Aflibercept for Retinopathy of Prematurity - Intravitreal Injection Versus Laser Therapy (FIREFLEYE)

Open-label, Randomized, Two-Arm, Controlled Study to Assess the Efficacy, Safety, and Tolerability of Intravitreal (IVT) Aflibercept Compared to Laser Photocoagulation in Patients With Retinopathy of Prematurity (ROP)

The purpose of this study is to demonstrate how well aflibercept works in babies with ROP, comparing it with laser therapy. The study also has the objective to demonstrate how safe aflibercept is when used in babies, and describe how the drug moves into, through and out of the body.

Study Overview

• Status: Completed
• Conditions: Retinopathy of Prematurity (ROP)
• Intervention / Treatment: Drug: Eylea (Aflibercept, BAY86-5321); Procedure: Laser photocoagulation

• Study Type: Interventional
• Enrollment (Actual): 113
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Multiple Locations, Argentina
    • Many Locations
  • San Juan, Argentina, 5400
    • Hospital Público Descentralizado "Dr. Guillermo Rawson"
• Austria
  • Linz, Austria, 4021
    • Kepler Universitätsklinikum Campus III
  • Multiple Locations, Austria
    • Many Locations
• Belgium
  • Brugge, Belgium, 8000
    • AZ St-Jan Brugge Oostende AV
  • Multiple Locations, Belgium
    • Many Locations
• Brazil
  • Multiple Locations, Brazil
    • Many Locations
  • Sao Paulo, Brazil, 04023-061
    • Unifesp/Epm
  • Sao Paulo
    • Botucatu, Sao Paulo, Brazil, 18618 970
      • Hospital das Clínicas de Botucatu - UNESP Botucatu
• Bulgaria
  • Multiple Locations, Bulgaria
    • Many Locations
  • Plovdiv, Bulgaria, 4002
    • UMHAT Sveti Georgi
  • Sofia, Bulgaria, 1407
    • Acibadem City Clinic Multiprofile Hospital for Active Treatm
  • Sofia, Bulgaria, 1504
    • II SOGHAT Sheinovo
  • Varna, Bulgaria, 9000
    • SHOGAT Prof Dimitar Stamatov
• Czechia
  • Multiple Locations, Czechia
    • Many Locations
  • Ostrava, Czechia, 708 52
    • Fakultni nemocnice Ostrava
  • Praha 2, Czechia, 12808
    • Vseobecna fakultni nemocnice v Praze
• Greece
  • Athens, Greece, 11527
    • P & A KYRIAKOU Children's Hospital
  • Ioannina, Greece, 45500
    • University General Hospital of Ioannina
  • Multiple Locations, Greece
    • Many Locations
  • Thessaloniki, Greece, 56403
    • Papageorgiou General Hospital of Thessaloniki
• Hong Kong
  • Hong Kong, Hong Kong
    • Queen Mary Hospital
  • Multiple Locations, Hong Kong
    • Many Locations
• Hungary
  • Budapest, Hungary, 1125
    • EKBC, Uj Szent Janos Korhaz es Szakrendelo
  • Multiple Locations, Hungary
    • Many Locations
• Israel
  • Multiple Locations, Israel
    • Many Locations
  • Rehovot, Israel, 7661041
    • Kaplan Medical Center
• Italy
  • Multiple Locations, Italy
    • Many Locations
  • Lazio
    • Roma, Lazio, Italy, 00165
      • IRCCS Ospedale Pediatrico Bambino Gesu
    • Roma, Lazio, Italy, 00168
      • Fondazione Policlinico Universitario Agostino Gemelli IRCCS
  • Lombardia
    • Milano, Lombardia, Italy, 20122
      • Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico
  • Umbria
    • Perugia, Umbria, Italy, 06129
      • A.O. di Perugia
• Japan
  • Fukuoka, Japan, 812-8582
    • Kyushu University Hospital
  • Fukuoka, Japan, 814-0180
    • Fukuoka University Hospital
  • Fukushima, Japan, 960-1295
    • Fukushima Medical University Hospital
  • Multiple Locations, Japan
    • Many Locations
  • Saitama, Japan, 330-8777
    • Saitama Children's Medical Center
  • Fukuoka
    • Kitakyushu, Fukuoka, Japan, 807-8556
      • University of Occupational and Environmental Health
    • Kurume, Fukuoka, Japan, 830-0011
      • Kurume University Hospital
  • Okinawa
    • Shimajiri-gun, Okinawa, Japan, 901-1193
      • Okinawa Prefectural Nanbu Medical Center and Children's MC
  • Tokyo
    • Fuchu, Tokyo, Japan, 183-8561
      • Tokyo Metropolitan Children's Medical Center
    • Shinagawa, Tokyo, Japan, 142-8666
      • Showa University Hospital
    • Sumida-ku, Tokyo, Japan, 130-8575
      • Tokyo Metropolitan Bokutoh Hospital
    • Toshima-ku, Tokyo, Japan, 170-8476
      • Tokyo Metropolitan Ohtsuka Hospital
• Korea, Republic of
  • Multiple Locations, Korea, Republic of
    • Many Locations
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center
  • Chungcheongnamdo
    • Cheonan-si, Chungcheongnamdo, Korea, Republic of
      • Soon Chun Hyang University Cheonan Hospital
• Malaysia
  • Kuala Lumpur, Malaysia, 50586
    • Hospital Kuala Lumpur
  • Multiple Locations, Malaysia
    • Many Locations
• Netherlands
  • Multiple Locations, Netherlands
    • Many Locations
  • Veldhoven, Netherlands, 5504 DB
    • Maxima Medisch Centrum, locatie Veldhoven
• Poland
  • Multiple Locations, Poland
    • Many Locations
  • Poznan, Poland, 60-535
    • Ginekologiczno-Polozniczy SK UM im. K. Marcinkowskiego
• Portugal
  • Lisboa, Portugal, 1449-005
    • CHLO - Hospital Sao Francisco Xavier
  • Multiple Locations, Portugal
    • Many Locations
  • Lisboa
    • Amadora, Lisboa, Portugal, 2720-276
      • Hospital Prof. Dr. Fernando Fonseca
• Romania
  • Iasi, Romania, 700038
    • Spitalul Clinic de Obstretica si Ginecologie "Cuza Voda"
  • Multiple Locations, Romania
    • Many Locations
  • Cluj
    • Cluj-Napoca, Cluj, Romania, 400006
      • Clinical Emergency County Hospital
• Russian Federation
  • Kaluga, Russian Federation, 248007
    • FSAI NMRC IRTC "Eye Microsurgery", Kaluga's Branch
  • Moscow, Russian Federation, 117997
    • Russian National Scientific Medical University
  • Moscow, Russian Federation, 119620
    • FGBUZ "NPC of special children care n.a. Voino-Yaseneckogo"
  • Multiple Locations, Russian Federation
    • Many Locations
  • Saint-Petersburg, Russian Federation, 194100
    • Pediatric Medical University
  • Saint-Petersburg, Russian Federation, 198205
    • City Children Hospital ¿1
• Singapore
  • Multiple Locations, Singapore
    • Many Locations
  • Singapore, Singapore, 229899
    • KK Women's and Children's Hospital
• Slovakia
  • Bratislava, Slovakia, 833 41
    • Narodny ustav detskych chorob
  • Multiple Locations, Slovakia
    • Many Locations
• Spain
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28046
    • Hospital Universitario "La Paz"
  • Multiple Locations, Spain
    • Many Locations
  • Málaga, Spain, 29011
    • Hospital Regional De Malaga
• Sweden
  • Göteborg, Sweden
    • Sahlgrenska Universitetssjukhuset
  • Multiple Locations, Sweden
    • Many Locations
• Taiwan
  • Kaohsiung, Taiwan, 80756
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Multiple Locations, Taiwan
    • Many Locations
  • Taipei, Taiwan, 10449
    • Mackay Memorial Hospital
• Turkey
  • Adana, Turkey, 4522
    • S.B.U. Adana Sehir Egitim ve Arastirma Hastanesi
  • Ankara, Turkey, 06100
    • Hacettepe Universitesi Tip Fakultesi
  • Ankara, Turkey, 06490
    • Baskent Universitesi Tip Fakultesi Hastanesi
  • Ankara, Turkey, 06500
    • Gazi Universitesi Tip Fakultesi
  • Antalya, Turkey, 07100
    • Saglik Bilimleri Universitesi Antalya EA Hastanesi
  • Eskisehir, Turkey, 26480
    • Eskisehir Osmangazi Universitesi Tip Fakultesi
  • Multiple Locations, Turkey
    • Many Locations
• Ukraine
  • Multiple Locations, Ukraine
    • Many Locations
  • Odesa, Ukraine, 65031
    • MI"Odesa Regional Children's Clinical Hospital"
• United Kingdom
  • Birmingham, United Kingdom, B15 2TG
    • Birmingham Womens Hospital
  • Multiple Locations, United Kingdom
    • Many Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 7 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Gestational age at birth ≤ 32 weeks or birth weight ≤ 1500 g

• Subjects with treatment-naïve ROP classified according to the International Classification for ROP in at least one eye as:

  • Zone I Stage 1 plus, or 2 plus, or 3 non-plus or 3 plus, or
  • Zone II Stage 2 plus or 3 plus, or
  • Aggressive posterior retinopathy of prematurity (AP-ROP)
• Weight at baseline (day of treatment) ≥ 800 g
• Signed informed consent from parent(s)/legally authorized representative(s), which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

• Known or suspected chromosomal abnormality, genetic disorder or syndrome
• Previous exposure to any IVT or systemic anti-vascular endothelial growth factor (VEGF) agent, including maternal exposure during pregnancy and/or during breastfeeding
• Clinically significant neurological disease (eg, intraventricular hemorrhage grade 3 or higher, periventricular leukomalacia, congenital brain lesions significantly impairing optic nerve function, severe hydrocephalus with significantly increased intracranial pressure)
• Pediatric conditions rendering the infant ineligible for study intervention at baseline or for repeated blood draws as evaluated by a NICU specialist and a study ophthalmologist
• Presence of active ocular infection within 5 days of the first treatment
• Advanced stages of ROP with partial or complete retinal detachment (ROP Stages 4 and 5)
• ROP involving only Zone III
• Ocular abnormalities that may interfere with the administration of study intervention or assessment of the study primary endpoint
• Postnatal treatment with oral or intravenous corticosteroids at an equivalent dose of prednisone ≥ 1 mg/kg/day for > 2 weeks within 14 days of the first study intervention
• Previous surgical or nonsurgical treatment for ROP (IVT anti-VEGF injection, ablative laser therapy, cryotherapy, and vitrectomy)
• Participation of the subject or the mother in other clinical trials requiring administration of investigational treatments (other than vitamins and minerals) at the time of screening, or within 30 days or 5 half-lives of administration of the previous study drug, whichever is longer

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aflibercept arm; Subjects randomized to aflibercept will receive a intravitreal (IVT) injection of Dose A aflibercept per eligible eye at baseline and, if needed, up to a defined number of additional injections in each eye.	Drug: Eylea (Aflibercept, BAY86-5321); Solution in a sterile glass vial, Dose A, IVT injection.
Active Comparator: Laser photocoagulation arm; Subjects randomized to laser photocoagulation will receive treatment in each eligible eye at baseline. Retreatments may be administered if needed.	Procedure: Laser photocoagulation; Transpupillary conventional laser ablative therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants With Absence of Active ROP and Unfavorable Structural Outcomes	Active ROP was defined as ROP requiring treatment. Unfavorable structural outcomes included retinal detachment, macular dragging, macular fold, or retrolental opacity.	At 24 weeks after starting study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants Requiring Intervention With a Second Treatment Modality	A second treatment modality for ROP was either rescue treatment or any other surgical or nonsurgical treatment for ROP (e.g. IVT anti-VEGF injection, ablative laser therapy, cryotherapy, or vitrectomy) captured as concomitant medication or surgery after study start.	From baseline (treatment) up to week 24.
Proportion of Participants With Recurrence of ROP	Participants with recurrence of ROP were defined as subjects requiring re-treatment or rescue treatment after in the past the absence of treatment-requiring active ROP had been confirmed by the investigator.	From baseline (treatment) up to week 24.
Exploration of ROP Activity Scale Proposed by the International Neonatal Consortium	Eyes were evaluated for change in ROP activity scale proposed by the International Neonatal Consortium (2018). ROP Activity Scale value range is from 0 to 22. Value 0 to 7 are considered mild, 8 to 12 are moderate, and 13 to 22 are severe. Value 0 means the best and value 22 means the worst. Eyes evaluation was done at baseline and each visit.	From baseline (treatment) up to week 24.
Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs)	A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that was observed or reported after the first and not later than 30 days after the last administration of study treatment. Participants treated after week 21 were followed-up for adverse events up to week 28. Ocular TEAEs in treated eyes only were reported	From baseline (treatment) up to week 24
Percentage of Participants With Ocular Serious Adverse Events (SAEs)	Participants treated after week 21 were followed-up for adverse events up to week 28. Ocular SAEs in treated eyes only were reported.	From baseline (treatment) up to week 24
Percentage of Participants With Systemic TEAEs	A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that was observed or reported after the first and not later than 30 days after the last administration of study treatment. Participants treated after week 21 were followed-up for adverse events up to week 28. Systemic TEAEs only were reported.	From baseline (treatment) up to week 24
Percentage of Participants With Systemic SAEs	Participants treated after week 21 were followed-up for adverse events up to week 28. Systemic SAEs only were reported.	From baseline (treatment) up to week 24
Concentrations of Free Aflibercept in Plasma	Blood samples for determination of aflibercept concentrations in plasma were collected in the aflibercept 0.4 mg arm at Day 1 (within 24 hours after injection), and at weeks 2 and 4, and if feasible also at weeks 8, 12 and 24. Statistics for week 8, 12, 24 not calculated as > 1/3 of the concentrations were below the lower limit of quantification. Free Aflibercept Concentrations in Plasma were only measured in the Aflibercept 0.4 mg treatment arm.	From Day 1 up to week 24.
Number of Participants With Anti-drug Antibodies (ADA)	Immunogenicity was characterized by anti-drug antibody (ADA) responses in patients in the aflibercept 0.4 mg arm. Serum samples were taken at baseline prior to the injection and at 12 weeks after injection. ADA titers were summarized for 3 categories: Low (titer <1,000); Moderate (1,000 ≤ titer ≤ 10,000); High (titer >10,000). ADA in serum were only measured in the Aflibercept 0.4 mg treatment arm.	Baseline (treatment) and 12 weeks after aflibercept injection
Number of Participants With Potential Neutralizing Antibodies (NAb)	NAb status was evaluated for the samples that were positive in the ADA assay and had sufficient volume to analyze. NAb were only measured in participants with positive ADA in the Aflibercept 0.4 mg treatment arm	At 12 weeks after aflibercept injection
Number of Aflibercept Administrations	Total number of injections in both eyes.	From baseline (treatment) up to week 24.
Number of Laser Treatments	Total number of laser treatment in both eyes. If multiple sessions of laser treatment were necessary within 1 week from baseline, they were counted as a single treatment.	From baseline (treatment) up to week 24.

Collaborators and Investigators

• Sponsor: Bayer
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• Stahl A, Sukgen EA, Wu WC, Lepore D, Nakanishi H, Mazela J, Moshfeghi DM, Vitti R, Athanikar A, Chu K, Iveli P, Zhao F, Schmelter T, Leal S, Kofuncu E, Azuma N; FIREFLEYE Study Group. Effect of Intravitreal Aflibercept vs Laser Photocoagulation on Treatment Success of Retinopathy of Prematurity: The FIREFLEYE Randomized Clinical Trial. JAMA. 2022 Jul 26;328(4):348-359. doi: 10.1001/jama.2022.10564.

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 products

Study record dates

Study Major Dates

• Study Start (Actual): September 25, 2019
• Primary Completion (Actual): February 12, 2021
• Study Completion (Actual): February 12, 2021

Study Registration Dates

• First Submitted: June 28, 2019
• First Submitted That Met QC Criteria: June 28, 2019
• First Posted (Actual): July 1, 2019

Study Record Updates

• Last Update Posted (Actual): May 6, 2022
• Last Update Submitted That Met QC Criteria: May 4, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Infant, Newborn, Diseases; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Infant, Premature, Diseases; Retinal Diseases; Premature Birth; Retinopathy of Prematurity; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Aflibercept
• Other Study ID Numbers: 20090; 2018-002611-99 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

IPD Plan Description

Availability of this study's data will be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access.

As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.

Drug and device information, study documents

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