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Anti-VEGF Treatment for Prevention of PDR/DME

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02634333
Recruitment Status : Active, not recruiting
First Posted : December 18, 2015
Results First Posted : November 24, 2021
Last Update Posted : November 24, 2021
Sponsor:
Collaborators:
Regeneron Pharmaceuticals
Juvenile Diabetes Research Foundation
National Eye Institute (NEI)
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Jaeb Center for Health Research

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Outcomes Assessor);   Primary Purpose: Prevention
Conditions Diabetic Retinopathy
Diabetic Macular Edema
Interventions Procedure: Prompt Sham
Drug: Prompt aflibercept
Procedure: Deferred laser
Drug: Deferred aflibercept
Enrollment 399
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Aflibercept Sham
Hide 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
Number of participants Number of units (Eyes) Number of participants Number of units (Eyes)
Started 200 [1] 200 199 [1] 199
Completed 160 [1] 160 167 [1] 167
Not Completed 40 40 32 32
Reason Not Completed
Completed out of Window             3                         2            
Missed Visit             5                         2            
Lost to Follow-up             12                         7            
Withdrawal by Subject             9                         13            
Death             11                         8            
[1]
Number of Eyes
Arm/Group Title Aflibercept Sham Total
Hide 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 Number of Baseline Participants 200 199 399
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
200 199 399
Hide Baseline 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.
Age, Continuous  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 200 participants 199 participants 399 participants
57
(51 to 63)
56
(48 to 62)
57
(51 to 64)
Sex/Gender, Customized  
Measure Type: Number
Unit of measure:  Eyes
Number Analyzed 200 participants 199 participants 399 participants
Female 83 86 139
Male 117 113 189
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Eyes
Number Analyzed 200 participants 199 participants 399 participants
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  
Measure Type: Number
Unit of measure:  Eyes
Number Analyzed 200 participants 199 participants 399 participants
Type 1 12 23 35
Type 2 188 176 364
Duration of Diabetes  
Median (Inter-Quartile Range)
Unit of measure:  Years
Number Analyzed 200 participants 199 participants 399 participants
17
(10 to 22)
16
(11 to 22)
16
(10 to 22)
Hemoglobin A1c   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Percent
Number Analyzed 200 participants 199 participants 399 participants
8.6
(7.1 to 10.0)
8.3
(7.3 to 9.7)
8.4
(7.2 to 9.9)
[1]
Measure Description: Hemoglobin A1c values were missing for 11 participants in the aflibercept group and 9 participants in the sham group
Mean arterial blood pressure   [1] 
Median (Inter-Quartile Range)
Unit of measure:  mmHg
Number Analyzed 200 participants 199 participants 399 participants
100
(92 to 107)
98
(91 to 106)
99
(92 to 106)
[1]
Measure Description: Mean arterial blood pressure = (Systolic blood pressure + 2*Diastolic blood pressure) / 3
Body mass index  
Median (Inter-Quartile Range)
Unit of measure:  Kg/m^2
Number Analyzed 200 participants 199 participants 399 participants
31
(28 to 37)
31
(27 to 36)
31
(28 to 36)
Prior myocardial infarction  
Measure Type: Number
Unit of measure:  Participant
Number Analyzed 200 participants 199 participants 399 participants
16 19 35
Prior stroke  
Measure Type: Number
Unit of measure:  Participant
Number Analyzed 200 participants 199 participants 399 participants
13 11 21
Pre-existing renal disease  
Measure Type: Number
Unit of measure:  Participant
Number Analyzed 200 participants 199 participants 399 participants
6 6 11
Visual acuity   [1] 
Mean (Inter-Quartile Range)
Unit of measure:  Letter score
Number Analyzed 200 participants 199 participants 399 participants
88
(84 to 90)
88
(85 to 91)
88
(84 to 90)
[1]
Measure Description: Measure Description: Best corrected visual acuity letter score as measured by a certified tester using an electronic visual acuity testing machine based on the Early Treatment Diabetic Retinopathy Study (ETDRS) method. Best value on the scale 97, worst 0.
Optical coherence tomography central subfield thickness   [1] 
Median (Inter-Quartile Range)
Unit of measure:  Microns
Number Analyzed 200 participants 199 participants 399 participants
283
(264 to 300)
283
(265 to 299)
283
(264 to 299)
[1]
Measure Description: Heidelberg Spectralis machine equivalent. Spectralis = 40.78 + 0.95 × cirrus.
Diabetic retinopathy severity scale level   [1] 
Measure Type: Number
Unit of measure:  Eyes
Number Analyzed 200 participants 199 participants 399 participants
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
[1]
Measure Description: NPDR= Non-proliferative diabetic retinopathy
Intraocular pressure  
Median (Inter-Quartile Range)
Unit of measure:  mmHg
Number Analyzed 200 participants 199 participants 399 participants
15
(13 to 17)
15
(13 to 17)
15
(13 to 17)
Lens status  
Measure Type: Number
Unit of measure:  Eyes
Number Analyzed 200 participants 199 participants 399 participants
Posterior chamber Intraocular lens 34 32 66
Phakic 166 167 333
Non-central diabetic macular edema   [1] [2] 
Measure Type: Number
Unit of measure:  Eyes
Number Analyzed 188 participants 195 participants 383 participants
75 83 158
[1]
Measure Description: At least 2 noncentral macular subfields with optical coherence tomography (OCT) thickness above threshold (average normal + 2 SD) or at least 1 noncentral macular subfield with OCT thickness at least 15 μm above threshold (average normal + 2 SD).
[2]
Measure Analysis Population Description: Missing for 12 eyes in the aflibercept group and 4 eyes in the sham group
Prior anti-vascular endothelial growth factor therapy for diabetic macular edema  
Measure Type: Number
Unit of measure:  Eyes
Number Analyzed 200 participants 199 participants 399 participants
8 5 13
Prior focal or grid laser for diabetic macular edema  
Measure Type: Number
Unit of measure:  Eyes
Number Analyzed 200 participants 199 participants 399 participants
12 19 31
1.Primary Outcome
Title Development of PDR and/or DME (Whichever Came First)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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.

Overall Number of Participants Analyzed 200 199
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
200 199
Measure Type: Number
Unit of Measure: Eyes
27 75
2.Secondary Outcome
Title Change in Visual Acuity From Baseline
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Aflibercept Sham
Hide 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.

Overall Number of Participants Analyzed 160 166
Overall Number of Units Analyzed
Type of Units Analyzed: Eyes
160 166
Mean (Standard Deviation)
Unit of Measure: Letter Score
-0.9  (5.8) -2.0  (6.1)
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
Hide 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 (%) Affected / at Risk (%) Affected / at Risk (%)
Total   9/129 (6.98%)      10/128 (7.81%)      5/71 (7.04%)    
Hide Serious Adverse Events
Aflibercept Sham Bilateral Participants
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   52/129 (40.31%)      50/128 (39.06%)      24/71 (33.80%)    
Blood and lymphatic system disorders       
Anemia  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Cardiac disorders       
AFib  1  1/129 (0.78%)  2 0/128 (0.00%)  0 1/71 (1.41%)  1
Atrial fibrillation  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Cardiac arrest  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  1
Cardiac arrhythmia  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Cardiogenic shock  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Cardiomyopathy  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Congestive heart failure  1  6/129 (4.65%)  8 6/128 (4.69%)  8 2/71 (2.82%)  5
Coronary artery disease  1  2/129 (1.55%)  2 2/128 (1.56%)  2 1/71 (1.41%)  1
Coronary artery occlusion  1  2/129 (1.55%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Endocarditis  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Heart failure  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Hypertensive heart disease  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Myocardial infarction  1  4/129 (3.10%)  5 6/128 (4.69%)  6 3/71 (4.23%)  3
Non ST segment elevation myocardial infarction  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Pericardial effusion  1  1/129 (0.78%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Pulmonary incompetence  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Tachycardia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Endocrine disorders       
Diabetic ketoacidosis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 2/71 (2.82%)  2
Hyperglycemia  1  1/129 (0.78%)  1 2/128 (1.56%)  2 2/71 (2.82%)  2
Hyperglycemic hyperosmolar nonketotic syndrome  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Eye disorders       
Endophthalmitis  1  2/129 (1.55%)  2 0/128 (0.00%)  0 1/71 (1.41%)  1
Rhegmatogenous retinal detachment  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Gastrointestinal disorders       
Achalasia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Appendicitis  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  1
Colitis collagenous  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Colon cancer  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Gastric ulcer  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Gastritis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Gastroenteritis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Gastrointestinal bleed  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Gastroparesis  1  1/129 (0.78%)  3 1/128 (0.78%)  2 0/71 (0.00%)  0
Pancreatitis  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Rectal bleeding  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
esophagus ulcer  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
General disorders       
Chest pain  1  1/129 (0.78%)  1 0/128 (0.00%)  0 2/71 (2.82%)  2
Death  1  2/129 (1.55%)  2 2/128 (1.56%)  2 2/71 (2.82%)  2
Fatigue  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
General Swelling  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Multi-organ failure  1  0/129 (0.00%)  0 2/128 (1.56%)  2 0/71 (0.00%)  0
Swelling of feet  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Hepatobiliary disorders       
Acute cholecystitis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Liver cirrhosis  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Immune system disorders       
Allergic reaction  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Infections and infestations       
Abscess NOS  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Bacteremia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
COVID-19  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Diverticulitis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Foot infection  1  2/129 (1.55%)  2 1/128 (0.78%)  1 0/71 (0.00%)  0
Helicobacter pylori infection  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Infection  1  1/129 (0.78%)  2 1/128 (0.78%)  1 1/71 (1.41%)  1
Infection (chronic) of amputation stump  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Influenza  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
MRSA  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Pseudomonas infection  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Sepsis  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Septic shock  1  0/129 (0.00%)  0 2/128 (1.56%)  2 1/71 (1.41%)  1
Septicemia  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  1
Staphylococcal infection NOS  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Injury, poisoning and procedural complications       
Burn  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Fall  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Gun shot wound  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Leg injury  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Wound  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Investigations       
Decreased hemoglobin  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Metabolism and nutrition disorders       
Acidosis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Dehydration  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Feeding intolerance  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Hyperkalemia  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Hypokalemia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Musculoskeletal and connective tissue disorders       
Ankle fracture  1  2/129 (1.55%)  3 0/128 (0.00%)  0 0/71 (0.00%)  0
Broken bones  1  0/129 (0.00%)  0 2/128 (1.56%)  2 1/71 (1.41%)  1
Charcot arthropathy  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Fractured ribs  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Knee fracture  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Neck pain  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Osteomyelitis  1  2/129 (1.55%)  2 1/128 (0.78%)  1 1/71 (1.41%)  1
Tendon disorder NOS  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Cancer (NOS)  1  3/129 (2.33%)  3 1/128 (0.78%)  1 0/71 (0.00%)  0
Desmoplastic small round cell tumor  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Liver cancer  1  1/129 (0.78%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Nervous system disorders       
Anoxic brain damage  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Coma  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Dizziness  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Encephalopathy  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Fainting  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Hemorrhage brain  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Neurologic disorder NOS  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Paralysis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Peripheral neuropathy NOS  1  2/129 (1.55%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Syncope  1  0/129 (0.00%)  0 1/128 (0.78%)  6 0/71 (0.00%)  0
Psychiatric disorders       
Panic attack  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Renal and urinary disorders       
Acute kidney injury  1  1/129 (0.78%)  2 1/128 (0.78%)  1 1/71 (1.41%)  1
Acute renal failure  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Bladder prolapse  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
End stage renal disease (ESRD)  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Kidney failure  1  3/129 (2.33%)  3 0/128 (0.00%)  0 0/71 (0.00%)  0
Kidney function abnormal  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Kidney stones  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Pyelonephritis  1  0/129 (0.00%)  0 0/128 (0.00%)  0 2/71 (2.82%)  2
Renal failure  1  0/129 (0.00%)  0 2/128 (1.56%)  3 1/71 (1.41%)  1
Urinary tract infection  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Reproductive system and breast disorders       
Breast cancer  1  0/129 (0.00%)  0 2/128 (1.56%)  2 0/71 (0.00%)  0
Erectile dysfunction  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Menorrhagia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Ovarian cyst  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Prostate cancer  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Prostatitis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Uterine cancer  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Acute respiratory failure  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Atelectasis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Difficulty breathing  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Dyspnea  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Exacerbation of asthma  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Hypoxia  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Lung cancer  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Pleural effusion  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Pneumonia  1  5/129 (3.88%)  6 5/128 (3.91%)  5 0/71 (0.00%)  0
Pulmonary embolism  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Pulmonary hypertension  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Shortness of breath  1  2/129 (1.55%)  2 1/128 (0.78%)  2 0/71 (0.00%)  0
Sore throat  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Skin and subcutaneous tissue disorders       
Cellulitis  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  1
Cellulitis of foot  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Cellulitis of leg  1  3/129 (2.33%)  3 2/128 (1.56%)  2 1/71 (1.41%)  1
Cellulitis of toe  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Shingles  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Surgical and medical procedures       
Bile duct stent insertion  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Bypass surgery  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Coronary angioplasty  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Coronary artery bypass graft  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Feeding tube insertion  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Foot surgery  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Gastric bypass surgery  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Leg amputation  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Surgery  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Thyroidectomy  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Toe amputation  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  1
Vascular disorders       
Deep vein thrombosis  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Embolism - blood clot  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Hematoma  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Hypertension worsened  1  3/129 (2.33%)  3 1/128 (0.78%)  1 0/71 (0.00%)  0
Hypertensive crisis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Hypotension  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Ischemic stroke  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Peripheral arterial disease  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Stroke  1  2/129 (1.55%)  2 2/128 (1.56%)  2 1/71 (1.41%)  1
Stroke (cerebrovascular accident)  1  2/129 (1.55%)  2 2/128 (1.56%)  2 1/71 (1.41%)  1
Stroke - Haemorrhagic  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Transient ischemic attacks  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
1
Term from vocabulary, MedDRA (Unspecified)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Aflibercept Sham Bilateral Participants
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   116/129 (89.92%)      112/128 (87.50%)      62/71 (87.32%)    
Blood and lymphatic system disorders       
Anemia  1  6/129 (4.65%)  6 4/128 (3.13%)  4 0/71 (0.00%)  0
Anemia, unspecified  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Macrocytosis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Thrombocytopenia  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Cardiac disorders       
Angina pectoris  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Atrial fibrillation  1  2/129 (1.55%)  2 0/128 (0.00%)  0 1/71 (1.41%)  1
Bundle branch block  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Cardiac arrhythmia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Cardiomegaly  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Congestive heart failure  1  4/129 (3.10%)  4 0/128 (0.00%)  0 0/71 (0.00%)  0
Coronary artery disease  1  2/129 (1.55%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Heart failure  1  1/129 (0.78%)  1 2/128 (1.56%)  2 0/71 (0.00%)  0
Left ventricular hypertrophy  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Palpitation  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Supraventricular tachycardia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Tachycardia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Ventricular tachycardia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Congenital, familial and genetic disorders       
Ventricular septal defect  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Ear and labyrinth disorders       
Ear infection  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Fluid in middle ear  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Inner ear disorder  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Otitis externa  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Tinnitus  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Endocrine disorders       
Diabetes mellitus poor control  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  1
Graves' disease  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Hyperglycemia  1  1/129 (0.78%)  1 2/128 (1.56%)  2 1/71 (1.41%)  1
Hypoglycemia  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Hypothyroidism  1  1/129 (0.78%)  1 1/128 (0.78%)  1 2/71 (2.82%)  2
Loss of control of blood sugar  1  3/129 (2.33%)  3 2/128 (1.56%)  2 2/71 (2.82%)  2
Thyroid nodule  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Worsening of diabetes  1  5/129 (3.88%)  5 4/128 (3.13%)  4 3/71 (4.23%)  3
Eye disorders       
Abnormal vision  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Allergic conjunctivitis  1  2/129 (1.55%)  2 1/128 (0.78%)  1 1/71 (1.41%)  2
Anatomical narrow angle borderline glaucoma  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Anterior chamber angle neovascularisation  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Anterior membrane dystrophy  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Atrophy of macula  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Blepharitis (eyelid irritation)  1  1/129 (0.78%)  1 3/128 (2.34%)  3 0/71 (0.00%)  0
Blepharo conjunctivitis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Blindness  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Blurred vision  1  8/129 (6.20%)  8 7/128 (5.47%)  8 7/71 (9.86%)  16
Blurry vision  1  1/129 (0.78%)  1 3/128 (2.34%)  3 7/71 (9.86%)  9
Burning eyes  1  1/129 (0.78%)  1 1/128 (0.78%)  1 2/71 (2.82%)  4
Cataract  1  23/129 (17.83%)  24 26/128 (20.31%)  27 17/71 (23.94%)  26
Cataract cortical  1  5/129 (3.88%)  6 2/128 (1.56%)  2 2/71 (2.82%)  2
Cataract subcapsular  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Chalazion  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Cloudy vision  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Conjunctival cyst  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Conjunctival injection  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Conjunctivitis  1  2/129 (1.55%)  2 1/128 (0.78%)  1 1/71 (1.41%)  2
Corneal abrasion  1  6/129 (4.65%)  6 3/128 (2.34%)  4 2/71 (2.82%)  2
Corneal disorder (NOS)  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Corneal guttata  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Corneal haze  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Cortical spoking  1  1/129 (0.78%)  1 3/128 (2.34%)  3 2/71 (2.82%)  3
Cotton wool spots  1  1/129 (0.78%)  1 2/128 (1.56%)  3 0/71 (0.00%)  0
Cystoid macular edema  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Diabetic macular edema  1  7/129 (5.43%)  7 14/128 (10.94%)  15 6/71 (8.45%)  7
Diplopia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 2/71 (2.82%)  3
Disc neovascularization  1  2/129 (1.55%)  2 3/128 (2.34%)  3 2/71 (2.82%)  2
Distorted vision  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  2
Dot hemorrhages  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Double vision  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Dry eye  1  10/129 (7.75%)  11 9/128 (7.03%)  9 9/71 (12.68%)  12
Epiretinal membrane  1  3/129 (2.33%)  3 3/128 (2.34%)  3 2/71 (2.82%)  2
Episcleritis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Eye ache  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Eye discharge  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Eye irritation  1  0/129 (0.00%)  0 6/128 (4.69%)  8 3/71 (4.23%)  6
Eye itching  1  2/129 (1.55%)  2 3/128 (2.34%)  3 3/71 (4.23%)  5
Eye pain  1  5/129 (3.88%)  5 6/128 (4.69%)  7 5/71 (7.04%)  8
Eye strain  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  2
Eye tearing  1  3/129 (2.33%)  3 1/128 (0.78%)  1 0/71 (0.00%)  0
Eye tired  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Eyelid disorder  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  2
Eyelid edema  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Eyelid twitching  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Floaters  1  19/129 (14.73%)  19 6/128 (4.69%)  8 7/71 (9.86%)  9
Fog in front of eyes  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  2
Foreign body sensation in eyes  1  2/129 (1.55%)  2 0/128 (0.00%)  0 2/71 (2.82%)  2
Glare  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  2
Glaucoma  1  2/129 (1.55%)  2 2/128 (1.56%)  2 1/71 (1.41%)  2
Hazy vision  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Hollenhorst plaque  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Hordeolum  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Hypopyon  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Intraretinal microvascular abnormalities  1  0/129 (0.00%)  0 2/128 (1.56%)  2 0/71 (0.00%)  0
Iris neovascularization  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Iritis (anterior uveitis, iridocyclitis)  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Ischemia retinal  1  1/129 (0.78%)  1 0/128 (0.00%)  0 2/71 (2.82%)  2
Ischemic optic neuropathy  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Keratopathy NOS  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Lid papilloma  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Macular cyst  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Macular cyst, hole, or pseudohole of retina  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Macular edema  1  0/129 (0.00%)  0 2/128 (1.56%)  2 2/71 (2.82%)  2
Macular hole  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Macular ischemia  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Macular puckering  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Meibomian gland obstruction  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Near vision disturbance  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  2
Nuclear sclerosis  1  4/129 (3.10%)  4 5/128 (3.91%)  5 0/71 (0.00%)  0
Ocular discomfort  1  0/129 (0.00%)  0 1/128 (0.78%)  1 3/71 (4.23%)  3
Optic nerve pallor  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Photophobia  1  2/129 (1.55%)  2 2/128 (1.56%)  2 1/71 (1.41%)  2
Photopsia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Pinguecula  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  2
Posterior capsule opacification  1  6/129 (4.65%)  6 5/128 (3.91%)  5 2/71 (2.82%)  4
Posterior subcapsular cataract  1  10/129 (7.75%)  11 6/128 (4.69%)  6 4/71 (5.63%)  5
Posterior vitreous detachment  1  5/129 (3.88%)  5 2/128 (1.56%)  2 5/71 (7.04%)  5
Preglaucoma, unspecified  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Preproliferative diabetic retinopathy  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Preretinal hemorrhage  1  0/129 (0.00%)  0 5/128 (3.91%)  5 1/71 (1.41%)  2
Proliferative diabetic retinopathy  1  2/129 (1.55%)  2 9/128 (7.03%)  9 7/71 (9.86%)  7
Ptosis  1  2/129 (1.55%)  2 0/128 (0.00%)  0 1/71 (1.41%)  1
Punctate epithelial erosion  1  1/129 (0.78%)  1 1/128 (0.78%)  1 2/71 (2.82%)  2
Red eye  1  2/129 (1.55%)  2 2/128 (1.56%)  2 0/71 (0.00%)  0
Retinal disorder NOS  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Retinal exudates  1  0/129 (0.00%)  0 3/128 (2.34%)  4 2/71 (2.82%)  2
Retinal hemorrhage  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Retinal hole  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Retinal neovascularization  1  4/129 (3.10%)  5 5/128 (3.91%)  5 4/71 (5.63%)  4
Retinal nonperfusion  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Retinal tear  1  0/129 (0.00%)  0 0/128 (0.00%)  0 2/71 (2.82%)  2
Retinal vein disorder NOS  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Retinal vessel avulsion  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Retinoschisis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Rhegmatogenous retinal detachment  1  1/129 (0.78%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Sensitivity to light (photophobia)  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  2
Silicone oil droplets  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Spots before eyes  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Stye  1  1/129 (0.78%)  1 2/128 (1.56%)  2 2/71 (2.82%)  2
Subconjunctival hemorrhage  1  8/129 (6.20%)  17 6/128 (4.69%)  6 3/71 (4.23%)  3
Subconjunctival/conjunctival hemorrhage  1  2/129 (1.55%)  2 1/128 (0.78%)  1 1/71 (1.41%)  2
Subhyaloid hemorrhage  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Superficial punctate keratitis  1  0/129 (0.00%)  0 4/128 (3.13%)  4 3/71 (4.23%)  6
Traction retinal detachment  1  1/129 (0.78%)  1 2/128 (1.56%)  2 0/71 (0.00%)  0
Trichiasis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Vision decreased  1  4/129 (3.10%)  5 2/128 (1.56%)  2 2/71 (2.82%)  4
Visual acuity decreased  1  0/129 (0.00%)  0 3/128 (2.34%)  3 1/71 (1.41%)  2
Visual disturbances  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Visual flashes  1  0/129 (0.00%)  0 2/128 (1.56%)  2 2/71 (2.82%)  3
Visual impairment transient  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Vitreomacular traction syndrome  1  1/129 (0.78%)  1 2/128 (1.56%)  4 1/71 (1.41%)  1
Vitreous detachment  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  1
Vitreous floater  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  2
Vitreous hemorrhage  1  7/129 (5.43%)  9 18/128 (14.06%)  21 5/71 (7.04%)  7
Watering eyes  1  2/129 (1.55%)  2 1/128 (0.78%)  1 0/71 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain  1  1/129 (0.78%)  1 2/128 (1.56%)  2 0/71 (0.00%)  0
Acid reflux (oesophageal)  1  1/129 (0.78%)  1 0/128 (0.00%)  0 2/71 (2.82%)  2
Anal irritation  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Bowel incontinence  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Clostridium difficile colitis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Colonic polyp  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Constipation  1  2/129 (1.55%)  2 1/128 (0.78%)  1 2/71 (2.82%)  2
Diabetic gastroparesis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Diarrhea  1  3/129 (2.33%)  3 3/128 (2.34%)  3 2/71 (2.82%)  2
Dysphagia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Esophagitis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
External hemorrhoids  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Gastric ulcer  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Gastritis  1  0/129 (0.00%)  0 2/128 (1.56%)  2 0/71 (0.00%)  0
Gastroenteritis  1  2/129 (1.55%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Gastroesophageal reflux  1  2/129 (1.55%)  3 1/128 (0.78%)  1 2/71 (2.82%)  2
Gastrointestinal stromal tumor  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Gastroparesis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Hiatal hernia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Internal hemorrhoids  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Nausea  1  2/129 (1.55%)  2 8/128 (6.25%)  8 0/71 (0.00%)  0
Oral lesion  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Pancreatitis  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Parotitis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Sessile colonic polyp  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Stomach pain  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Stomach virus  1  2/129 (1.55%)  2 3/128 (2.34%)  3 1/71 (1.41%)  1
Tooth abscess  1  3/129 (2.33%)  3 0/128 (0.00%)  0 1/71 (1.41%)  1
Tooth fracture  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Tooth infection  1  2/129 (1.55%)  2 1/128 (0.78%)  1 0/71 (0.00%)  0
Toothache  1  2/129 (1.55%)  2 0/128 (0.00%)  0 2/71 (2.82%)  2
Upset stomach  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Vomiting  1  3/129 (2.33%)  3 4/128 (3.13%)  4 1/71 (1.41%)  1
General disorders       
Catheter infection  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Chest pain  1  3/129 (2.33%)  3 2/128 (1.56%)  3 2/71 (2.82%)  2
Chills  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Chronic pain  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Cyst  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  2
Fatigue  1  1/129 (0.78%)  1 2/128 (1.56%)  2 1/71 (1.41%)  1
Fever  1  4/129 (3.10%)  4 1/128 (0.78%)  1 1/71 (1.41%)  1
General Swelling  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Hernia  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Injection site irritation  1  1/129 (0.78%)  1 0/128 (0.00%)  0 2/71 (2.82%)  3
Injection site swelling  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Leg edema  1  3/129 (2.33%)  4 4/128 (3.13%)  4 1/71 (1.41%)  1
Lethargy  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Necrosis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Pain NOS  1  2/129 (1.55%)  3 0/128 (0.00%)  0 0/71 (0.00%)  0
Pain in face  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Pedal edema  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Peripheral edema  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Swelling of feet  1  1/129 (0.78%)  1 2/128 (1.56%)  2 1/71 (1.41%)  1
Tiredness  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Hepatobiliary disorders       
Chronic cholecystitis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Hepatopathy  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Immune system disorders       
Allergic reaction  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Allergy NOS  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Gluten intolerance  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Seasonal allergy  1  2/129 (1.55%)  3 2/128 (1.56%)  2 0/71 (0.00%)  0
Systemic lupus erythematosis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Infections and infestations       
Abscess NOS  1  1/129 (0.78%)  1 1/128 (0.78%)  1 2/71 (2.82%)  2
Acute pharyngitis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Bacteremia  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
COVID-19  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Candidiasis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Foot infection  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Fungal skin infection  1  2/129 (1.55%)  2 1/128 (0.78%)  1 0/71 (0.00%)  0
Helicobacter pylori infection  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Infected toe  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Infection  1  3/129 (2.33%)  4 2/128 (1.56%)  2 3/71 (4.23%)  3
Infection NOS  1  2/129 (1.55%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Influenza  1  6/129 (4.65%)  7 6/128 (4.69%)  6 3/71 (4.23%)  3
Lyme disease  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
MRSA  1  2/129 (1.55%)  4 2/128 (1.56%)  2 1/71 (1.41%)  1
Respiratory tract infection fungal  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Sepsis  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Staphylococcal infection NOS  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Thrush  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Tinea pedis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Viral syndrome  1  2/129 (1.55%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Yeast infection  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Injury, poisoning and procedural complications       
Back injury  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Bee sting  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Bug bite  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Burn  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Fall  1  3/129 (2.33%)  3 5/128 (3.91%)  8 3/71 (4.23%)  4
Fibula fracture  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Foot injury  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Head injury  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Knee injury  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Laceration  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Laceration of leg  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Motor vehicle accident  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Spider bite  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Spinal fracture  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Wound  1  0/129 (0.00%)  0 2/128 (1.56%)  2 1/71 (1.41%)  1
Investigations       
Arteriogram  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Creatinine abnormal NOS  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Elevated liver enzymes  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Elevated white cell count  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Glucose high  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
HbA1C increased  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Heart murmur  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Heart rate low  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Intraocular pressure increased  1  1/129 (0.78%)  1 3/128 (2.34%)  3 0/71 (0.00%)  0
Laboratory test abnormal  1  1/129 (0.78%)  1 2/128 (1.56%)  2 0/71 (0.00%)  0
Protein urine present  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Testosterone low  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Troponin increased  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Weight loss  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Metabolism and nutrition disorders       
Acidosis  1  0/129 (0.00%)  0 2/128 (1.56%)  2 0/71 (0.00%)  0
Adrenal insufficiency  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Decreased appetite  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Dehydration  1  0/129 (0.00%)  0 1/128 (0.78%)  1 2/71 (2.82%)  2
Dyslipidemia  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Fluid overload - fluid volume increased  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Hypercholesteremia  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Hypercholesterolemia  1  3/129 (2.33%)  3 4/128 (3.13%)  4 0/71 (0.00%)  0
Hyperkalemia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Hyperlipidemia  1  3/129 (2.33%)  3 1/128 (0.78%)  1 1/71 (1.41%)  1
Hyponatremia  1  1/129 (0.78%)  1 2/128 (1.56%)  2 1/71 (1.41%)  1
Iron deficiency  1  2/129 (1.55%)  2 1/128 (0.78%)  1 0/71 (0.00%)  0
Malnutrition  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Metabolic alkalosis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Overweight  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Unintentional weight loss  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Vitamin B12 deficiency  1  0/129 (0.00%)  0 2/128 (1.56%)  2 0/71 (0.00%)  0
Vitamin D deficiency  1  2/129 (1.55%)  2 5/128 (3.91%)  5 1/71 (1.41%)  1
Water retention  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Adhesive capsulitis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Ankle fracture  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Arthritis NOS  1  3/129 (2.33%)  3 3/128 (2.34%)  3 2/71 (2.82%)  2
Back pain  1  4/129 (3.10%)  4 4/128 (3.13%)  5 2/71 (2.82%)  2
Baker's cyst  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Bone spur  1  1/129 (0.78%)  1 3/128 (2.34%)  3 0/71 (0.00%)  0
Broken bones  1  1/129 (0.78%)  1 3/128 (2.34%)  3 1/71 (1.41%)  1
Broken foot  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Broken wrist  1  0/129 (0.00%)  0 2/128 (1.56%)  2 0/71 (0.00%)  0
Bursitis  1  0/129 (0.00%)  0 1/128 (0.78%)  2 0/71 (0.00%)  0
Chest tenderness  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Degenerative disc disease  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Dislocated shoulder  1  1/129 (0.78%)  1 0/128 (0.00%)  0 1/71 (1.41%)  1
Foot fracture  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Foot pain  1  1/129 (0.78%)  1 2/128 (1.56%)  2 1/71 (1.41%)  1
Fractured tailbone  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Fractured toe  1  0/129 (0.00%)  0 2/128 (1.56%)  2 0/71 (0.00%)  0
Frozen shoulder  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Generalized muscle weakness  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Gout  1  3/129 (2.33%)  3 2/128 (1.56%)  2 0/71 (0.00%)  0
Hand pain  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Herniated disc  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Joint pain  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Knee pain  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  1
Leg pain  1  2/129 (1.55%)  2 0/128 (0.00%)  0 2/71 (2.82%)  3
Lumbar spondylosis  1  1/129 (0.78%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Muscle cramps  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  1
Muscle pain  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Muscle spasms  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Muscle weakness  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Neck pain  1  0/129 (0.00%)  0 2/128 (1.56%)  2 1/71 (1.41%)  1
Osteoarthritis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Osteomyelitis  1  2/129 (1.55%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Osteoporosis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Pain in arm  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Pain in elbow  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Pain in heel  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Pain in hip  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Plantar fasciitis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Rotator cuff tear  1  1/129 (0.78%)  1 2/128 (1.56%)  2 0/71 (0.00%)  0
Shoulder discomfort  1  0/129 (0.00%)  0 2/128 (1.56%)  2 0/71 (0.00%)  0
Shoulder pain  1  1/129 (0.78%)  1 1/128 (0.78%)  1 2/71 (2.82%)  2
Sore tailbone  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Sprain of unspecified site of wrist  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Sprained ankle  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Sprains and strains of ribs  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Tendonitis  1  2/129 (1.55%)  2 1/128 (0.78%)  1 1/71 (1.41%)  1
Trigger finger  1  0/129 (0.00%)  0 3/128 (2.34%)  3 1/71 (1.41%)  3
Wrist pain  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Abdominal tumor  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Breast lump (benign)  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Neuroma  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Non-Hodgkin's lymphoma  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Polyp of vocal cord or larynx  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Stomach cancer  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Nervous system disorders       
Bell's palsy  1  1/129 (0.78%)  1 3/128 (2.34%)  3 1/71 (1.41%)  1
Carpal tunnel syndrome  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Diabetic neuropathy  1  2/129 (1.55%)  2 1/128 (0.78%)  1 2/71 (2.82%)  2
Diabetic peripheral neuropathy  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Dizziness  1  6/129 (4.65%)  6 2/128 (1.56%)  2 0/71 (0.00%)  0
Drowsiness  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Dysphonia  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Encephalopathy  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Facial droop  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Fainting  1  2/129 (1.55%)  2 3/128 (2.34%)  3 0/71 (0.00%)  0
Head pain  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Headache  1  2/129 (1.55%)  2 8/128 (6.25%)  9 2/71 (2.82%)  6
Lightheadedness  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Lumbar radiculopathy  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Migraine headache  1  0/129 (0.00%)  0 2/128 (1.56%)  2 2/71 (2.82%)  2
Nerve compression  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Neuropathy  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Numbness in feet  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Numbness in hand  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Ophthalmic migraine  1  0/129 (0.00%)  0 0/128 (0.00%)  0 2/71 (2.82%)  3
Post herpetic neuralgia (infection)  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Sciatica  1  2/129 (1.55%)  2 2/128 (1.56%)  2 1/71 (1.41%)  1
Seizures  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Sleep paralysis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Spinal stenosis of unspecified region  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Syncope  1  0/129 (0.00%)  0 2/128 (1.56%)  2 0/71 (0.00%)  0
Tension headache  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Vasovagal attack  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Vertigo  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Pregnancy, puerperium and perinatal conditions       
Spontaneous abortion  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Psychiatric disorders       
Alcohol abuse  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Anxiety  1  4/129 (3.10%)  4 4/128 (3.13%)  4 1/71 (1.41%)  1
Depression  1  4/129 (3.10%)  4 3/128 (2.34%)  3 0/71 (0.00%)  0
Insomnia  1  0/129 (0.00%)  0 0/128 (0.00%)  0 2/71 (2.82%)  2
Mental state abnormal  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Renal and urinary disorders       
Acute kidney injury  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  1
Azotemia prerenal  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Bladder infection  1  3/129 (2.33%)  3 0/128 (0.00%)  0 2/71 (2.82%)  2
Bladder prolapse  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Chronic kidney disease  1  5/129 (3.88%)  5 6/128 (4.69%)  6 2/71 (2.82%)  2
Chronic renal failure worsened  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Dysuria  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
End stage renal disease (ESRD)  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Hematuria (blood in urine)  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Kidney failure  1  2/129 (1.55%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Kidney function abnormal  1  2/129 (1.55%)  2 1/128 (0.78%)  1 0/71 (0.00%)  0
Kidney infection  1  2/129 (1.55%)  2 1/128 (0.78%)  1 1/71 (1.41%)  2
Kidney stones  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Nephrolithiasis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Proteinuria  1  0/129 (0.00%)  0 2/128 (1.56%)  2 0/71 (0.00%)  0
Renal cyst  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Renal failure  1  1/129 (0.78%)  1 2/128 (1.56%)  3 0/71 (0.00%)  0
Renal insufficiency  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Renal pain  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Urinary incontinence  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Urinary tract infection  1  6/129 (4.65%)  10 7/128 (5.47%)  7 2/71 (2.82%)  2
Urinary urgency  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Urination frequency of  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Reproductive system and breast disorders       
Benign prostatic hyperplasia  1  1/129 (0.78%)  1 1/128 (0.78%)  1 1/71 (1.41%)  1
Benign prostatic hypertrophy  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Erectile dysfunction  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Menstrual cramps  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Ovarian cyst  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Uterine bleeding  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Vaginal disorder NOS  1  1/129 (0.78%)  2 0/128 (0.00%)  0 1/71 (1.41%)  1
Respiratory, thoracic and mediastinal disorders       
Acute respiratory failure  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Acute sinusitis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 2/71 (2.82%)  2
Asthma  1  1/129 (0.78%)  1 2/128 (1.56%)  2 0/71 (0.00%)  0
Bronchitis  1  4/129 (3.10%)  4 4/128 (3.13%)  5 2/71 (2.82%)  2
Bronchitis asthmatic  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Chronic obstructive pulmonary disease  1  0/129 (0.00%)  0 1/128 (0.78%)  1 2/71 (2.82%)  2
Cold  1  9/129 (6.98%)  11 5/128 (3.91%)  5 4/71 (5.63%)  5
Cough  1  3/129 (2.33%)  3 7/128 (5.47%)  8 0/71 (0.00%)  0
Difficulty breathing  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Dyspnea  1  0/129 (0.00%)  0 1/128 (0.78%)  2 0/71 (0.00%)  0
Exacerbation of asthma  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Hemoptysis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Hypoxemia  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Laryngitis  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Lung nodule  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Nasal congestion  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Nasal septum deviation  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Pleural effusion  1  2/129 (1.55%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Pneumonia  1  4/129 (3.10%)  4 1/128 (0.78%)  1 3/71 (4.23%)  3
Pulmonary edema  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Pulmonary hypertension  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Respiratory infection  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0
Shortness of breath  1  3/129 (2.33%)  3 2/128 (1.56%)  2 1/71 (1.41%)  1
Sinus infection  1  5/129 (3.88%)  8 3/128 (2.34%)  6 3/71 (4.23%)  3
Sinusitis  1  0/129 (0.00%)  0 0/128 (0.00%)  0 1/71 (1.41%)  1
Sleep apnea  1  1/129 (0.78%)  1 1/128 (0.78%)  1 2/71 (2.82%)  2
Sore throat  1  1/129 (0.78%)  1 1/128 (0.78%)  1 0/71 (0.00%)  0
Streptococcal sore throat  1  0/129 (0.00%)  0 1/128 (0.78%)  1 1/71 (1.41%)  1
Upper respiratory infection  1  7/129 (5.43%)  8 6/128 (4.69%)  7 1/71 (1.41%)  4
Vasomotor rhinitis  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Vocal cord dysfunction  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Wheezing  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Skin and subcutaneous tissue disorders       
Allergic dermatitis  1  1/129 (0.78%)  2 0/128 (0.00%)  0 0/71 (0.00%)  0
Basal cell carcinoma  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Blister  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Blister of foot and toe(s), without mention of infection  1  2/129 (1.55%)  3 0/128 (0.00%)  0 0/71 (0.00%)  0
Bruise  1  0/129 (0.00%)  0 1/128 (0.78%)  1 0/71 (0.00%)  0
Cellulitis  1  1/129 (0.78%)  1 0/128 (0.00%)  0 0/71 (0.00%)  0