Aflibercept for Retinopathy of Prematurity - Intravitreal Injection Versus Laser Therapy

Phase 3

Completed

Conditions: Retinopathy of Prematurity (ROP)

Interventions: Drug: Eylea (Aflibercept, BAY86-5321)
Procedure: Laser photocoagulation

Registration Number: NCT04004208

Lead Sponsor: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 113

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Aflibercept arm	Eylea (Aflibercept, BAY86-5321)	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.
Laser photocoagulation arm	Laser photocoagulation	Subjects randomized to laser photocoagulation will receive treatment in each eligible eye at baseline. Retreatments may be administered if needed.

Primary Outcome Measures

Name	Time	Method
Proportion of Participants With Absence of Active ROP and Unfavorable Structural Outcomes	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

Name	Time	Method
Percentage of Participants With Systemic TEAEs	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.
Proportion of Participants Requiring Intervention With a Second Treatment Modality	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.
Proportion of Participants With Recurrence of ROP	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.
Exploration of ROP Activity Scale Proposed by the International Neonatal Consortium	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.
Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs)	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
Percentage of Participants With Ocular Serious Adverse Events (SAEs)	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.
Percentage of Participants With Systemic SAEs	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.
Concentrations of Free Aflibercept in Plasma	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.
Number of Participants With Anti-drug Antibodies (ADA)	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.
Number of Participants With Potential Neutralizing Antibodies (NAb)	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
Number of Aflibercept Administrations	From baseline (treatment) up to week 24.	Total number of injections in both eyes.
Number of Laser Treatments	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.

Trial Locations

Locations (64): UMHAT Sveti Georgi
🇧🇬
Plovdiv, Bulgaria
SHOGAT Prof Dimitar Stamatov
🇧🇬
Varna, Bulgaria
Kurume University Hospital
🇯🇵
Kurume, Fukuoka, Japan
Kyushu University Hospital
🇯🇵
Fukuoka, Japan
Fukuoka University Hospital
🇯🇵
Fukuoka, Japan
Fukushima Medical University Hospital
🇯🇵
Fukushima, Japan
Saitama Children's Medical Center
🇯🇵
Saitama, Japan
Maxima Medisch Centrum, locatie Veldhoven
🇳🇱
Veldhoven, Netherlands
Ginekologiczno-Polozniczy SK UM im. K. Marcinkowskiego
🇵🇱
Poznan, Poland
CHLO - Hospital Sao Francisco Xavier
🇵🇹
Lisboa, Portugal
Tokyo Metropolitan Bokutoh Hospital
🇯🇵
Sumida-ku, Tokyo, Japan
Tokyo Metropolitan Ohtsuka Hospital
🇯🇵
Toshima-ku, Tokyo, Japan
Clinical Emergency County Hospital
🇷🇴
Cluj-Napoca, Cluj, Romania
KK Women's and Children's Hospital
🇸🇬
Singapore, Singapore
Gazi Universitesi Tip Fakultesi
🇹🇷
Ankara, Turkey
Eskisehir Osmangazi Universitesi Tip Fakultesi
🇹🇷
Eskisehir, Turkey
MI"Odesa Regional Children's Clinical Hospital"
🇺🇦
Odesa, Ukraine
Spitalul Clinic de Obstretica si Ginecologie "Cuza Voda"
🇷🇴
Iasi, Romania
FSAI NMRC IRTC "Eye Microsurgery", Kaluga's Branch
🇷🇺
Kaluga, Russian Federation
Pediatric Medical University
🇷🇺
Saint-Petersburg, Russian Federation
City Children Hospital ¿1
🇷🇺
Saint-Petersburg, Russian Federation
Russian National Scientific Medical University
🇷🇺
Moscow, Russian Federation
FGBUZ "NPC of special children care n.a. Voino-Yaseneckogo"
🇷🇺
Moscow, Russian Federation
Narodny ustav detskych chorob
🇸🇰
Bratislava, Slovakia
S.B.U. Adana Sehir Egitim ve Arastirma Hastanesi
🇹🇷
Adana, Turkey
Baskent Universitesi Tip Fakultesi Hastanesi
🇹🇷
Ankara, Turkey
Fakultni nemocnice Ostrava
🇨🇿
Ostrava, Czechia
Hospital das Clínicas de Botucatu - UNESP Botucatu
🇧🇷
Botucatu, Sao Paulo, Brazil
A.O. di Perugia
🇮🇹
Perugia, Umbria, Italy
Kepler Universitätsklinikum Campus III
🇦🇹
Linz, Austria
Many Locations
🇬🇧
Multiple Locations, United Kingdom
AZ St-Jan Brugge Oostende AV
🇧🇪
Brugge, Belgium
Unifesp/Epm
🇧🇷
Sao Paulo, Brazil
Acibadem City Clinic Multiprofile Hospital for Active Treatm
🇧🇬
Sofia, Bulgaria
P & A KYRIAKOU Children's Hospital
🇬🇷
Athens, Greece
Papageorgiou General Hospital of Thessaloniki
🇬🇷
Thessaloniki, Greece
Kaplan Medical Center
🇮🇱
Rehovot, Israel
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹
Roma, Lazio, Italy
IRCCS Ospedale Pediatrico Bambino Gesù
🇮🇹
Roma, Lazio, Italy
University of Occupational and Environmental Health
🇯🇵
Kitakyushu, Fukuoka, Japan
Tokyo Metropolitan Children's Medical Center
🇯🇵
Fuchu, Tokyo, Japan
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
🇮🇹
Milano, Lombardia, Italy
Vseobecna fakultni nemocnice v Praze
🇨🇿
Praha 2, Czechia
EKBC, Uj Szent Janos Korhaz es Szakrendelo
🇭🇺
Budapest, Hungary
Showa University Hospital
🇯🇵
Shinagawa, Tokyo, Japan
Okinawa Prefectural Nanbu Medical Center and Children's MC
🇯🇵
Shimajiri-gun, Okinawa, Japan
Hacettepe Universitesi Tip Fakultesi
🇹🇷
Ankara, Turkey
Hospital Kuala Lumpur
🇲🇾
Kuala Lumpur, Malaysia
Asan Medical Center
🇰🇷
Seoul, Korea, Republic of
Hospital Prof. Dr. Fernando Fonseca
🇵🇹
Amadora, Lisboa, Portugal
Sahlgrenska Universitetssjukhuset
🇸🇪
Göteborg, Sweden
Saglik Bilimleri Universitesi Antalya EA Hastanesi
🇹🇷
Antalya, Turkey
Birmingham Womens Hospital
🇬🇧
Birmingham, United Kingdom
Soon Chun Hyang University Cheonan Hospital
🇰🇷
Cheonan-si, Chungcheongnamdo, Korea, Republic of
Samsung Medical Center
🇰🇷
Seoul, Korea, Republic of
Hospital Universitario 12 de Octubre
🇪🇸
Madrid, Spain
Hospital Universitario "La Paz"
🇪🇸
Madrid, Spain
Hospital Regional de Málaga
🇪🇸
Málaga, Spain
University General Hospital of Ioannina
🇬🇷
Ioannina, Greece
Hospital Público Descentralizado "Dr. Guillermo Rawson"
🇦🇷
San Juan, Argentina
II SOGHAT Sheinovo
🇧🇬
Sofia, Bulgaria
Mackay Memorial Hospital
🇨🇳
Taipei, Taiwan
Kaohsiung Medical University Chung-Ho Memorial Hospital
🇨🇳
Kaohsiung, Taiwan
Queen Mary Hospital
🇭🇰
Hong Kong, Hong Kong