Study of a High-Dose Aflibercept in Participants With Diabetic Eye Disease (PHOTON)

A Randomized, Double-Masked, Active-Controlled Phase 2/3 Study of the Efficacy and Safety of High-Dose Aflibercept in Patients With Diabetic Macular Edema

The primary objective of the study is to determine if treatment with high-dose aflibercept (HD) at intervals of 12 or 16 weeks provides non-inferior best corrected visual acuity (BCVA) compared to aflibercept dosed every 8 weeks.

The secondary objectives of the study are as follows:

• To determine the effect of HD vs. aflibercept on anatomic and other visual measures of response
• To evaluate the safety, immunogenicity, and pharmacokinetics (PK) of aflibercept

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus; Diabetic Macular Edema; Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: aflibercept; Drug: High-dose aflibercept

• Study Type: Interventional
• Enrollment (Actual): 660
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2H 0C8
      • Regeneron Study Site
  • Ontario
    • Mississauga, Ontario, Canada, L4W 1W9
      • Regeneron Study Site
    • North York, Ontario, Canada, M3C 0G9
      • Regeneron Study Site
  • Quebec
    • Sherbrooke, Quebec, Canada, J1G 2V4
      • Regeneron Study Site
• Czechia
  • Pardubice, Czechia, 530 02
    • Regeneron Study Site
  • Prague 5, Czechia, 150 00
    • Regeneron Study Site
  • Praha 10, Czechia, 100 34
    • Regeneron Study Site
  • Praha 2, Czechia, 128 08
    • Regeneron Study Site
• Germany
  • Mecklenburg-Westfalen
    • Neubrandenburg, Mecklenburg-Westfalen, Germany, 17036
      • Regeneron Study Site
  • Nordrhein-Westfalen
    • Gottingen, Nordrhein-Westfalen, Germany, 37075
      • Regeneron Study Site
    • Munster, Nordrhein-Westfalen, Germany, 48145
      • Regeneron Study Site
• Hungary
  • Budapest, Hungary, H-1085
    • Regeneron Study Site
  • Budapest, Hungary, H-1106
    • Regeneron Study Site
  • Budapest, Hungary, H-1133
    • Regeneron Study Site
  • Budapest, Hungary, H-1145
    • Regeneron Study Site
  • Debrecen, Hungary, H-4032
    • Regeneron Study Site
  • Szeged, Hungary, H-6720
    • Regeneron Study Site
  • Baranya
    • Pecs, Baranya, Hungary, H-7621
      • Regeneron Study Site 1
  • Vas
    • Szombathely, Vas, Hungary, H-9700
      • Regeneron Study Site
  • Zala Megye
    • Zalaegerszeg, Zala Megye, Hungary, H-8900
      • Regeneron Study Site
• Japan
  • Fukuoka, Japan, 812-0011
    • Regeneron Study Site
  • Fukuoka, Japan, 819-8585
    • Regeneron Study Site
  • Kagoshima, Japan, 890-8520
    • Regeneron Study Site
  • Osaka, Japan, 545-8586
    • Regeneron Study Site
  • Saitama, Japan, 330-8553
    • Regeneron Study Site
  • Tokushima, Japan, 770-8503
    • Regeneron Study Site
  • Aichi
    • Nagakute, Aichi, Japan, 480-1195
      • Regeneron Study Site
    • Nagoya, Aichi, Japan, 466-8560
      • Regeneron Study Site
    • Nagoya, Aichi, Japan, 467-8602
      • Regeneron Study Site
  • Fukui
    • Yoshida-Gun, Fukui, Japan, 910-1193
      • Regeneron Study Site
  • Fukuoka
    • Kurume, Fukuoka, Japan, 830-0011
      • Regeneron Study Site
  • Fukushima
    • Koriyama, Fukushima, Japan, 963-8052
      • Regeneron Study Site
  • Hokkaido
    • Hakodate, Hokkaido, Japan, 041-0851
      • Regeneron Study Site
  • Hyogo
    • Kobe, Hyogo, Japan, 650-0017
      • Regeneron Study Site
  • Ibaraki
    • Mito, Ibaraki, Japan, 310-0845
      • Regeneron Study Site
    • Toride, Ibaraki, Japan, 302-0014
      • Regeneron Study Site
    • Tsuchiura-shi, Ibaraki, Japan, 300-0817
      • Regeneron Study Site
  • Kagawa
    • Kita-gun, Kagawa, Japan, 761-0793
      • Regeneron Study Site
  • Kanagawa
    • Kawasaki, Kanagawa, Japan, 216-8511
      • Regeneron Study Site
  • Nagano
    • Matsumoto, Nagano, Japan, 390-8621
      • Regeneron Study Site
  • Nagasaki
    • Nagasaki City, Nagasaki, Japan, 852-8501
      • Regeneron Study Site
  • Nara
    • Kashihara, Nara, Japan, 634-8522
      • Regeneron Study Site
  • Osaka
    • Hirakata, Osaka, Japan, 573-1191
      • Regeneron Study Site
  • Saitama
    • Tokorozawa, Saitama, Japan, 359-8513
      • Regeneron Study Site
  • Shizuoka
    • Susono, Shizuoka, Japan, 410-1102
      • Regeneron Study Site
  • Tokyo
    • Chiyoda-ku, Tokyo, Japan, 101-8309
      • Regeneron Study Site
    • Hachioji, Tokyo, Japan, 193-0998
      • Regeneron Study Site
    • Itabashi-ku, Tokyo, Japan, 173-0015
      • Regeneron Study Site
    • Meguro-ku, Tokyo, Japan, 152-8902
      • Regeneron Study Site
  • Totigi
    • Shimotsuke-shi, Totigi, Japan, 329-0498
      • Regeneron Study Site
  • Yamaguchi
    • Ube, Yamaguchi, Japan, 755-8505
      • Regeneron Study Site
• Puerto Rico
  • Arecibo, Puerto Rico, 00612
    • Regeneron Study Site
• United Kingdom
  • London, United Kingdom, EC1V 2PD
    • Regeneron Study Site
  • Tyne And Wear
    • Sunderland, Tyne And Wear, United Kingdom, SR2 9HP
      • Regeneron Study Site
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85021
      • Regeneron Study Site
  • California
    • Arcadia, California, United States, 91006
      • Regeneron Study Site
    • Beverly Hills, California, United States, 90211
      • Regeneron Study Site
    • Campbell, California, United States, 95008
      • Regeneron Study Site
    • Encino, California, United States, 91436
      • Regeneron Study Site
    • Fullerton, California, United States, 92835
      • Regeneron Study Site
    • Huntington Beach, California, United States, 92647
      • Regeneron Study Site
    • Long Beach, California, United States, 90807
      • Regeneron Study Site
    • Palo Alto, California, United States, 94303
      • Regeneron Study Site
    • Pasadena, California, United States, 91107
      • Regeneron Study Site
    • Poway, California, United States, 92064
      • Regeneron Study Site
    • Rancho Cordova, California, United States, 95670
      • Regeneron Study Site
    • Riverside, California, United States, 92505
      • Regeneron Study Site
    • Torrance, California, United States, 90509
      • Regeneron Study Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • Regeneron Study Site
    • Durango, Colorado, United States, 81301
      • Regeneron Study Site
    • Lakewood, Colorado, United States, 80228
      • Regeneron Study Site
  • Connecticut
    • Waterford, Connecticut, United States, 06385
      • Regeneron Study Site
  • Florida
    • Clearwater, Florida, United States, 33761
      • Regeneron Study Site
    • Fort Lauderdale, Florida, United States, 33308
      • Regeneron Study Site
    • Fort Myers, Florida, United States, 33912
      • Regeneron Study Site
    • Jacksonville, Florida, United States, 32216
      • Regeneron Study Site
    • Lakeland, Florida, United States, 33805
      • Regeneron Study Site
    • Largo, Florida, United States, 33770
      • Regeneron Study Site
    • Melbourne, Florida, United States, 32901
      • Regeneron Study Site
    • Miami, Florida, United States, 33126
      • Regeneron Study Site
    • Orlando, Florida, United States, 32806
      • Regeneron Study Site
    • Pinellas Park, Florida, United States, 33782
      • Regeneron Study Site
    • Plantation, Florida, United States, 33324
      • Regeneron Study Site
    • Saint Petersburg, Florida, United States, 33711
      • Regeneron Study Site
    • Stuart, Florida, United States, 34994
      • Regeneron Study Site
    • Winter Haven, Florida, United States, 33880
      • Regeneron Study Site
  • Georgia
    • Augusta, Georgia, United States, 30909
      • Regeneron Study Site
    • Marietta, Georgia, United States, 30060
      • Regeneron Study Site 1
    • Marietta, Georgia, United States, 30060
      • Regeneron Study Site 2
  • Hawaii
    • 'Aiea, Hawaii, United States, 96701
      • Regeneron Study Site
  • Illinois
    • Oak Forest, Illinois, United States, 60452
      • Regeneron Study Site
    • Springfield, Illinois, United States, 62703
      • Regeneron Study Site
    • Springfield, Illinois, United States, 62704
      • Regeneron Study Site
  • Indiana
    • Carmel, Indiana, United States, 46290
      • Regeneron Study Site
  • Kansas
    • Shawnee Mission, Kansas, United States, 66204
      • Regeneron Study Site
  • Maryland
    • Baltimore, Maryland, United States, 21209
      • Regeneron Study Site
    • Hagerstown, Maryland, United States, 21740
      • Regeneron Study Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Regeneron Study Site
  • Michigan
    • Royal Oak, Michigan, United States, 48073
      • Regeneron Study Site
  • Mississippi
    • Southaven, Mississippi, United States, 38671
      • Regeneron Study Site
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Regeneron Study Site
  • New Jersey
    • Bloomfield, New Jersey, United States, 07003
      • Regeneron Study Site
    • Edison, New Jersey, United States, 08820
      • Regeneron Study Site
    • Teaneck, New Jersey, United States, 07666
      • Regeneron Study Site
  • New York
    • Great Neck, New York, United States, 11021
      • Regeneron Study Site
    • Liverpool, New York, United States, 13088
      • Regeneron Study Site
    • New York, New York, United States, 11221
      • Regeneron Study Site
    • Oceanside, New York, United States, 11572
      • Regeneron Study Site
    • Shirley, New York, United States, 02114
      • Regeneron Study Site
  • North Carolina
    • Asheville, North Carolina, United States, 28803
      • Regeneron Study Site
    • Charlotte, North Carolina, United States, 28210
      • Regeneron Study Site
  • Ohio
    • Beachwood, Ohio, United States, 44122
      • Regeneron Study Site
    • Cincinnati, Ohio, United States, 45202
      • Regeneron Study Site
    • Cincinnati, Ohio, United States, 45242
      • Regeneron Study Site
    • Cleveland, Ohio, United States, 44130
      • Regeneron Study Site
    • Dublin, Ohio, United States, 43016
      • Regeneron Study Site
  • Oklahoma
    • Edmond, Oklahoma, United States, 73013
      • Regeneron Study Site
    • Tulsa, Oklahoma, United States, 74114
      • Regeneron Study Site
  • Oregon
    • Portland, Oregon, United States, 97225
      • Regeneron Study Site
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Regeneron Study Site
    • Kingston, Pennsylvania, United States, 18704
      • Regeneron Study Site
    • Monroeville, Pennsylvania, United States, 15146
      • Regeneron Study Site
  • South Carolina
    • Beaufort, South Carolina, United States, 29902
      • Regeneron Study Site
    • Ladson, South Carolina, United States, 29456
      • Regeneron Study Site
    • West Columbia, South Carolina, United States, 29169
      • Regeneron Study Site
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Regeneron Study Site
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Regeneron Study Site
    • Knoxville, Tennessee, United States, 37922
      • Regeneron Study Site
    • Nashville, Tennessee, United States, 37203
      • Regeneron Study Site
  • Texas
    • Abilene, Texas, United States, 79606
      • Regeneron Study Site
    • Bellaire, Texas, United States, 77401
      • Regeneron Study Site
    • San Antonio, Texas, United States, 78240
      • Regeneron Study Site 2
    • The Woodlands, Texas, United States, 77384
      • Regeneron Study Site
    • Willow Park, Texas, United States, 76087
      • Regeneron Study Site
  • Utah
    • Salt Lake City, Utah, United States, 84107
      • Regeneron Study Site 1
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Regeneron Study Site
    • Norfolk, Virginia, United States, 23502
      • Regeneron Study Site
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Regeneron Study Site

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

• Diabetic macular edema (DME) with central involvement in the study eye
• Best corrected visual acuity (BCVA) early treatment diabetic retinopathy study (ETDRS) letter score of 78 to 24 (approximate Snellen equivalent of 20/32 to 20/320) in the study eye with decreased vision determined to be primarily the result of DME
• Willing and able to comply with clinic visits and study-related procedures
• Provide informed consent signed by study participant or legally acceptable representative

Extension Phase: All randomized patients that complete visit 26, week 96, as long as the patient 1) provides informed consent and 2) no treatment for DME has been given in the study eye other than the randomized study treatment.

Key Exclusion Criteria:

• Evidence of macular edema due to any cause other than diabetes mellitus in either eye
• Active proliferative diabetic retinopathy in the study eye
• IVT anti-VEGF treatment (aflibercept, ranibizumab, bevacizumab, brolucizumab, pegaptanib sodium) or panretinal laser photocoagulation (PRP) /macular laser photocoagulation within 12 weeks (84 days) or intraocular or periocular corticosteroids within 16 weeks (112 days) of the screening visit in the study eye
• Prior IVT investigational agents in either eye (eg, anti-ang-2/anti-VEGF bispecific monoclonal antibodies, gene therapy, etc.) at any time
• Treatment with ocriplasmin (JETREA®) in the study eye at any time

NOTE: Other Protocol Defined Inclusion/Exclusion Criteria Apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: aflibercept Q8; Administered every 8 weeks after a loading phase	Drug: aflibercept; Intravitreally (IVT) administered as a liquid formulation in a vial; Other Names: BAY86-5321; EYLEA®
Experimental: High-Dose aflibercept Q12; Administered every 12 weeks after a loading phase	Drug: High-dose aflibercept; Intravitreally (IVT) administered as a liquid formulation in a vial
Experimental: High-Dose aflibercept Q16; Administered every 16 weeks after a loading phase	Drug: High-dose aflibercept; Intravitreally (IVT) administered as a liquid formulation in a vial

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Best Corrected Visual Acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] Letter Score) in the Study Eye at Week 48	Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best).	Baseline, Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With a ≥2 Step Improvement From Baseline in Diabetic Retinopathy Severity Scale (DRSS) Score at Week 48	The DRSS was assessed according to the following scale: 10 = Diabetic retinopathy (DR) absent, 14 = DR questionable, 15 = DR questionable, 20 = Micro-aneurysms only, 35 = Mild Non-proliferative diabetic retinopathy (NPDR), 43 = Moderate NPDR, 47 = Moderately severe NPDR, 53 = Severe NPDR, 61 = Mild Proliferative diabetic retinopathy (PDR), 65 = Moderate PDR, 71 = High-risk PDR, 75 = High-risk PDR, 81 = Advanced PDR: fundus partially obscured, center of macula attached, 85 = Advanced PDR: posterior fundus obscured, or center of macula detached, 90 = cannot grade, even sufficiently for level 81 or 85.	Baseline, Week 48
Percentage of Participants Gaining ≥15 Letters in BCVA From Baseline at Week 48	Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). Only one study eye per participant was analyzed within the study	Baseline, Week 48
Percentage of Participants With BCVA ≥69 Letters at Week 48	Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best).	At Week 48
Percentage of Participants Without Fluid at Foveal Center at Week 48	Retinal fluid status was evaluated using spectral domain optical coherence tomography (SD-OCT) on the study eye.	At Week 48
Change From Baseline in Central Retinal Thickness (CRT) in the Study Eye at Week 48	Central Retinal Thickness (CRT) was measured in the study eye by spectral domain optical coherence tomography (SD-OCT).	Baseline, Week 48
Percentage of Participants Without Leakage on Fluorescein Angiography (FA) at Week 48	Leakage is the release of fluorescein dye from diseased retinal vessels.	At Week 48
Change From Baseline in National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) Total Score at Week 48	Vision-specific quality of life is assessed with the NEI VFQ-25 (National Eye Institute Visual Function Questionnaire), i.e. a 25-item questionnaire that gives a score on a scale from 0 (worst) to 100 (best = no vision problems).	Baseline, Week 48
Systemic Pharmacokinetics (PK) of Aflibercept as Assessed by Plasma Concentrations Through Week 48	Concentrations of Free Aflibercept in Plasma by Time and Treatment Group	Through Week 48
Change From Baseline in BCVA in the Study Eye in Participants With Both Baseline and Week 48 BCVA	Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). (Per Statistical Analysis Plan (SAP) Version 2.0 Appendix 10.9 for US Only)	Baseline, Week 48
Change From 8-weeks Post Initial Treatment Phase in BCVA in the Study Eye in Participants With Both 8-weeks Post Initial Treatment Phase BCVA and Week 48 BCVA	Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best). (Per SAP Version 2.0 Appendix 10.9 for US Only)	Baseline, Week 48
Change From Baseline in BCVA (Region-specific Analysis) in the Study Eye at Week 60	Visual function of the study eye was assessed at a distance of 4 meters at every study visit using the Early Treatment Diabetic Retinopathy Study (ETDRS) Best Corrected Visual Acuity (BCVA) letter score. BCVA scale range is 0 (worst) to 100 (best).	Baseline, Week 60
Assessment of Immunogenicity to Aflibercept by Measuring the Incidence of Treatment-emergent Anti-drug Antibodies (ADA) Response Through Week 96	Number of participants with pre-existing immunoreactivity and treatment-emergent ADA response reported	Through Week 96
Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Through Week 96	A TEAE is an AE starting after the first dose of study drug to the last dose of study drug (active or sham) plus 30 days. Additionally, for patients who are still participating in the study (ie, have not been withdrawn and are continuing in the extension phase of the study) as of the week 96 visit all AEs up through the date of the week 96 visit were considered treatment-emergent.	Through Week 96
Number of Participants With Any Serious TEAE Through Week 96	A TEAE is an AE starting after the first dose of study drug to the last dose of study drug (active or sham) plus 30 days. Additionally, for patients who are still participating in the study (ie, have not been withdrawn and are continuing in the extension phase of the study) as of the week 96 visit all AEs up through the date of the week 96 visit were considered treatment-emergent.	Through Week 96
Number of Participants With Any TEAE Through Week 156	TEAEs are defined as AEs starting after the first dose of study drug to the last dose of study drug (active or sham) plus 30 days or week 156 visit, whichever was later.	Through Week 156
Number of Participants With Any Serious TEAE Through Week 156		Through Week 156

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Collaborators: Bayer
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2020
• Primary Completion (Actual): May 30, 2022
• Study Completion (Actual): June 18, 2024

Study Registration Dates

• First Submitted: May 26, 2020
• First Submitted That Met QC Criteria: June 10, 2020
• First Posted (Actual): June 12, 2020

Study Record Updates

• Last Update Posted (Actual): August 8, 2025
• Last Update Submitted That Met QC Criteria: July 18, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Eye Diseases; Retinal Diseases; Retinal Degeneration; Macular Degeneration; Diabetes Mellitus, Type 2; Diabetes Mellitus; Diabetes Mellitus, Type 1; Macular Edema; Antineoplastic Agents; Physiological Effects of Drugs; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept
• Other Study ID Numbers: VGFTe-HD-DME-1934; 2019-003643-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All IPD that underlie results in a publication.
• IPD Sharing Time Frame: Individual de-identified participant data will be made available once the indication has been approved by a regulatory body, if there is participant consent and there is not a reasonable likelihood of participant re-identification.
• IPD Sharing Access Criteria: Qualified researchers may request access to study documents (including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan) that support the methods and findings reported in a manuscript. Individual de-identified participant data will be made available once the indication has been approved by a regulatory body, if there is participant consent and there is not a reasonable likelihood of participant re-identification.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No