Efficacy and Safety of Three Different Aflibercept Regimens in Subjects With Diabetic Macular Edema (DME) (VIOLET)

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)

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)

Study Overview

• Status: Completed
• Conditions: Macular Edema
• Intervention / Treatment: Drug: Aflibercept (Eylea, VEGF Trap-Eye, BAY86-5321)

• Study Type: Interventional
• Enrollment (Actual): 463
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria, 1090
  • Steiermark
    • Graz, Steiermark, Austria, 8036
• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
  • Ontario
    • Mississauga, Ontario, Canada, L4W 1W9
    • Toronto, Ontario, Canada, M3C 0G9
  • Quebec
    • Montreal, Quebec, Canada, H4P 2S4
    • Sherbrooke, Quebec, Canada, J1G 2V4
• Czechia
  • Hradec Kralove, Czechia, 500 05
  • Praha 10, Czechia, 100 34
• France
  • Creteil Cedex, France, 94010
• Germany
  • Hessen
    • Darmstadt, Hessen, Germany, 64297
    • Frankfurt, Hessen, Germany, 60596
    • Marburg, Hessen, Germany, 35043
  • Niedersachsen
    • Göttingen, Niedersachsen, Germany, 37075
  • Nordrhein-Westfalen
    • Bonn, Nordrhein-Westfalen, Germany, 53105
    • Köln, Nordrhein-Westfalen, Germany, 50924
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
• Hungary
  • Budapest, Hungary, 1085
  • Budapest, Hungary, 1106
  • Budapest, Hungary, 1133
  • Debrecen, Hungary, 4032
  • Pecs, Hungary, 7621
• Italy
  • Lazio
    • Roma, Lazio, Italy, 00133
  • Liguria
    • Genova, Liguria, Italy, 16132
  • Lombardia
    • Milano, Lombardia, Italy, 20132
    • Milano, Lombardia, Italy, 20122
  • Piemonte
    • Torino, Piemonte, Italy, 10122
  • Sardegna
    • Cagliari, Sardegna, Italy, 09124
    • Sassari, Sardegna, Italy, 07100
  • Toscana
    • Firenze, Toscana, Italy, 50134
  • Veneto
    • Padova, Veneto, Italy, 35128
• Lithuania
  • Kaunas, Lithuania, LT-50009
  • Vilnius, Lithuania, LT-08661
• Poland
  • Bydgoszcz, Poland, 85-631
  • Gdansk, Poland, 80-809
  • Katowice, Poland, 40-594
  • Krakow, Poland, 31-501
  • Lodz, Poland, 91-134
  • Lublin, Poland, 20-081
  • Poznan, Poland, 61-285
  • Warszawa, Poland, 04-141
  • Warszawa, Poland, 01-013
• Portugal
  • Coimbra, Portugal, 3000-548
  • Leiria, Portugal, 2410-197
  • Lisboa, Portugal, 1649-035
  • Porto, Portugal, 4200-319
  • Lisboa
    • Vila Franca de Xira, Lisboa, Portugal, 2600-178
• Slovakia
  • Bratislava, Slovakia, 826 06
  • Bratislava, Slovakia, 851 07
  • Nitra, Slovakia, 949 01
  • Zilina, Slovakia, 01207
  • Zvolen, Slovakia, 960 01
• Spain
  • Albacete, Spain, 02006
  • Barcelona, Spain, 08036
  • Barcelona, Spain, 08035
  • Valencia, Spain, 46014
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
    • Sant Cugat del Vallés, Barcelona, Spain, 08195
• Switzerland
  • Bern, Switzerland
  • Genève, Switzerland, 1204
• United Kingdom
  • London, United Kingdom, EC1V 2PD
  • Hampshire
    • Southampton, Hampshire, United Kingdom, SO16 6YD
  • Tyne And Wear
    • Sunderland, Tyne And Wear, United Kingdom, SR2 9HP
  • West Yorkshire
    • Leeds, West Yorkshire, United Kingdom, LS9 7TF

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at 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.	From baseline to Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 52	Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT).	From baseline to week 52
Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at 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	From baseline to week 52
Mean Change From Baseline in Best Corrected Visual Acuity (BCVA) at 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.	From baseline to Week 100
Mean Change From Baseline in Central Retinal Thickness (CRT) at Week 100	Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT).	From baseline to Week 100
Number of Participants With Categorized Changes From Baseline in Best Corrected Visual Acuity (BCVA) at 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	From baseline to Week 100
Number of Participants With Treatment-emergent Adverse Event (TEAE)	AEs that started after the first application of aflibercept under this protocol until 30 days after the last dose of study drug administration	Up to Week 100

Collaborators and Investigators

• Sponsor: Bayer

Publications and helpful links

General Publications

• Garweg JG, Stefanickova J, Hoyng C, Niesen T, Schmelter T, Leal S, Sivaprasad S; VIOLET Investigators. Dosing Regimens of Intravitreal Aflibercept for Diabetic Macular Edema Beyond the First Year: VIOLET, a Prospective Randomized Trial. Adv Ther. 2022 Jun;39(6):2701-2716. doi: 10.1007/s12325-022-02119-z. Epub 2022 Apr 12.

Helpful Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe
• Click here to find results for studies related to Bayer Healthcare products

Study record dates

Study Major Dates

• Study Start (Actual): November 16, 2016
• Primary Completion (Actual): November 13, 2018
• Study Completion (Actual): September 24, 2019

Study Registration Dates

• First Submitted: June 28, 2016
• First Submitted That Met QC Criteria: June 29, 2016
• First Posted (Estimate): June 30, 2016

Study Record Updates

• Last Update Posted (Actual): July 31, 2020
• Last Update Submitted That Met QC Criteria: July 15, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Diabetic macular edema; DME
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Degeneration; Retinal Diseases; Macular Degeneration; Macular Edema; Edema; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept
• Other Study ID Numbers: 17613; 2014-004938-25 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes