VIOLET: Efficacy and Safety of Three Different Aflibercept Regimens in Subjects With Diabetic Macular Edema (DME)
Sponsor
Bayer (Industry)
Overall Status
Completed
CT.gov ID
NCT02818998
Collaborator
(none)
463
64
3
34.2
7.2
0.2
Study Details
Study Description
Brief Summary
To evaluate the efficacy of long-term treatment with 2 mg aflibercept via different intravitreal (IVT) treatment regimens to participants with DME pretreated with 2 mg aflibercept every 8 weeks after 5 initial monthly injections for approximately 1 year or more (according to the EU label for the first year of treatment)
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Study Design
Study Type:
Interventional
Actual Enrollment
:
463 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-label, Randomized, Active-controlled, Parallel-group, Phase-3b Study of the Efficacy, Safety, and Tolerability of Three Different Treatment Regimens of 2 mg Aflibercept Administered by Intravitreal Injections to Subjects With Diabetic Macular Edema (DME)
Actual Study Start Date
:
Nov 16, 2016
Actual Primary Completion Date
:
Nov 13, 2018
Actual Study Completion Date
:
Sep 24, 2019
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Aflibercept 2 mg fixed Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks |
Drug: Aflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)
|
| Experimental: Aflibercept 2 mg flexible Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 week |
Drug: Aflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)
|
| Experimental: Aflibercept 2 mg PRN Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) |
Drug: Aflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)
|
Outcome Measures
Primary Outcome Measures
- Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 [From baseline to Week 52]
Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity.
Secondary Outcome Measures
- Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 52 [From baseline to week 52]
Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT).
- Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 [From baseline to week 52]
Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity
- Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 [From baseline to Week 100]
Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity.
- Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 100 [From baseline to Week 100]
Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT).
- Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 [From baseline to Week 100]
Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity
- Number of Participants With Treatment-emergent Adverse Event (TEAE) [Up to Week 100]
AEs that started after the first application of aflibercept under this protocol until 30 days after the last dose of study drug administration
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
The subject's history of aflibercept treatment met all of the following:
-
Treatment in the study eye was initiated with five monthly (-1 week /+2 weeks) doses of 2 mg aflibercept and improvements of visual and anatomic outcomes were observed and documented.
-
Following the above initiation phase, the intervals between treatments were between 6 weeks and 12 weeks (one exception was allowed).
-
The interval between the last 2 pre-study injections was ≥ 8 weeks, and visual and anatomic outcomes had been stable over this interval.
-
The subject received the last intravitreal (IVT) injection of aflibercept in the study eye 8 weeks (±10 days) before the first planned treatment /randomization in this study.
-
Total prior treatment duration with aflibercept (i.e. from first aflibercept treatment ever to enrollment into this study) was 1 year or longer.
To be met at initiation of pre-study aflibercept treatment:
-
Type 1 or 2 diabetes mellitus (DM)
-
Diagnosis of diabetic macular edema (DME) secondary to DM involving the center of the macula (defined as the area of the center subfield on optical coherence tomography [OCT]) in the study eye
-
Decrease in vision determined to be primarily the result of DME in the study eye
-
Best corrected visual acuity (BCVA) in the study eye of Early Treatment Diabetic Retinopathy Study (ETDRS) letter score 73 to 24
Exclusion Criteria:
At initiation of pre-study aflibercept treatment:
- Previous treatment with anti-angiogenic drugs in study eye (e.g., pegaptanib sodium, bevacizumab, ranibizumab, or aflibercept) within the last 12 weeks before initiation of aflibercept pre-study treatment
At initiation of pre-study aflibercept treatment, screening for this study, and baseline for this study:
-
Prior treatment of the study eye with long acting steroids, either periocular or intraocular, in the preceding 120 days or Iluvien intravitreal implant at any time
-
Active proliferative diabetic retinopathy, current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment in the study eye
-
Cataract surgery or any other intraocular surgery within 90 days of aflibercept treatment in the study eye
-
Ocular inflammation (including trace or above) or history of uveitis in the study eye
-
Structural damage to the center of the macula in the study eye that was likely to preclude improvement in BCVA following the resolution of macular edema including atrophy of the retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia or organized hard exudates
-
Concurrent disease in the study eye, other than DME, that could compromise visual acuity, require medical or surgical intervention during the study period, or could confound interpretation of the results (including advanced glaucoma, retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause)
-
Uncontrolled DM as defined by hemoglobin (Hb) A1c > 12.0% at screening and baseline for this study
-
Any ocular or periocular infection in the preceding 4 weeks in either eye
-
History of either cerebral vascular accident and/or myocardial infarction within 180 days before aflibercept treatment
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Graz | Steiermark | Austria | 8036 | |
| 2 | Wien | Austria | 1090 | ||
| 3 | Halifax | Nova Scotia | Canada | B3H 2Y9 | |
| 4 | Mississauga | Ontario | Canada | L4W 1W9 | |
| 5 | Toronto | Ontario | Canada | M3C 0G9 | |
| 6 | Montreal | Quebec | Canada | H4P 2S4 | |
| 7 | Sherbrooke | Quebec | Canada | J1G 2V4 | |
| 8 | Hradec Kralove | Czechia | 500 05 | ||
| 9 | Praha 10 | Czechia | 100 34 | ||
| 10 | Creteil Cedex | France | 94010 | ||
| 11 | Darmstadt | Hessen | Germany | 64297 | |
| 12 | Frankfurt | Hessen | Germany | 60596 | |
| 13 | Marburg | Hessen | Germany | 35043 | |
| 14 | Göttingen | Niedersachsen | Germany | 37075 | |
| 15 | Bonn | Nordrhein-Westfalen | Germany | 53105 | |
| 16 | Köln | Nordrhein-Westfalen | Germany | 50924 | |
| 17 | Dresden | Sachsen | Germany | 01307 | |
| 18 | Budapest | Hungary | 1085 | ||
| 19 | Budapest | Hungary | 1106 | ||
| 20 | Budapest | Hungary | 1133 | ||
| 21 | Debrecen | Hungary | 4032 | ||
| 22 | Pecs | Hungary | 7621 | ||
| 23 | Roma | Lazio | Italy | 00133 | |
| 24 | Genova | Liguria | Italy | 16132 | |
| 25 | Milano | Lombardia | Italy | 20122 | |
| 26 | Milano | Lombardia | Italy | 20132 | |
| 27 | Torino | Piemonte | Italy | 10122 | |
| 28 | Cagliari | Sardegna | Italy | 09124 | |
| 29 | Sassari | Sardegna | Italy | 07100 | |
| 30 | Firenze | Toscana | Italy | 50134 | |
| 31 | Padova | Veneto | Italy | 35128 | |
| 32 | Kaunas | Lithuania | LT-50009 | ||
| 33 | Vilnius | Lithuania | LT-08661 | ||
| 34 | Bydgoszcz | Poland | 85-631 | ||
| 35 | Gdansk | Poland | 80-809 | ||
| 36 | Katowice | Poland | 40-594 | ||
| 37 | Krakow | Poland | 31-501 | ||
| 38 | Lodz | Poland | 91-134 | ||
| 39 | Lublin | Poland | 20-081 | ||
| 40 | Poznan | Poland | 61-285 | ||
| 41 | Warszawa | Poland | 01-013 | ||
| 42 | Warszawa | Poland | 04-141 | ||
| 43 | Vila Franca de Xira | Lisboa | Portugal | 2600-178 | |
| 44 | Coimbra | Portugal | 3000-548 | ||
| 45 | Leiria | Portugal | 2410-197 | ||
| 46 | Lisboa | Portugal | 1649-035 | ||
| 47 | Porto | Portugal | 4200-319 | ||
| 48 | Bratislava | Slovakia | 826 06 | ||
| 49 | Bratislava | Slovakia | 851 07 | ||
| 50 | Nitra | Slovakia | 949 01 | ||
| 51 | Zilina | Slovakia | 01207 | ||
| 52 | Zvolen | Slovakia | 960 01 | ||
| 53 | L'Hospitalet de Llobregat | Barcelona | Spain | 08907 | |
| 54 | Sant Cugat del Vallés | Barcelona | Spain | 08195 | |
| 55 | Albacete | Spain | 02006 | ||
| 56 | Barcelona | Spain | 08035 | ||
| 57 | Barcelona | Spain | 08036 | ||
| 58 | Valencia | Spain | 46014 | ||
| 59 | Bern | Switzerland | |||
| 60 | Genève | Switzerland | 1204 | ||
| 61 | Southampton | Hampshire | United Kingdom | SO16 6YD | |
| 62 | Sunderland | Tyne And Wear | United Kingdom | SR2 9HP | |
| 63 | Leeds | West Yorkshire | United Kingdom | LS9 7TF | |
| 64 | London | United Kingdom | EC1V 2PD |
Sponsors and Collaborators
- Bayer
Investigators
- Study Director: Bayer Study Director, Bayer
Study Documents (Full-Text)
More Information
Additional Information:
- Click here to find results for studies related to Bayer Healthcare products
- Click here to find information about studies related to Bayer Healthcare products conducted in Europe
Publications
None provided.Responsible Party:
Bayer
ClinicalTrials.gov Identifier:
NCT02818998
Other Study ID Numbers:
- 17613
- 2014-004938-25
First Posted:
Jun 30, 2016
Last Update Posted:
Jul 31, 2020
Last Verified:
Jul 1, 2020
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
Yes
Keywords provided by Bayer
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | Study was conducted at multiple centers in 14 countries between 16-Nov-2016 (first participant first visit) and 24-Sep-2019 (last participant last visit). |
|---|---|
| Pre-assignment Detail | A total of 500 participants were screened in this study. Of these, 37 participants did not enter the treatment period (31 were screening failures; 3 were lost to follow-up; 2 had an adverse event (AE) and 1 was not randomized due to an "other" reason). A total of 463 participants were randomized and received treatment. |
| Arm/Group Title | Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN |
|---|---|---|---|
| Arm/Group Description | Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 weeks | Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) |
| Period Title: Overall Study | |||
| STARTED | 155 | 154 | 154 |
| Completed Week 52 Visit | 144 | 146 | 140 |
| COMPLETED | 137 | 138 | 136 |
| NOT COMPLETED | 18 | 16 | 18 |
Baseline Characteristics
| Arm/Group Title | Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN | Total |
|---|---|---|---|---|
| Arm/Group Description | Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 weeks | Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) | Total of all reporting groups |
| Overall Participants | 155 | 154 | 154 | 463 |
| Age (Years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [Years] |
64.3
(8.7)
|
64.8
(10.1)
|
65.4
(9.3)
|
64.8
(9.4)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
55
35.5%
|
59
38.3%
|
64
41.6%
|
178
38.4%
|
| Male |
100
64.5%
|
95
61.7%
|
90
58.4%
|
285
61.6%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
1
0.6%
|
2
1.3%
|
4
2.6%
|
7
1.5%
|
| Not Hispanic or Latino |
144
92.9%
|
142
92.2%
|
142
92.2%
|
428
92.4%
|
| Unknown or Not Reported |
10
6.5%
|
10
6.5%
|
8
5.2%
|
28
6%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
2
1.3%
|
1
0.6%
|
0
0%
|
3
0.6%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
1
0.6%
|
0
0%
|
0
0%
|
1
0.2%
|
| White |
141
91%
|
144
93.5%
|
147
95.5%
|
432
93.3%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
11
7.1%
|
9
5.8%
|
7
4.5%
|
27
5.8%
|
| Best Corrected Visual Acuity (BCVA) (Scores on a scale) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [Scores on a scale] |
72.8
(10.38)
|
72.5
(11.35)
|
71.0
(10.87)
|
72.1
(10.88)
|
| Central Retinal Thickness (CRT) (Microns) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [Microns] |
289.8
(66.46)
|
285.3
(76.01)
|
294.5
(80.72)
|
289.9
(74.55)
|
Outcome Measures
| Title | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 |
|---|---|
| Description | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity. |
| Time Frame | From baseline to Week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full Analysis Set (FAS): included all randomized participants who received any study drug and had a baseline BCVA assessment and at least one post-baseline BCVA assessment. |
| Arm/Group Title | Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN |
|---|---|---|---|
| Arm/Group Description | Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 weeks | Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) |
| Measure Participants | 153 | 152 | 153 |
| Mean (Standard Deviation) [Scores on a scale] |
0.4
(6.7)
|
0.5
(6.7)
|
1.7
(6.8)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg Extended |
|---|---|---|
| Comments | Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | Non-inferiority margin: 4 letters | |
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Non-inferiority was demonstrated if the p-value (adjusted for multiplicity using the Hochberg procedure) was < 0.025 | |
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares mean difference |
| Estimated Value | 0.01 | |
| Confidence Interval |
(2-Sided) 95% -1.46 to 1.47 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg PRN |
|---|---|---|
| Comments | Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | Non-inferiority margin: 4 letters | |
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | Non-inferiority was demonstrated if the p-value (adjusted for multiplicity using the Hochberg procedure) was < 0.025 | |
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares mean difference |
| Estimated Value | 0.95 | |
| Confidence Interval |
(2-Sided) 95% -0.52 to 2.42 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 52 |
|---|---|
| Description | Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT). |
| Time Frame | From baseline to week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in FAS taken into account for this analysis |
| Arm/Group Title | Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN |
|---|---|---|---|
| Arm/Group Description | Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 weeks | Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) |
| Measure Participants | 147 | 147 | 153 |
| Mean (Standard Deviation) [Microns] |
-18.8
(45.5)
|
-2.1
(56.2)
|
2.2
(77.8)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg Extended |
|---|---|---|
| Comments | Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0105 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Square mean difference |
| Estimated Value | 14.38 | |
| Confidence Interval |
(2-Sided) 95% 3.39 to 25.37 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg PRN |
|---|---|---|
| Comments | Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0023 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Square mean difference |
| Estimated Value | 21.22 | |
| Confidence Interval |
(2-Sided) 95% 7.65 to 34.80 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 52 |
|---|---|
| Description | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity |
| Time Frame | From baseline to week 52 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full Analysis Set (FAS): included all randomized participants who received any study drug and had a baseline BCVA assessment and at least one post-baseline BCVA assessment |
| Arm/Group Title | Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN |
|---|---|---|---|
| Arm/Group Description | Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 weeks | Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) |
| Measure Participants | 153 | 152 | 153 |
| ≥15 letter gain |
4
2.6%
|
5
3.2%
|
4
2.6%
|
| ≥10 letter gain |
10
6.5%
|
14
9.1%
|
13
8.4%
|
| ≥30 letter loss |
1
0.6%
|
0
0%
|
0
0%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg Extended |
|---|---|---|
| Comments | ≥ 15 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | 0.68 | |
| Confidence Interval |
(2-Sided) 95% -3.14 to 4.49 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg Extended |
|---|---|---|
| Comments | ≥10 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | 2.66 | |
| Confidence Interval |
(2-Sided) 95% -3.40 to 8.73 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg Extended |
|---|---|---|
| Comments | ≥30 letter loss: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | -0.66 | |
| Confidence Interval |
(2-Sided) 95% -1.94 to 0.63 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg PRN |
|---|---|---|
| Comments | ≥15 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | -0.13 | |
| Confidence Interval |
(2-Sided) 95% -3.68 to 3.41 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg PRN |
|---|---|---|
| Comments | ≥10 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | 1.72 | |
| Confidence Interval |
(2-Sided) 95% -4.10 to 7.54 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg PRN |
|---|---|---|
| Comments | ≥30 letter loss: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | -0.68 | |
| Confidence Interval |
(2-Sided) 95% -2.00 to 0.65 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 |
|---|---|
| Description | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity. |
| Time Frame | From baseline to Week 100 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full Analysis Set (FAS): included all randomized participants who received any study drug and had a baseline BCVA assessment and at least one post-baseline BCVA assessment. |
| Arm/Group Title | Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN |
|---|---|---|---|
| Arm/Group Description | Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 weeks | Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) |
| Measure Participants | 153 | 152 | 153 |
| Mean (Standard Deviation) [Scores on a scale] |
0.1
(7.2)
|
-0.1
(9.1)
|
1.8
(9.0)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg Extended |
|---|---|---|
| Comments | Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | Non-inferiority margin: 4 letters | |
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares mean difference |
| Estimated Value | -0.30 | |
| Confidence Interval |
(2-Sided) 95% -2.13 to 1.52 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg PRN |
|---|---|---|
| Comments | Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Non-Inferiority | |
| Comments | Non-inferiority margin: 4 letters | |
| Statistical Test of Hypothesis | p-Value | <0.0001 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Squares mean difference |
| Estimated Value | 1.39 | |
| Confidence Interval |
(2-Sided) 95% -0.40 to 3.19 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 100 |
|---|---|
| Description | Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT). |
| Time Frame | From baseline to Week 100 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Participants in FAS taken into account for this analysis |
| Arm/Group Title | Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN |
|---|---|---|---|
| Arm/Group Description | Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 weeks | Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) |
| Measure Participants | 147 | 147 | 153 |
| Mean (Standard Deviation) [Microns] |
-15.5
(64.3)
|
2.3
(81.8)
|
-13.9
(74.4)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg Extended |
|---|---|---|
| Comments | Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0416 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Square mean difference |
| Estimated Value | 16.14 | |
| Confidence Interval |
(2-Sided) 95% 0.62 to 31.66 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg PRN |
|---|---|---|
| Comments | Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.5524 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Least Square mean difference |
| Estimated Value | 4.12 | |
| Confidence Interval |
(2-Sided) 95% -9.52 to 17.77 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at Week 100 |
|---|---|
| Description | Best Corrected Visual Acuity (BCVA) was measured in the study eye by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score starting at 4 meters. The ETDRS chart includes 70 letters in total and the letter score ranges from 0 to 100. More letters read correctly results in a higher letter score, which represents better visual acuity |
| Time Frame | From baseline to Week 100 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set (FAS) |
| Arm/Group Title | Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN |
|---|---|---|---|
| Arm/Group Description | Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 weeks | Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) |
| Measure Participants | 153 | 152 | 153 |
| ≥15 letter gain |
3
1.9%
|
4
2.6%
|
6
3.9%
|
| ≥10 letter gain |
10
6.5%
|
17
11%
|
22
14.3%
|
| ≥30 letter loss |
1
0.6%
|
2
1.3%
|
2
1.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg Extended |
|---|---|---|
| Comments | ≥ 15 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | 0.67 | |
| Confidence Interval |
(2-Sided) 95% -2.72 to 4.05 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg Extended |
|---|---|---|
| Comments | ≥10 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | 4.63 | |
| Confidence Interval |
(2-Sided) 95% -1.73 to 10.98 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg Extended |
|---|---|---|
| Comments | ≥30 letter loss: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | 0.66 | |
| Confidence Interval |
(2-Sided) 95% -1.56 to 2.87 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg PRN |
|---|---|---|
| Comments | ≥15 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | 1.90 | |
| Confidence Interval |
(2-Sided) 95% -1.89 to 5.69 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 5
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg PRN |
|---|---|---|
| Comments | ≥10 letter gain: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | 7.54 | |
| Confidence Interval |
(2-Sided) 95% 0.81 to 14.28 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Statistical Analysis 6
| Statistical Analysis Overview | Comparison Group Selection | Aflibercept 2 mg Fixed, Aflibercept 2 mg PRN |
|---|---|---|
| Comments | ≥30 letter loss: Aflibercept 2 mg fixed was regarded as the reference arm | |
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Treatment Difference |
| Estimated Value | 0.63 | |
| Confidence Interval |
(2-Sided) 95% -1.61 to 2.88 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Number of Participants With Treatment-emergent Adverse Event (TEAE) |
|---|---|
| Description | AEs that started after the first application of aflibercept under this protocol until 30 days after the last dose of study drug administration |
| Time Frame | Up to Week 100 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Safety analysis set (SAF): included all participants who received any study drug under the protocol. |
| Arm/Group Title | Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN |
|---|---|---|---|
| Arm/Group Description | Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | Participants received flexible dosing of 2 mg aflibercept at injection intervals of ≥8 weeks | Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) |
| Measure Participants | 155 | 154 | 154 |
| Count of Participants [Participants] |
129
83.2%
|
128
83.1%
|
129
83.8%
|
Adverse Events
| Time Frame | After the first application of Aflibercept under this protocol and within 30 days after the last dose of study drug administration, assessed up to Week 100. | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN | |||
| Arm/Group Description | Participants received fixed dosing of 2 mg aflibercept at injection intervals of 8 weeks | Participants received flexible dosing of 2 mg aflibercept at injection intervals of >=8 week | Participants received monthly monitoring with 2 mg aflibercept injection pro re nata (PRN, as needed) | |||
All Cause Mortality |
||||||
| Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/155 (1.9%) | 6/154 (3.9%) | 8/154 (5.2%) | |||
Serious Adverse Events |
||||||
| Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 35/155 (22.6%) | 38/154 (24.7%) | 37/154 (24%) | |||
| Blood and lymphatic system disorders | ||||||
| Iron deficiency anaemia | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Thrombocytopenia | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Cardiac disorders | ||||||
| Acute myocardial infarction | 1/155 (0.6%) | 1 | 2/154 (1.3%) | 2 | 2/154 (1.3%) | 3 |
| Angina pectoris | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 1/154 (0.6%) | 2 |
| Angina unstable | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Arteriosclerosis coronary artery | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Atrial fibrillation | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Atrioventricular block complete | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Atrioventricular block second degree | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Bradycardia | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Cardiac arrest | 0/155 (0%) | 0 | 3/154 (1.9%) | 3 | 1/154 (0.6%) | 1 |
| Cardiac failure | 1/155 (0.6%) | 1 | 2/154 (1.3%) | 2 | 2/154 (1.3%) | 2 |
| Cardiac failure acute | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Cardiac failure chronic | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Cardiac failure congestive | 0/155 (0%) | 0 | 2/154 (1.3%) | 2 | 0/154 (0%) | 0 |
| Cardiogenic shock | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Coronary artery disease | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Coronary artery occlusion | 2/155 (1.3%) | 2 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Myocardial infarction | 5/155 (3.2%) | 5 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Myocardial ischaemia | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 1/154 (0.6%) | 1 |
| Ventricular tachycardia | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Acute coronary syndrome | 2/155 (1.3%) | 2 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Ear and labyrinth disorders | ||||||
| Vertigo | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Neurosensory hypoacusis | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Eye disorders | ||||||
| Cataract | 0/155 (0%) | 0 | 3/154 (1.9%) | 4 | 1/154 (0.6%) | 1 |
| Cataract nuclear | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Cataract subcapsular | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Posterior capsule opacification | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Retinal detachment | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 1/154 (0.6%) | 1 |
| Vitreous haemorrhage | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Choroidal neovascularisation | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Macular fibrosis | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Gastrointestinal haemorrhage | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Inguinal hernia | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Pancreatitis acute | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Large intestine polyp | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Small intestinal haemorrhage | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| General disorders | ||||||
| Chest pain | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Death | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Fatigue | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Non-cardiac chest pain | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Hepatobiliary disorders | ||||||
| Cholecystitis acute | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Cholelithiasis | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Hepatic failure | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Infections and infestations | ||||||
| Cellulitis | 2/155 (1.3%) | 3 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Cystitis | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Endocarditis | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Erysipelas | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Gangrene | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 1/154 (0.6%) | 1 |
| Herpes zoster | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Influenza | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Osteomyelitis | 2/155 (1.3%) | 2 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Pneumonia | 1/155 (0.6%) | 1 | 2/154 (1.3%) | 2 | 2/154 (1.3%) | 2 |
| Postoperative wound infection | 1/155 (0.6%) | 1 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Pyelonephritis acute | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Sepsis | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Urinary tract infection | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Wound infection | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Urosepsis | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Peritonsillitis | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Arthritis bacterial | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 1/154 (0.6%) | 2 |
| Biliary sepsis | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Diabetic foot infection | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Injury, poisoning and procedural complications | ||||||
| Ankle fracture | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Facial bones fracture | 1/155 (0.6%) | 3 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Fall | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Femoral neck fracture | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Femur fracture | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Head injury | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Hip fracture | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Jaw fracture | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Radius fracture | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Subdural haematoma | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Lower limb fracture | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Investigations | ||||||
| Angiocardiogram | 0/155 (0%) | 0 | 2/154 (1.3%) | 2 | 0/154 (0%) | 0 |
| Metabolism and nutrition disorders | ||||||
| Diabetes mellitus | 3/155 (1.9%) | 3 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Diabetic ketoacidosis | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Hypercholesterolaemia | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Hyperglycaemia | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Hypoglycaemia | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Obesity | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Tetany | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Diabetic metabolic decompensation | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 1/154 (0.6%) | 1 |
| Cardiometabolic syndrome | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Dupuytren's contracture | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Lumbar spinal stenosis | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Adenocarcinoma of colon | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Benign lung neoplasm | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Breast cancer stage III | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Bronchial carcinoma | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Meningioma | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Metastases to bone | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Prostate cancer stage IV | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Metastatic bronchial carcinoma | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Benign spleen tumour | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Prostate cancer | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Hepatic cancer | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Nervous system disorders | ||||||
| Epilepsy | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Haemorrhagic stroke | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Transient ischaemic attack | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 2/154 (1.3%) | 2 |
| Ischaemic stroke | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 1/154 (0.6%) | 1 |
| Lacunar stroke | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Product Issues | ||||||
| Device loosening | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Psychiatric disorders | ||||||
| Completed suicide | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Renal and urinary disorders | ||||||
| Dysuria | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Nephropathy | 0/155 (0%) | 0 | 1/154 (0.6%) | 2 | 0/154 (0%) | 0 |
| Urinary retention | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Diabetic nephropathy | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Renal impairment | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Chronic kidney disease | 1/155 (0.6%) | 1 | 1/154 (0.6%) | 1 | 1/154 (0.6%) | 1 |
| Acute kidney injury | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| End stage renal disease | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Reproductive system and breast disorders | ||||||
| Benign prostatic hyperplasia | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 2/154 (1.3%) | 2 |
| Uterine prolapse | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Acute respiratory failure | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Dyspnoea | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Pneumothorax | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Pulmonary oedema | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Skin and subcutaneous tissue disorders | ||||||
| Diabetic neuropathic ulcer | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Skin ulcer | 1/155 (0.6%) | 1 | 2/154 (1.3%) | 2 | 0/154 (0%) | 0 |
| Diabetic foot | 1/155 (0.6%) | 1 | 1/154 (0.6%) | 1 | 3/154 (1.9%) | 3 |
| Ischaemic skin ulcer | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Surgical and medical procedures | ||||||
| Angioplasty | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Cardiac pacemaker insertion | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Toe amputation | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 1/154 (0.6%) | 1 |
| Coronary arterial stent insertion | 0/155 (0%) | 0 | 1/154 (0.6%) | 1 | 0/154 (0%) | 0 |
| Cardiac rehabilitation therapy | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Rehabilitation therapy | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Abdominal hernia repair | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Heart valve replacement | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Cataract operation | 2/155 (1.3%) | 2 | 1/154 (0.6%) | 1 | 1/154 (0.6%) | 1 |
| Intraocular lens implant | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Peripheral artery bypass | 0/155 (0%) | 0 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Vascular disorders | ||||||
| Aortic stenosis | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Hypertension | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Peripheral ischaemia | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 1/154 (0.6%) | 1 |
| Peripheral artery occlusion | 0/155 (0%) | 0 | 1/154 (0.6%) | 2 | 0/154 (0%) | 0 |
| Peripheral arterial occlusive disease | 1/155 (0.6%) | 2 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
| Arterial occlusive disease | 1/155 (0.6%) | 1 | 0/154 (0%) | 0 | 0/154 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||||
| Aflibercept 2 mg Fixed | Aflibercept 2 mg Extended | Aflibercept 2 mg PRN | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 97/155 (62.6%) | 85/154 (55.2%) | 98/154 (63.6%) | |||
| Eye disorders | ||||||
| Cataract | 27/155 (17.4%) | 37 | 29/154 (18.8%) | 41 | 24/154 (15.6%) | 35 |
| Cataract cortical | 8/155 (5.2%) | 11 | 7/154 (4.5%) | 10 | 6/154 (3.9%) | 10 |
| Cataract nuclear | 9/155 (5.8%) | 11 | 0/154 (0%) | 0 | 7/154 (4.5%) | 8 |
| Cataract subcapsular | 7/155 (4.5%) | 10 | 9/154 (5.8%) | 10 | 8/154 (5.2%) | 10 |
| Diabetic retinal oedema | 12/155 (7.7%) | 15 | 13/154 (8.4%) | 17 | 14/154 (9.1%) | 17 |
| Diabetic retinopathy | 14/155 (9%) | 18 | 14/154 (9.1%) | 18 | 18/154 (11.7%) | 23 |
| Macular oedema | 8/155 (5.2%) | 10 | 11/154 (7.1%) | 14 | 17/154 (11%) | 32 |
| Maculopathy | 3/155 (1.9%) | 4 | 1/154 (0.6%) | 2 | 13/154 (8.4%) | 20 |
| Posterior capsule opacification | 5/155 (3.2%) | 6 | 9/154 (5.8%) | 9 | 10/154 (6.5%) | 12 |
| Retinal haemorrhage | 4/155 (2.6%) | 7 | 3/154 (1.9%) | 3 | 10/154 (6.5%) | 21 |
| Visual acuity reduced | 25/155 (16.1%) | 42 | 22/154 (14.3%) | 30 | 22/154 (14.3%) | 30 |
| Cystoid macular oedema | 14/155 (9%) | 25 | 12/154 (7.8%) | 17 | 10/154 (6.5%) | 15 |
| Macular fibrosis | 7/155 (4.5%) | 7 | 6/154 (3.9%) | 7 | 10/154 (6.5%) | 11 |
| Infections and infestations | ||||||
| Conjunctivitis | 4/155 (2.6%) | 7 | 1/154 (0.6%) | 1 | 8/154 (5.2%) | 12 |
| Influenza | 8/155 (5.2%) | 8 | 3/154 (1.9%) | 3 | 8/154 (5.2%) | 8 |
| Nasopharyngitis | 14/155 (9%) | 18 | 14/154 (9.1%) | 18 | 17/154 (11%) | 24 |
| Investigations | ||||||
| Intraocular pressure increased | 11/155 (7.1%) | 14 | 4/154 (2.6%) | 5 | 11/154 (7.1%) | 14 |
| Metabolism and nutrition disorders | ||||||
| Diabetes mellitus | 24/155 (15.5%) | 26 | 10/154 (6.5%) | 10 | 15/154 (9.7%) | 15 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Therapeutic Area Head |
|---|---|
| Organization | Bayer |
| Phone | (+) 1-888-8422937 |
| clinical-trials-contact@bayer.com |
Responsible Party:
Bayer
ClinicalTrials.gov Identifier:
NCT02818998
Other Study ID Numbers:
- 17613
- 2014-004938-25
First Posted:
Jun 30, 2016
Last Update Posted:
Jul 31, 2020
Last Verified:
Jul 1, 2020