 (1.6%) 3 0/128 (0%) 0 0/71 (0%) 0
    Broken bones 0/129 (0%) 0 2/128 (1.6%) 2 1/71 (1.4%) 1
    Charcot arthropathy 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Fractured ribs 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Knee fracture 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Neck pain 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Osteomyelitis 2/129 (1.6%) 2 1/128 (0.8%) 1 1/71 (1.4%) 1
    Tendon disorder NOS 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer (NOS) 3/129 (2.3%) 3 1/128 (0.8%) 1 0/71 (0%) 0
    Desmoplastic small round cell tumor 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Liver cancer 1/129 (0.8%) 2 0/128 (0%) 0 0/71 (0%) 0
    Nervous system disorders
    Anoxic brain damage 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Coma 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Dizziness 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Encephalopathy 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Fainting 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Hemorrhage brain 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Neurologic disorder NOS 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Paralysis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Peripheral neuropathy NOS 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Syncope 0/129 (0%) 0 1/128 (0.8%) 6 0/71 (0%) 0
    Psychiatric disorders
    Panic attack 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 1/129 (0.8%) 2 1/128 (0.8%) 1 1/71 (1.4%) 1
    Acute renal failure 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Bladder prolapse 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    End stage renal disease (ESRD) 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Kidney failure 3/129 (2.3%) 3 0/128 (0%) 0 0/71 (0%) 0
    Kidney function abnormal 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Kidney stones 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Pyelonephritis 0/129 (0%) 0 0/128 (0%) 0 2/71 (2.8%) 2
    Renal failure 0/129 (0%) 0 2/128 (1.6%) 3 1/71 (1.4%) 1
    Urinary tract infection 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Reproductive system and breast disorders
    Breast cancer 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Erectile dysfunction 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Menorrhagia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Ovarian cyst 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Prostate cancer 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Prostatitis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Uterine cancer 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Atelectasis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Difficulty breathing 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Dyspnea 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Exacerbation of asthma 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Hypoxia 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Lung cancer 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Pleural effusion 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Pneumonia 5/129 (3.9%) 6 5/128 (3.9%) 5 0/71 (0%) 0
    Pulmonary embolism 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Pulmonary hypertension 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Shortness of breath 2/129 (1.6%) 2 1/128 (0.8%) 2 0/71 (0%) 0
    Sore throat 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Skin and subcutaneous tissue disorders
    Cellulitis 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Cellulitis of foot 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Cellulitis of leg 3/129 (2.3%) 3 2/128 (1.6%) 2 1/71 (1.4%) 1
    Cellulitis of toe 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Shingles 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Surgical and medical procedures
    Bile duct stent insertion 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Bypass surgery 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Coronary angioplasty 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Coronary artery bypass graft 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Feeding tube insertion 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Foot surgery 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Gastric bypass surgery 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Leg amputation 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Surgery 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Thyroidectomy 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Toe amputation 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Vascular disorders
    Deep vein thrombosis 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Embolism - blood clot 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Hematoma 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Hypertension worsened 3/129 (2.3%) 3 1/128 (0.8%) 1 0/71 (0%) 0
    Hypertensive crisis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Hypotension 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Ischemic stroke 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Peripheral arterial disease 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Stroke 2/129 (1.6%) 2 2/128 (1.6%) 2 1/71 (1.4%) 1
    Stroke (cerebrovascular accident) 2/129 (1.6%) 2 2/128 (1.6%) 2 1/71 (1.4%) 1
    Stroke - Haemorrhagic 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Transient ischemic attacks 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Other (Not Including Serious) Adverse Events
    Aflibercept Sham Bilateral Participants
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 116/129 (89.9%) 112/128 (87.5%) 62/71 (87.3%)
    Blood and lymphatic system disorders
    Anemia 6/129 (4.7%) 6 4/128 (3.1%) 4 0/71 (0%) 0
    Anemia, unspecified 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Macrocytosis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Thrombocytopenia 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Cardiac disorders
    Angina pectoris 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Atrial fibrillation 2/129 (1.6%) 2 0/128 (0%) 0 1/71 (1.4%) 1
    Bundle branch block 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Cardiac arrhythmia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Cardiomegaly 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Congestive heart failure 4/129 (3.1%) 4 0/128 (0%) 0 0/71 (0%) 0
    Coronary artery disease 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Heart failure 1/129 (0.8%) 1 2/128 (1.6%) 2 0/71 (0%) 0
    Left ventricular hypertrophy 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Palpitation 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Supraventricular tachycardia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Tachycardia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Ventricular tachycardia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Congenital, familial and genetic disorders
    Ventricular septal defect 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Ear and labyrinth disorders
    Ear infection 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Fluid in middle ear 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Inner ear disorder 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Otitis externa 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Tinnitus 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Endocrine disorders
    Diabetes mellitus poor control 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Graves' disease 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Hyperglycemia 1/129 (0.8%) 1 2/128 (1.6%) 2 1/71 (1.4%) 1
    Hypoglycemia 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Hypothyroidism 1/129 (0.8%) 1 1/128 (0.8%) 1 2/71 (2.8%) 2
    Loss of control of blood sugar 3/129 (2.3%) 3 2/128 (1.6%) 2 2/71 (2.8%) 2
    Thyroid nodule 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Worsening of diabetes 5/129 (3.9%) 5 4/128 (3.1%) 4 3/71 (4.2%) 3
    Eye disorders
    Abnormal vision 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Allergic conjunctivitis 2/129 (1.6%) 2 1/128 (0.8%) 1 1/71 (1.4%) 2
    Anatomical narrow angle borderline glaucoma 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Anterior chamber angle neovascularisation 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Anterior membrane dystrophy 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Atrophy of macula 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Blepharitis (eyelid irritation) 1/129 (0.8%) 1 3/128 (2.3%) 3 0/71 (0%) 0
    Blepharo conjunctivitis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Blindness 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Blurred vision 8/129 (6.2%) 8 7/128 (5.5%) 8 7/71 (9.9%) 16
    Blurry vision 1/129 (0.8%) 1 3/128 (2.3%) 3 7/71 (9.9%) 9
    Burning eyes 1/129 (0.8%) 1 1/128 (0.8%) 1 2/71 (2.8%) 4
    Cataract 23/129 (17.8%) 24 26/128 (20.3%) 27 17/71 (23.9%) 26
    Cataract cortical 5/129 (3.9%) 6 2/128 (1.6%) 2 2/71 (2.8%) 2
    Cataract subcapsular 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Chalazion 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Cloudy vision 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Conjunctival cyst 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Conjunctival injection 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Conjunctivitis 2/129 (1.6%) 2 1/128 (0.8%) 1 1/71 (1.4%) 2
    Corneal abrasion 6/129 (4.7%) 6 3/128 (2.3%) 4 2/71 (2.8%) 2
    Corneal disorder (NOS) 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Corneal guttata 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Corneal haze 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Cortical spoking 1/129 (0.8%) 1 3/128 (2.3%) 3 2/71 (2.8%) 3
    Cotton wool spots 1/129 (0.8%) 1 2/128 (1.6%) 3 0/71 (0%) 0
    Cystoid macular edema 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Diabetic macular edema 7/129 (5.4%) 7 14/128 (10.9%) 15 6/71 (8.5%) 7
    Diplopia 0/129 (0%) 0 1/128 (0.8%) 1 2/71 (2.8%) 3
    Disc neovascularization 2/129 (1.6%) 2 3/128 (2.3%) 3 2/71 (2.8%) 2
    Distorted vision 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 2
    Dot hemorrhages 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Double vision 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Dry eye 10/129 (7.8%) 11 9/128 (7%) 9 9/71 (12.7%) 12
    Epiretinal membrane 3/129 (2.3%) 3 3/128 (2.3%) 3 2/71 (2.8%) 2
    Episcleritis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Eye ache 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Eye discharge 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Eye irritation 0/129 (0%) 0 6/128 (4.7%) 8 3/71 (4.2%) 6
    Eye itching 2/129 (1.6%) 2 3/128 (2.3%) 3 3/71 (4.2%) 5
    Eye pain 5/129 (3.9%) 5 6/128 (4.7%) 7 5/71 (7%) 8
    Eye strain 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 2
    Eye tearing 3/129 (2.3%) 3 1/128 (0.8%) 1 0/71 (0%) 0
    Eye tired 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Eyelid disorder 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 2
    Eyelid edema 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Eyelid twitching 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Floaters 19/129 (14.7%) 19 6/128 (4.7%) 8 7/71 (9.9%) 9
    Fog in front of eyes 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 2
    Foreign body sensation in eyes 2/129 (1.6%) 2 0/128 (0%) 0 2/71 (2.8%) 2
    Glare 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 2
    Glaucoma 2/129 (1.6%) 2 2/128 (1.6%) 2 1/71 (1.4%) 2
    Hazy vision 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Hollenhorst plaque 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Hordeolum 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Hypopyon 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Intraretinal microvascular abnormalities 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Iris neovascularization 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Iritis (anterior uveitis, iridocyclitis) 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Ischemia retinal 1/129 (0.8%) 1 0/128 (0%) 0 2/71 (2.8%) 2
    Ischemic optic neuropathy 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Keratopathy NOS 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Lid papilloma 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Macular cyst 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Macular cyst, hole, or pseudohole of retina 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Macular edema 0/129 (0%) 0 2/128 (1.6%) 2 2/71 (2.8%) 2
    Macular hole 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Macular ischemia 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Macular puckering 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Meibomian gland obstruction 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Near vision disturbance 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 2
    Nuclear sclerosis 4/129 (3.1%) 4 5/128 (3.9%) 5 0/71 (0%) 0
    Ocular discomfort 0/129 (0%) 0 1/128 (0.8%) 1 3/71 (4.2%) 3
    Optic nerve pallor 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Photophobia 2/129 (1.6%) 2 2/128 (1.6%) 2 1/71 (1.4%) 2
    Photopsia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Pinguecula 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 2
    Posterior capsule opacification 6/129 (4.7%) 6 5/128 (3.9%) 5 2/71 (2.8%) 4
    Posterior subcapsular cataract 10/129 (7.8%) 11 6/128 (4.7%) 6 4/71 (5.6%) 5
    Posterior vitreous detachment 5/129 (3.9%) 5 2/128 (1.6%) 2 5/71 (7%) 5
    Preglaucoma, unspecified 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Preproliferative diabetic retinopathy 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Preretinal hemorrhage 0/129 (0%) 0 5/128 (3.9%) 5 1/71 (1.4%) 2
    Proliferative diabetic retinopathy 2/129 (1.6%) 2 9/128 (7%) 9 7/71 (9.9%) 7
    Ptosis 2/129 (1.6%) 2 0/128 (0%) 0 1/71 (1.4%) 1
    Punctate epithelial erosion 1/129 (0.8%) 1 1/128 (0.8%) 1 2/71 (2.8%) 2
    Red eye 2/129 (1.6%) 2 2/128 (1.6%) 2 0/71 (0%) 0
    Retinal disorder NOS 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Retinal exudates 0/129 (0%) 0 3/128 (2.3%) 4 2/71 (2.8%) 2
    Retinal hemorrhage 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Retinal hole 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Retinal neovascularization 4/129 (3.1%) 5 5/128 (3.9%) 5 4/71 (5.6%) 4
    Retinal nonperfusion 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Retinal tear 0/129 (0%) 0 0/128 (0%) 0 2/71 (2.8%) 2
    Retinal vein disorder NOS 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Retinal vessel avulsion 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Retinoschisis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Rhegmatogenous retinal detachment 1/129 (0.8%) 2 0/128 (0%) 0 0/71 (0%) 0
    Sensitivity to light (photophobia) 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 2
    Silicone oil droplets 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Spots before eyes 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Stye 1/129 (0.8%) 1 2/128 (1.6%) 2 2/71 (2.8%) 2
    Subconjunctival hemorrhage 8/129 (6.2%) 17 6/128 (4.7%) 6 3/71 (4.2%) 3
    Subconjunctival/conjunctival hemorrhage 2/129 (1.6%) 2 1/128 (0.8%) 1 1/71 (1.4%) 2
    Subhyaloid hemorrhage 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Superficial punctate keratitis 0/129 (0%) 0 4/128 (3.1%) 4 3/71 (4.2%) 6
    Traction retinal detachment 1/129 (0.8%) 1 2/128 (1.6%) 2 0/71 (0%) 0
    Trichiasis 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Vision decreased 4/129 (3.1%) 5 2/128 (1.6%) 2 2/71 (2.8%) 4
    Visual acuity decreased 0/129 (0%) 0 3/128 (2.3%) 3 1/71 (1.4%) 2
    Visual disturbances 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Visual flashes 0/129 (0%) 0 2/128 (1.6%) 2 2/71 (2.8%) 3
    Visual impairment transient 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Vitreomacular traction syndrome 1/129 (0.8%) 1 2/128 (1.6%) 4 1/71 (1.4%) 1
    Vitreous detachment 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Vitreous floater 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 2
    Vitreous hemorrhage 7/129 (5.4%) 9 18/128 (14.1%) 21 5/71 (7%) 7
    Watering eyes 2/129 (1.6%) 2 1/128 (0.8%) 1 0/71 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 1/129 (0.8%) 1 2/128 (1.6%) 2 0/71 (0%) 0
    Acid reflux (oesophageal) 1/129 (0.8%) 1 0/128 (0%) 0 2/71 (2.8%) 2
    Anal irritation 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Bowel incontinence 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Clostridium difficile colitis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Colonic polyp 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Constipation 2/129 (1.6%) 2 1/128 (0.8%) 1 2/71 (2.8%) 2
    Diabetic gastroparesis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Diarrhea 3/129 (2.3%) 3 3/128 (2.3%) 3 2/71 (2.8%) 2
    Dysphagia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Esophagitis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    External hemorrhoids 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Gastric ulcer 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Gastritis 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Gastroenteritis 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Gastroesophageal reflux 2/129 (1.6%) 3 1/128 (0.8%) 1 2/71 (2.8%) 2
    Gastrointestinal stromal tumor 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Gastroparesis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Hiatal hernia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Internal hemorrhoids 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Nausea 2/129 (1.6%) 2 8/128 (6.3%) 8 0/71 (0%) 0
    Oral lesion 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Pancreatitis 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Parotitis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Sessile colonic polyp 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Stomach pain 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Stomach virus 2/129 (1.6%) 2 3/128 (2.3%) 3 1/71 (1.4%) 1
    Tooth abscess 3/129 (2.3%) 3 0/128 (0%) 0 1/71 (1.4%) 1
    Tooth fracture 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Tooth infection 2/129 (1.6%) 2 1/128 (0.8%) 1 0/71 (0%) 0
    Toothache 2/129 (1.6%) 2 0/128 (0%) 0 2/71 (2.8%) 2
    Upset stomach 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Vomiting 3/129 (2.3%) 3 4/128 (3.1%) 4 1/71 (1.4%) 1
    General disorders
    Catheter infection 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Chest pain 3/129 (2.3%) 3 2/128 (1.6%) 3 2/71 (2.8%) 2
    Chills 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Chronic pain 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Cyst 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 2
    Fatigue 1/129 (0.8%) 1 2/128 (1.6%) 2 1/71 (1.4%) 1
    Fever 4/129 (3.1%) 4 1/128 (0.8%) 1 1/71 (1.4%) 1
    General Swelling 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Hernia 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Injection site irritation 1/129 (0.8%) 1 0/128 (0%) 0 2/71 (2.8%) 3
    Injection site swelling 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Leg edema 3/129 (2.3%) 4 4/128 (3.1%) 4 1/71 (1.4%) 1
    Lethargy 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Necrosis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Pain NOS 2/129 (1.6%) 3 0/128 (0%) 0 0/71 (0%) 0
    Pain in face 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Pedal edema 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Peripheral edema 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Swelling of feet 1/129 (0.8%) 1 2/128 (1.6%) 2 1/71 (1.4%) 1
    Tiredness 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Hepatobiliary disorders
    Chronic cholecystitis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Hepatopathy 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Immune system disorders
    Allergic reaction 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Allergy NOS 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Gluten intolerance 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Seasonal allergy 2/129 (1.6%) 3 2/128 (1.6%) 2 0/71 (0%) 0
    Systemic lupus erythematosis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Infections and infestations
    Abscess NOS 1/129 (0.8%) 1 1/128 (0.8%) 1 2/71 (2.8%) 2
    Acute pharyngitis 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Bacteremia 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    COVID-19 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Candidiasis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Foot infection 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Fungal skin infection 2/129 (1.6%) 2 1/128 (0.8%) 1 0/71 (0%) 0
    Helicobacter pylori infection 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Infected toe 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Infection 3/129 (2.3%) 4 2/128 (1.6%) 2 3/71 (4.2%) 3
    Infection NOS 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Influenza 6/129 (4.7%) 7 6/128 (4.7%) 6 3/71 (4.2%) 3
    Lyme disease 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    MRSA 2/129 (1.6%) 4 2/128 (1.6%) 2 1/71 (1.4%) 1
    Respiratory tract infection fungal 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Sepsis 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Staphylococcal infection NOS 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Thrush 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Tinea pedis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Viral syndrome 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Yeast infection 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Injury, poisoning and procedural complications
    Back injury 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Bee sting 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Bug bite 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Burn 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Fall 3/129 (2.3%) 3 5/128 (3.9%) 8 3/71 (4.2%) 4
    Fibula fracture 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Foot injury 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Head injury 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Knee injury 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Laceration 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Laceration of leg 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Motor vehicle accident 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Spider bite 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Spinal fracture 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Wound 0/129 (0%) 0 2/128 (1.6%) 2 1/71 (1.4%) 1
    Investigations
    Arteriogram 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Creatinine abnormal NOS 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Elevated liver enzymes 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Elevated white cell count 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Glucose high 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    HbA1C increased 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Heart murmur 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Heart rate low 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Intraocular pressure increased 1/129 (0.8%) 1 3/128 (2.3%) 3 0/71 (0%) 0
    Laboratory test abnormal 1/129 (0.8%) 1 2/128 (1.6%) 2 0/71 (0%) 0
    Protein urine present 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Testosterone low 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Troponin increased 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Weight loss 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Metabolism and nutrition disorders
    Acidosis 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Adrenal insufficiency 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Decreased appetite 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Dehydration 0/129 (0%) 0 1/128 (0.8%) 1 2/71 (2.8%) 2
    Dyslipidemia 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Fluid overload - fluid volume increased 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Hypercholesteremia 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Hypercholesterolemia 3/129 (2.3%) 3 4/128 (3.1%) 4 0/71 (0%) 0
    Hyperkalemia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Hyperlipidemia 3/129 (2.3%) 3 1/128 (0.8%) 1 1/71 (1.4%) 1
    Hyponatremia 1/129 (0.8%) 1 2/128 (1.6%) 2 1/71 (1.4%) 1
    Iron deficiency 2/129 (1.6%) 2 1/128 (0.8%) 1 0/71 (0%) 0
    Malnutrition 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Metabolic alkalosis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Overweight 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Unintentional weight loss 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Vitamin B12 deficiency 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Vitamin D deficiency 2/129 (1.6%) 2 5/128 (3.9%) 5 1/71 (1.4%) 1
    Water retention 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Musculoskeletal and connective tissue disorders
    Adhesive capsulitis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Ankle fracture 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Arthritis NOS 3/129 (2.3%) 3 3/128 (2.3%) 3 2/71 (2.8%) 2
    Back pain 4/129 (3.1%) 4 4/128 (3.1%) 5 2/71 (2.8%) 2
    Baker's cyst 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Bone spur 1/129 (0.8%) 1 3/128 (2.3%) 3 0/71 (0%) 0
    Broken bones 1/129 (0.8%) 1 3/128 (2.3%) 3 1/71 (1.4%) 1
    Broken foot 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Broken wrist 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Bursitis 0/129 (0%) 0 1/128 (0.8%) 2 0/71 (0%) 0
    Chest tenderness 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Degenerative disc disease 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Dislocated shoulder 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Foot fracture 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Foot pain 1/129 (0.8%) 1 2/128 (1.6%) 2 1/71 (1.4%) 1
    Fractured tailbone 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Fractured toe 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Frozen shoulder 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Generalized muscle weakness 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Gout 3/129 (2.3%) 3 2/128 (1.6%) 2 0/71 (0%) 0
    Hand pain 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Herniated disc 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Joint pain 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Knee pain 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Leg pain 2/129 (1.6%) 2 0/128 (0%) 0 2/71 (2.8%) 3
    Lumbar spondylosis 1/129 (0.8%) 2 0/128 (0%) 0 0/71 (0%) 0
    Muscle cramps 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Muscle pain 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Muscle spasms 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Muscle weakness 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Neck pain 0/129 (0%) 0 2/128 (1.6%) 2 1/71 (1.4%) 1
    Osteoarthritis 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Osteomyelitis 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Osteoporosis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Pain in arm 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Pain in elbow 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Pain in heel 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Pain in hip 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Plantar fasciitis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Rotator cuff tear 1/129 (0.8%) 1 2/128 (1.6%) 2 0/71 (0%) 0
    Shoulder discomfort 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Shoulder pain 1/129 (0.8%) 1 1/128 (0.8%) 1 2/71 (2.8%) 2
    Sore tailbone 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Sprain of unspecified site of wrist 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Sprained ankle 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Sprains and strains of ribs 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Tendonitis 2/129 (1.6%) 2 1/128 (0.8%) 1 1/71 (1.4%) 1
    Trigger finger 0/129 (0%) 0 3/128 (2.3%) 3 1/71 (1.4%) 3
    Wrist pain 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Abdominal tumor 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Breast lump (benign) 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Neuroma 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Non-Hodgkin's lymphoma 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Polyp of vocal cord or larynx 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Stomach cancer 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Nervous system disorders
    Bell's palsy 1/129 (0.8%) 1 3/128 (2.3%) 3 1/71 (1.4%) 1
    Carpal tunnel syndrome 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Diabetic neuropathy 2/129 (1.6%) 2 1/128 (0.8%) 1 2/71 (2.8%) 2
    Diabetic peripheral neuropathy 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Dizziness 6/129 (4.7%) 6 2/128 (1.6%) 2 0/71 (0%) 0
    Drowsiness 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Dysphonia 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Encephalopathy 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Facial droop 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Fainting 2/129 (1.6%) 2 3/128 (2.3%) 3 0/71 (0%) 0
    Head pain 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Headache 2/129 (1.6%) 2 8/128 (6.3%) 9 2/71 (2.8%) 6
    Lightheadedness 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Lumbar radiculopathy 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Migraine headache 0/129 (0%) 0 2/128 (1.6%) 2 2/71 (2.8%) 2
    Nerve compression 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Neuropathy 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Numbness in feet 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Numbness in hand 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Ophthalmic migraine 0/129 (0%) 0 0/128 (0%) 0 2/71 (2.8%) 3
    Post herpetic neuralgia (infection) 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Sciatica 2/129 (1.6%) 2 2/128 (1.6%) 2 1/71 (1.4%) 1
    Seizures 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Sleep paralysis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Spinal stenosis of unspecified region 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Syncope 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Tension headache 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Vasovagal attack 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Vertigo 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Pregnancy, puerperium and perinatal conditions
    Spontaneous abortion 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Psychiatric disorders
    Alcohol abuse 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Anxiety 4/129 (3.1%) 4 4/128 (3.1%) 4 1/71 (1.4%) 1
    Depression 4/129 (3.1%) 4 3/128 (2.3%) 3 0/71 (0%) 0
    Insomnia 0/129 (0%) 0 0/128 (0%) 0 2/71 (2.8%) 2
    Mental state abnormal 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Azotemia prerenal 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Bladder infection 3/129 (2.3%) 3 0/128 (0%) 0 2/71 (2.8%) 2
    Bladder prolapse 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Chronic kidney disease 5/129 (3.9%) 5 6/128 (4.7%) 6 2/71 (2.8%) 2
    Chronic renal failure worsened 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Dysuria 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    End stage renal disease (ESRD) 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Hematuria (blood in urine) 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Kidney failure 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Kidney function abnormal 2/129 (1.6%) 2 1/128 (0.8%) 1 0/71 (0%) 0
    Kidney infection 2/129 (1.6%) 2 1/128 (0.8%) 1 1/71 (1.4%) 2
    Kidney stones 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Nephrolithiasis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Proteinuria 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Renal cyst 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Renal failure 1/129 (0.8%) 1 2/128 (1.6%) 3 0/71 (0%) 0
    Renal insufficiency 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Renal pain 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Urinary incontinence 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Urinary tract infection 6/129 (4.7%) 10 7/128 (5.5%) 7 2/71 (2.8%) 2
    Urinary urgency 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Urination frequency of 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Benign prostatic hypertrophy 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Erectile dysfunction 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Menstrual cramps 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Ovarian cyst 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Uterine bleeding 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Vaginal disorder NOS 1/129 (0.8%) 2 0/128 (0%) 0 1/71 (1.4%) 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Acute sinusitis 1/129 (0.8%) 1 0/128 (0%) 0 2/71 (2.8%) 2
    Asthma 1/129 (0.8%) 1 2/128 (1.6%) 2 0/71 (0%) 0
    Bronchitis 4/129 (3.1%) 4 4/128 (3.1%) 5 2/71 (2.8%) 2
    Bronchitis asthmatic 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Chronic obstructive pulmonary disease 0/129 (0%) 0 1/128 (0.8%) 1 2/71 (2.8%) 2
    Cold 9/129 (7%) 11 5/128 (3.9%) 5 4/71 (5.6%) 5
    Cough 3/129 (2.3%) 3 7/128 (5.5%) 8 0/71 (0%) 0
    Difficulty breathing 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Dyspnea 0/129 (0%) 0 1/128 (0.8%) 2 0/71 (0%) 0
    Exacerbation of asthma 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Hemoptysis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Hypoxemia 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Laryngitis 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Lung nodule 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Nasal congestion 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Nasal septum deviation 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Pleural effusion 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Pneumonia 4/129 (3.1%) 4 1/128 (0.8%) 1 3/71 (4.2%) 3
    Pulmonary edema 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Pulmonary hypertension 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Respiratory infection 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Shortness of breath 3/129 (2.3%) 3 2/128 (1.6%) 2 1/71 (1.4%) 1
    Sinus infection 5/129 (3.9%) 8 3/128 (2.3%) 6 3/71 (4.2%) 3
    Sinusitis 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Sleep apnea 1/129 (0.8%) 1 1/128 (0.8%) 1 2/71 (2.8%) 2
    Sore throat 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Streptococcal sore throat 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1
    Upper respiratory infection 7/129 (5.4%) 8 6/128 (4.7%) 7 1/71 (1.4%) 4
    Vasomotor rhinitis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Vocal cord dysfunction 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Wheezing 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Skin and subcutaneous tissue disorders
    Allergic dermatitis 1/129 (0.8%) 2 0/128 (0%) 0 0/71 (0%) 0
    Basal cell carcinoma 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Blister 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Blister of foot and toe(s), without mention of infection 2/129 (1.6%) 3 0/128 (0%) 0 0/71 (0%) 0
    Bruise 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Cellulitis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Cellulitis of arm 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Cellulitis of foot 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Cellulitis of leg 0/129 (0%) 0 0/128 (0%) 0 1/71 (1.4%) 1
    Cellulitis of toe 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Contact dermatitis 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Dermatochalasis 2/129 (1.6%) 2 1/128 (0.8%) 1 0/71 (0%) 0
    Diabetic dermopathy 0/129 (0%) 0 2/128 (1.6%) 2 0/71 (0%) 0
    Diabetic foot ulcer 4/129 (3.1%) 4 3/128 (2.3%) 3 0/71 (0%) 0
    Ecchymosis - skin 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Epidermal cyst 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Erythematous conditions 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Folliculitis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Foot ulcer 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Gangrene 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Hair thinning 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Ingrown toe nail 1/129 (0.8%) 1 2/128 (1.6%) 2 0/71 (0%) 0
    Leg ulcer 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Poison ivy rash 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 2
    Psoriasis 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Rash 3/129 (2.3%) 3 2/128 (1.6%) 2 3/71 (4.2%) 3
    Rosacea 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 1
    Sebaceous cyst 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Shingles 1/129 (0.8%) 1 2/128 (1.6%) 2 1/71 (1.4%) 1
    Skin callus 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Skin cancer 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Skin infection 1/129 (0.8%) 1 0/128 (0%) 0 1/71 (1.4%) 1
    Stasis dermatitis 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Swelling of face 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Surgical and medical procedures
    Achilles tendon elongation 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Atherectomy 0/129 (0%) 0 1/128 (0.8%) 3 0/71 (0%) 0
    Cardiac pacemaker replacement 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Cataract extraction 1/129 (0.8%) 1 1/128 (0.8%) 1 1/71 (1.4%) 2
    Coronary angioplasty 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Dental implantation 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Foot surgery 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Knee surgery NOS 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Skin graft 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Skin lesion excision 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Stent placement 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Surgery 2/129 (1.6%) 2 1/128 (0.8%) 2 1/71 (1.4%) 2
    Toe amputation 3/129 (2.3%) 3 1/128 (0.8%) 1 0/71 (0%) 0
    Tooth extraction 2/129 (1.6%) 2 3/128 (2.3%) 3 1/71 (1.4%) 1
    Wrist surgery 0/129 (0%) 0 1/128 (0.8%) 1 0/71 (0%) 0
    Vascular disorders
    Aortic dilatation 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Atherosclerosis 2/129 (1.6%) 2 0/128 (0%) 0 0/71 (0%) 0
    Embolism - blood clot 0/129 (0%) 0 0/128 (0%) 0 2/71 (2.8%) 2
    Hypertension 7/129 (5.4%) 7 5/128 (3.9%) 5 1/71 (1.4%) 1
    Hypertension worsened 9/129 (7%) 9 6/128 (4.7%) 7 6/71 (8.5%) 8
    Hypotension 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Orthostatic hypotension 1/129 (0.8%) 1 1/128 (0.8%) 1 0/71 (0%) 0
    Peripheral vascular disease 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Poor peripheral circulation 1/129 (0.8%) 1 0/128 (0%) 0 0/71 (0%) 0
    Varicose veins 0/129 (0%) 0 2/128 (1.6%) 3 1/71 (1.4%) 1
    Venous insufficiency 0/129 (0%) 0 1/128 (0.8%) 1 1/71 (1.4%) 1

    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.

    Results Point of Contact

    Name/Title Adam Glassman
    Organization JAEB CENTER FOR HEALTH RESEARCH
    Phone 8139758690
    Email mhuggins@jaeb.org
    Responsible Party:
    Jaeb Center for Health Research
    ClinicalTrials.gov Identifier:
    NCT02634333
    Other Study ID Numbers:
    • DRCR.net Protocol W
    • EY14231
    • EY23207
    • EY18817
    First Posted:
    Dec 18, 2015
    Last Update Posted:
    Aug 17, 2022
    Last Verified:
    Aug 1, 2022