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Retinopathy of Prematurity (ROP)Phase 3FIREFLEYENCT04004208

Aflibercept for Retinopathy of Prematurity - Intravitreal Injection Versus Laser Therapy

A Phase 3 study testing Eylea (Aflibercept, BAY86-5321) and Laser photocoagulation in people with Retinopathy of Prematurity (ROP), run by Bayer at 90 sites in 27 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages Up to 32 weeks
Conditions the study is for
Retinopathy of Prematurity (ROP)
What is being tested?
Eylea (Aflibercept, BAY86-5321) and Laser photocoagulation
Could I receive a placebo?
No, everyone receives an active treatment
How many people
113 participants
Where
90 sitesin 27 countries
Study dates
25 Sep 2019to 12 Feb 2021
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 32 weeks
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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.

Who cannot join

  • 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)
Show all 11Show fewer
  • 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

Trial locations and contacts

90 sites in 27 countries.

90 sites in 27 countries

Japan12 sites
  • Tokyo Metropolitan Children's Medical Center

    Fuchū, Tokyo, 183-8561

  • Kyushu University Hospital

    Fukuoka, 812-8582

  • Fukuoka University Hospital

    Fukuoka, 814-0180

  • Fukushima Medical University Hospital

    Fukushima, 960-1295

  • University of Occupational and Environmental Health

    Kitakyushu, Fukuoka, 807-8556

  • Kurume University Hospital

    Kurume, Fukuoka, 830-0011

  • Many Locations

    Multiple Locations

  • Saitama Children's Medical Center

    Saitama, 330-8777

  • Okinawa Prefectural Nanbu Medical Center and Children's MC

    Shimajiri-gun, Okinawa, 901-1193

  • Showa University Hospital

    Shinagawa, Tokyo, 142-8666

  • Tokyo Metropolitan Bokutoh Hospital

    Sumida-ku, Tokyo, 130-8575

  • Tokyo Metropolitan Ohtsuka Hospital

    Toshima-ku, Tokyo, 170-8476

Other trials in Japan

Turkey (Türkiye)7 sites
  • S.B.U. Adana Sehir Egitim ve Arastirma Hastanesi

    Adana, 4522

  • Hacettepe Universitesi Tip Fakultesi

    Ankara, 06100

  • Baskent Universitesi Tip Fakultesi Hastanesi

    Ankara, 06490

  • Gazi Universitesi Tip Fakultesi

    Ankara, 06500

  • Saglik Bilimleri Universitesi Antalya EA Hastanesi

    Antalya, 07100

  • Eskisehir Osmangazi Universitesi Tip Fakultesi

    Eskişehir, 26480

  • Many Locations

    Multiple Locations

Other trials in Turkey (Türkiye)

Russia6 sites
  • FSAI NMRC IRTC "Eye Microsurgery", Kaluga's Branch

    Kaluga, 248007

  • Russian National Scientific Medical University

    Moscow, 117997

  • FGBUZ "NPC of special children care n.a. Voino-Yaseneckogo"

    Moscow, 119620

  • Many Locations

    Multiple Locations

  • Pediatric Medical University

    Saint Petersburg, 194100

  • City Children Hospital ¿1

    Saint Petersburg, 198205

Other trials in Russia

Bulgaria5 sites
  • Many Locations

    Multiple Locations

  • UMHAT Sveti Georgi

    Plovdiv, 4002

  • Acibadem City Clinic Multiprofile Hospital for Active Treatm

    Sofia, 1407

  • II SOGHAT Sheinovo

    Sofia, 1504

  • SHOGAT Prof Dimitar Stamatov

    Varna, 9000

Other trials in Bulgaria

Italy5 sites
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

    Milan, Lombardy, 20122

  • Many Locations

    Multiple Locations

  • A.O. di Perugia

    Perugia, Umbria, 06129

  • IRCCS Ospedale Pediatrico Bambino Gesù

    Rome, Lazio, 00165

  • Fondazione Policlinico Universitario Agostino Gemelli IRCCS

    Rome, Lazio, 00168

Other trials in Italy

Greece4 sites
  • P & A KYRIAKOU Children's Hospital

    Athens, 11527

  • University General Hospital of Ioannina

    Ioannina, 45500

  • Many Locations

    Multiple Locations

  • Papageorgiou General Hospital of Thessaloniki

    Thessaloniki, 56403

Other trials in Greece

South Korea4 sites
  • Soon Chun Hyang University Cheonan Hospital

    Cheonan-si, Chungcheongnam-do

  • Many Locations

    Multiple Locations

  • Asan Medical Center

    Seoul, 05505

  • Samsung Medical Center

    Seoul, 06351

Other trials in South Korea

Spain4 sites
  • Hospital Universitario 12 de Octubre

    Madrid, 28041

  • Hospital Universitario "La Paz"

    Madrid, 28046

  • Hospital Regional de Málaga

    Málaga, 29011

  • Many Locations

    Multiple Locations

Other trials in Spain

Brazil3 sites
  • Hospital das Clínicas de Botucatu - UNESP Botucatu

    Botucatu, São Paulo, 18618 970

  • Many Locations

    Multiple Locations

  • Unifesp/Epm

    São Paulo, 04023-061

Other trials in Brazil

Czechia3 sites
  • Many Locations

    Multiple Locations

  • Fakultni nemocnice Ostrava

    Ostrava, 708 52

  • Vseobecna fakultni nemocnice v Praze

    Prague, 12808

Other trials in Czechia

Portugal3 sites
  • Hospital Prof. Dr. Fernando Fonseca

    Amadora, Lisbon District, 2720-276

  • CHLO - Hospital Sao Francisco Xavier

    Lisbon, 1449-005

  • Many Locations

    Multiple Locations

Other trials in Portugal

Romania3 sites
  • Clinical Emergency County Hospital

    Cluj-Napoca, Cluj, 400006

  • Spitalul Clinic de Obstretica si Ginecologie "Cuza Voda"

    Iași, 700038

  • Many Locations

    Multiple Locations

Other trials in Romania

Taiwan3 sites
  • Kaohsiung Medical University Chung-Ho Memorial Hospital

    Kaohsiung City, 80756

  • Many Locations

    Multiple Locations

  • Mackay Memorial Hospital

    Taipei, 10449

Other trials in Taiwan

Argentina2 sites
  • Many Locations

    Multiple Locations

  • Hospital Público Descentralizado "Dr. Guillermo Rawson"

    San Juan, 5400

Other trials in Argentina

Austria2 sites
  • Kepler Universitätsklinikum Campus III

    Linz, 4021

  • Many Locations

    Multiple Locations

Other trials in Austria

Belgium2 sites
  • AZ St-Jan Brugge Oostende AV

    Bruges, 8000

  • Many Locations

    Multiple Locations

Other trials in Belgium

Hong Kong2 sites
  • Queen Mary Hospital

    Hong Kong

  • Many Locations

    Multiple Locations

Other trials in Hong Kong

Hungary2 sites
  • EKBC, Uj Szent Janos Korhaz es Szakrendelo

    Budapest, 1125

  • Many Locations

    Multiple Locations

Other trials in Hungary

Israel2 sites
  • Many Locations

    Multiple Locations

  • Kaplan Medical Center

    Rehovot, 7661041

Other trials in Israel

Malaysia2 sites
  • Hospital Kuala Lumpur

    Kuala Lumpur, 50586

  • Many Locations

    Multiple Locations

Other trials in Malaysia

Netherlands2 sites
  • Many Locations

    Multiple Locations

  • Maxima Medisch Centrum, locatie Veldhoven

    Veldhoven, 5504 DB

Other trials in Netherlands

Poland2 sites
  • Many Locations

    Multiple Locations

  • Ginekologiczno-Polozniczy SK UM im. K. Marcinkowskiego

    Poznan, 60-535

Other trials in Poland

Singapore2 sites
  • Many Locations

    Multiple Locations

  • KK Women's and Children's Hospital

    Singapore, 229899

Other trials in Singapore

Slovakia2 sites
  • Narodny ustav detskych chorob

    Bratislava, 833 41

  • Many Locations

    Multiple Locations

Other trials in Slovakia

Sweden2 sites
  • Sahlgrenska Universitetssjukhuset

    Gothenburg

  • Many Locations

    Multiple Locations

Other trials in Sweden

Ukraine2 sites
  • Many Locations

    Multiple Locations

  • MI"Odesa Regional Children's Clinical Hospital"

    Odesa, 65031

Other trials in Ukraine

United Kingdom2 sites
  • Birmingham Womens Hospital

    Birmingham, B15 2TG

  • Many Locations

    Multiple Locations

Other trials in United Kingdom

About this study

Official title: 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.

Being tested
Eylea (Aflibercept, BAY86-5321), Laser photocoagulation
Medical subject headings
Retinopathy of Prematurity

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Eylea (Aflibercept, BAY86-5321)Drug

    Solution in a sterile glass vial, Dose A, IVT injection.

  • Laser photocoagulationProcedure or surgery

    Transpupillary conventional laser ablative therapy

Study groups in NCT04004208
Study groupRoleWhat they receive
Aflibercept armExperimentalSubjects 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.
Receives: Drug: Eylea (Aflibercept, BAY86-5321)
Laser photocoagulation armActive comparatorSubjects randomized to laser photocoagulation will receive treatment in each eligible eye at baseline. Retreatments may be administered if needed.
Receives: Procedure: Laser photocoagulation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: At 24 weeks after starting study treatment

Secondary outcomes (12)
  1. 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.

    Measured: From baseline (treatment) up to week 24.

  2. 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.

    Measured: From baseline (treatment) up to week 24.

  3. 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.

    Measured: From baseline (treatment) up to week 24.

  4. 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

    Measured: From baseline (treatment) up to week 24

  5. 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.

    Measured: From baseline (treatment) up to week 24

  6. 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.

    Measured: From baseline (treatment) up to week 24

  7. 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.

    Measured: From baseline (treatment) up to week 24

  8. 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.

    Measured: From Day 1 up to week 24.

  9. 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.

    Measured: Baseline (treatment) and 12 weeks after aflibercept injection

  10. 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

    Measured: At 12 weeks after aflibercept injection

  11. Number of Aflibercept Administrations

    Total number of injections in both eyes.

    Measured: From baseline (treatment) up to week 24.

  12. 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.

    Measured: From baseline (treatment) up to week 24.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Jul 2019
  2. Study start25 Sep 2019
  3. Primary completion12 Feb 2021
  4. Study completion12 Feb 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
113 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04004208
Sponsor's protocol ID
20090
Other IDs
2018-002611-99, 2018
Acronym
FIREFLEYE
Status last verified
May 2022
First submitted
28 Jun 2019
Last updated
6 May 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Undecided: 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.

Publications

  • Stahl A, Azuma N, Wu WC, Lepore D, Sukgen E, Nakanishi H, Mazela J, Leal S, Pieper A, Schlief S, Eissing T, Turner KC, Zhao A, Winkler J, Hochel J, Kofuncu E, Zimmermann T; FIREFLEYE Study Group. Systemic exposure to aflibercept after intravitreal injection in premature neonates with retinopathy of prematurity: results from the FIREFLEYE randomized phase 3 study. Eye (Lond). 2024 Jun;38(8):1444-1453. doi: 10.1038/s41433-023-02919-9. Epub 2024 Jan 10.

    PubMed 38200320
  • 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.

    PubMed 35881122

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Eylea (Aflibercept, BAY86-5321) and Laser photocoagulation in people with Retinopathy of Prematurity (ROP), run by Bayer at 90 sites in 27 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 May 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 90 sites in Japan, Turkey (Türkiye), Russia, Bulgaria, Italy and 22 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 6 May 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of Participants With Absence of Active ROP and Unfavorable Structural Outcomes (time frame: At 24 weeks after starting study treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04004208, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 May 2022.

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