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Managing Neovascular (Known as "Wet") Age-related Macular Degeneration Over 2 Years Using Different Treatment Schedules of 2 mg Intravitreal Aflibercept Injected in the Eye (ARIES)

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ClinicalTrials.gov Identifier: NCT02581891
Recruitment Status : Completed
First Posted : October 21, 2015
Results First Posted : May 21, 2020
Last Update Posted : May 21, 2020
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Bayer

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Macular Degeneration
Intervention Drug: Eylea (Intravitreal Aflibercept, VEGF Trap-Eye, BAY86-5321)
Enrollment 287
Recruitment Details This study was conducted from 19-Nov-2015 (First Patient First Visit) to 26-Apr-2019 (Last Patient Last Visit).
Pre-assignment Details A total of 443 participants were screened in this study. Of these, 156 participants were screening failures and did not enter the treatment period. Of the 287 treated participants, 16 were treated during the initiation phase, but were not randomized to a treatment arm after the initiation phase.
Arm/Group Title Early-start T&E Arm Late-start T&E Arm
Hide Arm/Group Description All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria. All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
Period Title: Overall Study
Started [1] 135 136
Completed Treatment 120 117
Completed [2] 119 117
Not Completed 16 19
Reason Not Completed
Adverse Event             4             6
Death             3             4
Lost to Follow-up             1             2
Physician Decision             0             1
Withdrawal by Subject             4             5
Other Reasons             3             1
Discontinued during followup             1             0
[1]
Randomized
[2]
Completed Study
Arm/Group Title Early-start T&E Arm Late-start T&E Arm Total
Hide Arm/Group Description All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria. All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria. Total of all reporting groups
Overall Number of Baseline Participants 135 136 271
Hide Baseline Analysis Population Description
All 271 participants were included in the SAF (287), who received any study drug in this study. 269 participants were included in the FAS, excluding 16 participants who were treated but not randomized and 1 participant in each treatment arm from SAF. Of the 269 participants in FAS, 59 participants in total were excluded from the PPS (210).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 135 participants 136 participants 271 participants
76  (8.8) 76.9  (8.2) 76.5  (8.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 135 participants 136 participants 271 participants
Female
81
  60.0%
73
  53.7%
154
  56.8%
Male
54
  40.0%
63
  46.3%
117
  43.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 135 participants 136 participants 271 participants
Hispanic or Latino
3
   2.2%
7
   5.1%
10
   3.7%
Not Hispanic or Latino
126
  93.3%
122
  89.7%
248
  91.5%
Unknown or Not Reported
6
   4.4%
7
   5.1%
13
   4.8%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 135 participants 136 participants 271 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
2
   1.5%
1
   0.7%
3
   1.1%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
   0.7%
0
   0.0%
1
   0.4%
White
131
  97.0%
127
  93.4%
258
  95.2%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
1
   0.7%
8
   5.9%
9
   3.3%
Baseline BCVA letters scores (study eye)   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Letters
Number Analyzed 106 participants 104 participants 210 participants
60.2  (12.1) 61.3  (10.8) 60.8  (11.4)
[1]
Measure Description: BCVA = best corrected visual acuity
[2]
Measure Analysis Population Description: PPS (Per-protocol set): all participants in the FAS (full analysis set) without any major protocol deviation.
Baseline CRT   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  μm
Number Analyzed 106 participants 104 participants 210 participants
443.7  (120.0) 448.3  (133.1) 446.0  (126.4)
[1]
Measure Description: CRT = central retinal thickness
[2]
Measure Analysis Population Description: PPS (Per-protocol set): all participants in the FAS (full analysis set) without any major protocol deviation.
1.Primary Outcome
Title Change in BCVA as Measured by the ETDRS Letter Score
Hide Description BCVA (best corrected visual acuity) was measured by the ETDRS (Early Treatment Diabetic Retinopathy Study) letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye at 4 meters; a higher score represents better functioning.
Time Frame From Week 16 to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
PPS (Per-protocol set): all participants in the FAS (full analysis set) without any major protocol deviation.
Arm/Group Title Early-start T&E Arm Late-start T&E Arm
Hide Arm/Group Description:
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
Overall Number of Participants Analyzed 106 104
Mean (Standard Deviation)
Unit of Measure: Letters correctly read
-2.1  (11.4) -0.4  (8.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Early-start T&E Arm, Late-start T&E Arm
Comments [Not Specified]
Type of Statistical Test Non-Inferiority
Comments The non-inferiority margin is set to 5 letters.
Statistical Test of Hypothesis P-Value 0.0162
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS mean difference
Estimated Value -2.0199
Confidence Interval (2-Sided) 95%
-4.7470 to 0.7073
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.3833
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants Maintaining Vision (<3 Lines Loss) at Week 104 Compared With Baseline
Hide Description Participants maintained 3 lines (15 letters) vision loss in BCVA (Best-corrected visual acuity) as measured by the ETDRS (Early Treatment Diabetic Retinopathy Study) letter.
Time Frame at Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
PPS (Per-protocol set): all participants in the FAS (full analysis set) without any major protocol deviation.
Arm/Group Title Early-start T&E Arm Late-start T&E Arm
Hide Arm/Group Description:
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: Percentage
93.4 96.2
3.Secondary Outcome
Title Change in BCVA From Baseline to Week 52, Baseline to Week 104, and Week 16 to Week 52
Hide Description BCVA (best corrected visual acuity) was measured by the ETDRS (Early Treatment Diabetic Retinopathy Study) letter score of 73 to 25 (= Acuity of 20/40 to 20/320) in the study eye at 4 meters; a higher score represents better functioning.
Time Frame from baseline to Week 52, baseline to Week 104, and Week 16 to Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
PPS (Per-protocol set): all participants in the FAS (full analysis set) without any major protocol deviation.
Arm/Group Title Early-start T&E Arm Late-start T&E Arm
Hide Arm/Group Description:
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
Overall Number of Participants Analyzed 106 104
Mean (Standard Deviation)
Unit of Measure: Letters
From baseline to Week 52 7.8  (9.4) 10.2  (9.3)
From baseline to Week 104 4.3  (13.4) 7.9  (11.9)
Week 16 66.7  (13.0) 69.6  (11.6)
From Week 16 to Week 52 1.3  (6.4) 2.0  (5.3)
4.Secondary Outcome
Title Percentage of Participants Maintaining Vision (<3 Lines Loss) at Week 52 Compared With Baseline
Hide Description Participants maintained 3 lines (15 letters) vision loss in BCVA (Best-corrected visual acuity) as measured by the ETDRS (Early Treatment Diabetic Retinopathy Study) letter.
Time Frame At week 52
Hide Outcome Measure Data
Hide Analysis Population Description
PPS (Per-protocol set): all participants in the FAS (full analysis set) without any major protocol deviation.
Arm/Group Title Early-start T&E Arm Late-start T&E Arm
Hide Arm/Group Description:
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: Percentage
100.0 100.0
5.Secondary Outcome
Title Percentage of Participants Gained 3-line at Week 52 and Week 104 Compared With Baseline
Hide Description Participants gained 3 lines (15 letters) in BCVA (Best-corrected visual acuity) as measured by the ETDRS (Early Treatment Diabetic Retinopathy Study) letter.
Time Frame At Week 52 and Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
PPS (Per-protocol set): all participants in the FAS (full analysis set) without any major protocol deviation.
Arm/Group Title Early-start T&E Arm Late-start T&E Arm
Hide Arm/Group Description:
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: Percentage
Week 52 19.8 27.9
Week 104 18.9 22.1
6.Secondary Outcome
Title Change in Central Retinal Thickness (CRT)
Hide Description CRT were evaluated using spectral domain Optical coherence tomograph (OCT).
Time Frame From baseline to Week 52, baseline to Week 104, Week 16 to Week 52, and Week 16 to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
PPS (Per-protocol set): all participants in the FAS (full analysis set) without any major protocol deviation.
Arm/Group Title Early-start T&E Arm Late-start T&E Arm
Hide Arm/Group Description:
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
Overall Number of Participants Analyzed 106 104
Mean (Standard Deviation)
Unit of Measure: μm
From baseline to Week 52 -164.9  (117.3) -167.1  (117.1)
From baseline to Week 104 -161.6  (135.6) -158.6  (125.1)
Week 16 321.4  (93.4) 322.5  (104.0)
From Week 16 to Week 52 -28.5  (56.3) -28.7  (54.0)
From Week 16 to Week 104 -25.1  (68.9) -20.2  (70.0)
7.Secondary Outcome
Title Number of Study Drug Injections From Baseline to Week 52 and Baseline to Week 104
Hide Description [Not Specified]
Time Frame At Week 52 and Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
PPS (Per-protocol set): all participants in the FAS (full analysis set) without any major protocol deviation.
Arm/Group Title Early-start T&E Arm Late-start T&E Arm
Hide Arm/Group Description:
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
Overall Number of Participants Analyzed 106 104
Mean (Standard Deviation)
Unit of Measure: injections
Week 52 7.1  (0.8) 8.0  (0.2)
Week 104 12.0  (2.3) 13.0  (1.8)
8.Secondary Outcome
Title Duration of Last Treatment Interval
Hide Description [Not Specified]
Time Frame Early-Start T&E: from week 16 up to Week 104 or early termination; Late-Start T&E: From end of Year 1 up to Week 104 or early termination
Hide Outcome Measure Data
Hide Analysis Population Description
PPS (Per-protocol set): all participants in the FAS (full analysis set) without any major protocol deviation.
Arm/Group Title Early-start T&E Arm Late-start T&E Arm
Hide Arm/Group Description:
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
Overall Number of Participants Analyzed 106 104
Mean (Standard Deviation)
Unit of Measure: Weeks
11.5  (3.7) 11.4  (3.7)
9.Secondary Outcome
Title Percentage of Participants Requiring Retreatment at 8 Weeks, 10 Weeks, 12 Weeks, 14 Weeks, and 16 Weeks as the Last Treatment Interval
Hide Description [Not Specified]
Time Frame at 8 weeks, 10 weeks, 12 weeks, 14 weeks, and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
PPS (Per-protocol set): all participants in the FAS (full analysis set) without any major protocol deviation.
Arm/Group Title Early-start T&E Arm Late-start T&E Arm
Hide Arm/Group Description:
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria.
Overall Number of Participants Analyzed 106 104
Measure Type: Number
Unit of Measure: percentage
<8 weeks 5.7 7.7
8 weeks 27.4 29.8
10 weeks 19.8 10.6
12 weeks 8.5 13.5
14 weeks 8.5 11.5
16 weeks 25.5 25.0
>16 weeks 4.7 1.9
Time Frame Treatment-emergent adverse events (TEAEs) were AEs that started after the first application of aflibercept up to 30 days after last study drug Injection in the study. TEAEs were collected from Week 0 till End of study/Week 104 or early termination.
Adverse Event Reporting Description Below adverse events were reported based on Safety Analysis Set (SAF), which included all participants who received any study drug in this study. The participants who dropped out after start of treatment before randomization were not allocated to a treatment arm, but were included in this SAF.
 
Arm/Group Title Early-start T&E Arm Late-start T&E Arm Treated, But Not Randomized
Hide Arm/Group Description All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 to Week 104 participants randomized to Early-start T&E arm (Treat and Extend arm) received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria. All participants during the initiation phase received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4, and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks) at Week 16. From Week 16 participants randomized to Late-start T&E arm received four 2Q8 injections. In Year 2 starting at Week 48, participants received treatment in individualized intervals of between 8 to16 weeks based on anatomical criteria. Participants were treated during the initiation phase, received Aflibercept (Eylea, BAY86-5321) 3 doses at Weeks 0, 4 and 8 followed by one dose 2Q8 (2 mg administered every 8 weeks)at Week 16, but were not randomized to a treatment arm after the initiation phase.
All-Cause Mortality
Early-start T&E Arm Late-start T&E Arm Treated, But Not Randomized
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/135 (2.22%)      4/136 (2.94%)      0/16 (0.00%)    
Hide Serious Adverse Events
Early-start T&E Arm Late-start T&E Arm Treated, But Not Randomized
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   29/135 (21.48%)      35/136 (25.74%)      3/16 (18.75%)    
Cardiac disorders       
Acute myocardial infarction * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 1/16 (6.25%)  1
Atrial fibrillation * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Atrial flutter * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Atrioventricular block * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Atrioventricular block second degree * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Cardiac arrest * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Cardiac failure congestive * 1  2/135 (1.48%)  2 0/136 (0.00%)  0 0/16 (0.00%)  0
Cor pulmonale acute * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Coronary artery stenosis * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Myocardial infarction * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Pericardial haemorrhage * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Ventricular tachycardia * 1  1/135 (0.74%)  2 0/136 (0.00%)  0 0/16 (0.00%)  0
Congestive cardiomyopathy * 1  0/135 (0.00%)  0 1/136 (0.74%)  2 0/16 (0.00%)  0
Cardiac valve disease * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Eye disorders       
Eye inflammation * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Retinal artery embolism * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Visual acuity reduced * 1  0/135 (0.00%)  0 2/136 (1.47%)  2 0/16 (0.00%)  0
Visual impairment * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Eyelid cyst * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain * 1  2/135 (1.48%)  2 0/136 (0.00%)  0 0/16 (0.00%)  0
Constipation * 1  1/135 (0.74%)  2 0/136 (0.00%)  0 0/16 (0.00%)  0
Duodenal ulcer perforation * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Gastritis * 1  1/135 (0.74%)  1 1/136 (0.74%)  1 0/16 (0.00%)  0
Gastrointestinal haemorrhage * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Haematochezia * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Ileus * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Inguinal hernia * 1  2/135 (1.48%)  2 1/136 (0.74%)  1 0/16 (0.00%)  0
Intestinal perforation * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Pancreatitis acute * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Small intestinal obstruction * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Upper gastrointestinal haemorrhage * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Large intestine polyp * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Noninfective sialoadenitis * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
General disorders       
Hernia * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Pyrexia * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Multiple organ dysfunction syndrome * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Hepatobiliary disorders       
Acute hepatic failure * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Biliary colic * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Cholangitis * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Cholecystitis * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Cholecystitis acute * 1  2/135 (1.48%)  2 2/136 (1.47%)  2 0/16 (0.00%)  0
Cholelithiasis * 1  1/135 (0.74%)  1 1/136 (0.74%)  1 0/16 (0.00%)  0
Infections and infestations       
Bronchitis * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Cystitis * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Influenza * 1  2/135 (1.48%)  2 0/136 (0.00%)  0 0/16 (0.00%)  0
Pneumonia * 1  3/135 (2.22%)  4 5/136 (3.68%)  5 0/16 (0.00%)  0
Pneumonia pseudomonal * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Sepsis * 1  1/135 (0.74%)  1 1/136 (0.74%)  1 0/16 (0.00%)  0
Enterococcal sepsis * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Infective exacerbation of chronic obstructive airways disease * 1  3/135 (2.22%)  4 0/136 (0.00%)  0 0/16 (0.00%)  0
Adenovirus infection * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Injury, poisoning and procedural complications       
Concussion * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Facial bones fracture * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Hip fracture * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Rib fracture * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Splenic rupture * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Traumatic fracture * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Inflammation of wound * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Pelvic fracture * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Metabolism and nutrition disorders       
Fluid overload * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Intervertebral disc protrusion * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Intervertebral disc disorder * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Fracture pain * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Adenocarcinoma of colon * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Basal cell carcinoma * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Bladder neoplasm * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Breast cancer * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Chronic myeloid leukaemia * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Lung neoplasm malignant * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Lung neoplasm * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Epithelioid mesothelioma * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Papillary renal cell carcinoma * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Nervous system disorders       
Carotid artery stenosis * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Cerebral infarction * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Cerebrovascular accident * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 2/16 (12.50%)  2
Haemorrhagic stroke * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Hemiplegia * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Vertebrobasilar insufficiency * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Psychiatric disorders       
Suicide attempt * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Renal and urinary disorders       
Acute kidney injury * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
End stage renal disease * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Chronic obstructive pulmonary disease * 1  1/135 (0.74%)  2 0/136 (0.00%)  0 0/16 (0.00%)  0
Cough * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Dyspnoea * 1  0/135 (0.00%)  0 2/136 (1.47%)  3 0/16 (0.00%)  0
Pleural effusion * 1  0/135 (0.00%)  0 1/136 (0.74%)  2 0/16 (0.00%)  0
Pulmonary embolism * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Surgical and medical procedures       
Implantable defibrillator replacement * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Vascular disorders       
Aortic aneurysm * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Aortic dissection * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Haematoma * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Hypovolaemic shock * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Intermittent claudication * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Deep vein thrombosis * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
Extremity necrosis * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Peripheral arterial occlusive disease * 1  1/135 (0.74%)  1 0/136 (0.00%)  0 0/16 (0.00%)  0
Peripheral artery stenosis * 1  0/135 (0.00%)  0 1/136 (0.74%)  1 0/16 (0.00%)  0
1
Term from vocabulary, MedDRA (22.0)
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Early-start T&E Arm Late-start T&E Arm Treated, But Not Randomized
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   93/135 (68.89%)      80/136 (58.82%)      10/16 (62.50%)    
Eye disorders       
Blepharitis * 1  2/135 (1.48%)  6 11/136 (8.09%)  25 0/16 (0.00%)  0
Cataract * 1  9/135 (6.67%)  14 8/136 (5.88%)  13 0/16 (0.00%)  0
Cataract nuclear * 1  2/135 (1.48%)  4 7/136 (5.15%)  16 0/16 (0.00%)  0
Conjunctival haemorrhage * 1  20/135 (14.81%)  26 18/136 (13.24%)  20 0/16 (0.00%)  0
Corneal erosion * 1  5/135 (3.70%)  6 2/136 (1.47%)  3 1/16 (6.25%)  1
Dry eye * 1  6/135 (4.44%)  11 11/136 (8.09%)  18 0/16 (0.00%)  0
Erythema of eyelid * 1  0/135 (0.00%)  0 0/136 (0.00%)  0 1/16 (6.25%)  2
Macular degeneration * 1  6/135 (4.44%)  6 5/136 (3.68%)  5 1/16 (6.25%)  1
Punctate keratitis * 1  10/135 (7.41%)  23 5/136 (3.68%)  9 1/16 (6.25%)  1
Retinal haemorrhage * 1  4/135 (2.96%)  4 6/136 (4.41%)  7 2/16 (12.50%)  2
Swelling of eyelid * 1  0/135 (0.00%)  0 0/136 (0.00%)  0 1/16 (6.25%)  2
Visual acuity reduced * 1  21/135 (15.56%)  24 17/136 (12.50%)  19 1/16 (6.25%)  1
Visual impairment * 1  8/135 (5.93%)  11 4/136 (2.94%)  4 0/16 (0.00%)  0
Vitreous floaters * 1  8/135 (5.93%)  8 4/136 (2.94%)  5 0/16 (0.00%)  0
Vitreous adhesions * 1  1/135 (0.74%)  1 2/136 (1.47%)  2 1/16 (6.25%)  1
Choroidal neovascularisation * 1  7/135 (5.19%)  7 5/136 (3.68%)  5 0/16 (0.00%)  0
Retinal pigment epithelial tear * 1  3/135 (2.22%)  3 2/136 (1.47%)  2 1/16 (6.25%)  1
Neovascular age-related macular degeneration * 1  15/135 (11.11%)  15 14/136 (10.29%)  14 1/16 (6.25%)  1
Macular fibrosis * 1  2/135 (1.48%)  2 6/136 (4.41%)  6 1/16 (6.25%)  1
Infections and infestations       
Gastroenteritis * 1  0/135 (0.00%)  0 3/136 (2.21%)  3 1/16 (6.25%)  1
Influenza * 1  11/135 (8.15%)  12 12/136 (8.82%)  13 0/16 (0.00%)  0
Nasopharyngitis * 1  18/135 (13.33%)  21 17/136 (12.50%)  22 0/16 (0.00%)  0
Injury, poisoning and procedural complications       
Foreign body in eye * 1  0/135 (0.00%)  0 0/136 (0.00%)  0 1/16 (6.25%)  1
Post procedural swelling * 1  0/135 (0.00%)  0 0/136 (0.00%)  0 1/16 (6.25%)  1
Metabolism and nutrition disorders       
Dyslipidaemia * 1  0/135 (0.00%)  0 0/136 (0.00%)  0 1/16 (6.25%)  1
Musculoskeletal and connective tissue disorders       
Back pain * 1  8/135 (5.93%)  9 1/136 (0.74%)  1 0/16 (0.00%)  0
Musculoskeletal pain * 1  1/135 (0.74%)  1 2/136 (1.47%)  2 1/16 (6.25%)  1
Vascular disorders       
Hypertension * 1  13/135 (9.63%)  15 11/136 (8.09%)  11 0/16 (0.00%)  0
1
Term from vocabulary, MedDRA (22.0)
*
Indicates events were collected by non-systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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
Layout table for Results Point of Contact information
Name/Title: Therapeutic Area Head
Organization: Bayer
Phone: (+) 1-888-8422937
EMail: clinical-trials-contact@bayer.com
Layout table for additonal information
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02581891    
Other Study ID Numbers: 17508
2014-003132-39 ( EudraCT Number )
First Submitted: October 20, 2015
First Posted: October 21, 2015
Results First Submitted: April 21, 2020
Results First Posted: May 21, 2020
Last Update Posted: May 21, 2020