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

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ClinicalTrials.gov Identifier: NCT04004208
Recruitment Status : Completed
First Posted : July 1, 2019
Results First Posted : May 6, 2022
Last Update Posted : May 6, 2022
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Bayer

Brief 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.

Condition or disease Intervention/treatment Phase
Retinopathy of Prematurity (ROP) Drug: Eylea (Aflibercept, BAY86-5321) Procedure: Laser photocoagulation Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 113 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : September 25, 2019
Actual Primary Completion Date : February 12, 2021
Actual Study Completion Date : February 12, 2021

Resource links provided by the National Library of Medicine


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




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


Secondary Outcome Measures :
  1. Proportion of Participants Requiring Intervention With a Second Treatment Modality [ Time Frame: From baseline (treatment) up to week 24. ]
    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.

  2. Proportion of Participants With Recurrence of ROP [ Time Frame: From baseline (treatment) up to week 24. ]
    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.

  3. Exploration of ROP Activity Scale Proposed by the International Neonatal Consortium [ Time Frame: From baseline (treatment) up to week 24. ]
    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.

  4. Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From baseline (treatment) up to week 24 ]
    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

  5. Percentage of Participants With Ocular Serious Adverse Events (SAEs) [ Time Frame: From baseline (treatment) up to week 24 ]
    Participants treated after week 21 were followed-up for adverse events up to week 28. Ocular SAEs in treated eyes only were reported.

  6. Percentage of Participants With Systemic TEAEs [ Time Frame: From baseline (treatment) up to week 24 ]
    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.

  7. Percentage of Participants With Systemic SAEs [ Time Frame: From baseline (treatment) up to week 24 ]
    Participants treated after week 21 were followed-up for adverse events up to week 28. Systemic SAEs only were reported.

  8. Concentrations of Free Aflibercept in Plasma [ Time Frame: From Day 1 up to week 24. ]
    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.

  9. Number of Participants With Anti-drug Antibodies (ADA) [ Time Frame: Baseline (treatment) and 12 weeks after aflibercept injection ]
    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.

  10. Number of Participants With Potential Neutralizing Antibodies (NAb) [ Time Frame: At 12 weeks after aflibercept injection ]
    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

  11. Number of Aflibercept Administrations [ Time Frame: From baseline (treatment) up to week 24. ]
    Total number of injections in both eyes.

  12. Number of Laser Treatments [ Time Frame: From baseline (treatment) up to week 24. ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 32 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04004208


Locations
Show Show 90 study locations
Sponsors and Collaborators
Bayer
Regeneron Pharmaceuticals
  Study Documents (Full-Text)

Documents provided by Bayer:
Study Protocol  [PDF] June 23, 2020
Statistical Analysis Plan  [PDF] May 10, 2021

Additional Information:
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT04004208    
Other Study ID Numbers: 20090
2018-002611-99 ( EudraCT Number )
First Posted: July 1, 2019    Key Record Dates
Results First Posted: May 6, 2022
Last Update Posted: May 6, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
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.


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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
Additional relevant MeSH terms:
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Retinal Diseases
Retinopathy of Prematurity
Premature Birth
Eye Diseases
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Infant, Premature, Diseases
Infant, Newborn, Diseases
Aflibercept
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents