Aflibercept for Retinopathy of Prematurity - Intravitreal Injection Versus Laser Therapy

Retinopathy of Prematurity (ROP) Clinical Trial

— FIREFLEYE  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04004208
• Other study ID #: 20090
• Secondary ID: 2018-002611-99
• Status: Completed
• Phase: Phase 3
• Start date: September 25, 2019
• Est. completion date: February 12, 2021

Study information

• Verified date: May 2022
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 113
• Est. completion date: February 12, 2021
• Est. primary completion date: February 12, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 32 Weeks

Eligibility

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

Related Conditions & MeSH terms

• Premature Birth
• Retinal Diseases
• Retinopathy of Prematurity
• Retinopathy of Prematurity (ROP)

Intervention

Drug:
• Eylea (Aflibercept, BAY86-5321)
Solution in a sterile glass vial, Dose A, IVT injection.

Procedure:
• Laser photocoagulation
Transpupillary conventional laser ablative therapy

Locations

Country	Name	City	State
Argentina	Many Locations	Multiple Locations
Argentina	Hospital Público Descentralizado "Dr. Guillermo Rawson"	San Juan
Austria	Kepler Universitätsklinikum Campus III	Linz
Austria	Many Locations	Multiple Locations
Belgium	AZ St-Jan Brugge Oostende AV	Brugge
Belgium	Many Locations	Multiple Locations
Brazil	Hospital das Clínicas de Botucatu - UNESP Botucatu	Botucatu	Sao Paulo
Brazil	Many Locations	Multiple Locations
Brazil	Unifesp/Epm	Sao Paulo
Bulgaria	Many Locations	Multiple Locations
Bulgaria	UMHAT Sveti Georgi	Plovdiv
Bulgaria	Acibadem City Clinic Multiprofile Hospital for Active Treatm	Sofia
Bulgaria	II SOGHAT Sheinovo	Sofia
Bulgaria	SHOGAT Prof Dimitar Stamatov	Varna
Czechia	Many Locations	Multiple Locations
Czechia	Fakultni nemocnice Ostrava	Ostrava
Czechia	Vseobecna fakultni nemocnice v Praze	Praha 2
Greece	P & A KYRIAKOU Children's Hospital	Athens
Greece	University General Hospital of Ioannina	Ioannina
Greece	Many Locations	Multiple Locations
Greece	Papageorgiou General Hospital of Thessaloniki	Thessaloniki
Hong Kong	Queen Mary Hospital	Hong Kong
Hong Kong	Many Locations	Multiple Locations
Hungary	EKBC, Uj Szent Janos Korhaz es Szakrendelo	Budapest
Hungary	Many Locations	Multiple Locations
Israel	Many Locations	Multiple Locations
Israel	Kaplan Medical Center	Rehovot
Italy	Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico	Milano	Lombardia
Italy	Many Locations	Multiple Locations
Italy	A.O. di Perugia	Perugia	Umbria
Italy	Fondazione Policlinico Universitario Agostino Gemelli IRCCS	Roma	Lazio
Italy	IRCCS Ospedale Pediatrico Bambino Gesù	Roma	Lazio
Japan	Tokyo Metropolitan Children's Medical Center	Fuchu	Tokyo
Japan	Fukuoka University Hospital	Fukuoka
Japan	Kyushu University Hospital	Fukuoka
Japan	Fukushima Medical University Hospital	Fukushima
Japan	University of Occupational and Environmental Health	Kitakyushu	Fukuoka
Japan	Kurume University Hospital	Kurume	Fukuoka
Japan	Many Locations	Multiple Locations
Japan	Saitama Children's Medical Center	Saitama
Japan	Okinawa Prefectural Nanbu Medical Center and Children's MC	Shimajiri-gun	Okinawa
Japan	Showa University Hospital	Shinagawa	Tokyo
Japan	Tokyo Metropolitan Bokutoh Hospital	Sumida-ku	Tokyo
Japan	Tokyo Metropolitan Ohtsuka Hospital	Toshima-ku	Tokyo
Korea, Republic of	Soon Chun Hyang University Cheonan Hospital	Cheonan-si	Chungcheongnamdo
Korea, Republic of	Many Locations	Multiple Locations
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Malaysia	Hospital Kuala Lumpur	Kuala Lumpur
Malaysia	Many Locations	Multiple Locations
Netherlands	Many Locations	Multiple Locations
Netherlands	Maxima Medisch Centrum, locatie Veldhoven	Veldhoven
Poland	Many Locations	Multiple Locations
Poland	Ginekologiczno-Polozniczy SK UM im. K. Marcinkowskiego	Poznan
Portugal	Hospital Prof. Dr. Fernando Fonseca	Amadora	Lisboa
Portugal	CHLO - Hospital Sao Francisco Xavier	Lisboa
Portugal	Many Locations	Multiple Locations
Romania	Clinical Emergency County Hospital	Cluj-Napoca	Cluj
Romania	Spitalul Clinic de Obstretica si Ginecologie "Cuza Voda"	Iasi
Romania	Many Locations	Multiple Locations
Russian Federation	FSAI NMRC IRTC "Eye Microsurgery", Kaluga's Branch	Kaluga
Russian Federation	FGBUZ "NPC of special children care n.a. Voino-Yaseneckogo"	Moscow
Russian Federation	Russian National Scientific Medical University	Moscow
Russian Federation	Many Locations	Multiple Locations
Russian Federation	City Children Hospital ¿1	Saint-Petersburg
Russian Federation	Pediatric Medical University	Saint-Petersburg
Singapore	Many Locations	Multiple Locations
Singapore	KK Women's and Children's Hospital	Singapore
Slovakia	Narodny ustav detskych chorob	Bratislava
Slovakia	Many Locations	Multiple Locations
Spain	Hospital Universitario "La Paz"	Madrid
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	Hospital Regional de Málaga	Málaga
Spain	Many Locations	Multiple Locations
Sweden	Sahlgrenska Universitetssjukhuset	Göteborg
Sweden	Many Locations	Multiple Locations
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	Many Locations	Multiple Locations
Taiwan	Mackay Memorial Hospital	Taipei
Turkey	S.B.U. Adana Sehir Egitim ve Arastirma Hastanesi	Adana
Turkey	Baskent Universitesi Tip Fakultesi Hastanesi	Ankara
Turkey	Gazi Universitesi Tip Fakultesi	Ankara
Turkey	Hacettepe Universitesi Tip Fakultesi	Ankara
Turkey	Saglik Bilimleri Universitesi Antalya EA Hastanesi	Antalya
Turkey	Eskisehir Osmangazi Universitesi Tip Fakultesi	Eskisehir
Turkey	Many Locations	Multiple Locations
Ukraine	Many Locations	Multiple Locations
Ukraine	MI"Odesa Regional Children's Clinical Hospital"	Odesa
United Kingdom	Birmingham Womens Hospital	Birmingham
United Kingdom	Many Locations	Multiple Locations

Sponsors (2)

Lead Sponsor	Collaborator
Bayer	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

Argentina,  Austria,  Belgium,  Brazil,  Bulgaria,  Czechia,  Greece,  Hong Kong,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Netherlands,  Poland,  Portugal,  Romania,  Russian Federation,  Singapore,  Slovakia,  Spain,  Sweden,  Taiwan,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	Number of Aflibercept Administrations	Total number of injections in both eyes.	From baseline (treatment) up to week 24.
Secondary	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.

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