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Aflibercept for Retinopathy of Prematurity - Intravitreal Injection Versus Laser Therapy
Phase 3 trial testing Eylea (Aflibercept, BAY86-5321) in Retinopathy of Prematurity (ROP) in 113 participants. Completed in 12 February 2021.
| Lead sponsor | Bayer |
|---|---|
| Phase | Phase 3 |
| Status | Completed |
| Study type | INTERVENTIONAL |
| Allocation | randomized |
| Design | parallel |
| Masking | none |
| Primary purpose | treatment |
| Enrollment | 113 |
| Start date | 25 September 2019 |
| Primary completion | 12 February 2021 |
| Estimated completion | 12 February 2021 |
| Sites | 90 locations across Hong Kong, Italy, Japan, Malaysia, Taiwan, Poland, South Korea, Netherlands |
Bayer — full company profile →
Under 32 Weeks, any sex, with Retinopathy of Prematurity (ROP). Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
Active ROP was defined as ROP requiring treatment. Unfavorable structural outcomes included retinal detachment, macular dragging, macular fold, or retrolental opacity.
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 0.855 | |
| Laser Photocoagulation | 0.821 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 0.072 | |
| Laser Photocoagulation | 0.096 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 0.161 | |
| Laser Photocoagulation | 0.063 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 16.20 | ± 2.81 |
| Laser Photocoagulation | 15.63 | ± 3.53 |
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | -15.42 | ± 4.46 |
| Laser Photocoagulation | -14.77 | ± 4.19 |
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
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 38.7 | |
| Laser Photocoagulation | 36.8 |
Participants treated after week 21 were followed-up for adverse events up to week 28. Ocular SAEs in treated eyes only were reported.
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 13.3 | |
| Laser Photocoagulation | 7.9 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 52.0 | |
| Laser Photocoagulation | 63.2 |
Participants treated after week 21 were followed-up for adverse events up to week 28. Systemic SAEs only were reported.
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 24.0 | |
| Laser Photocoagulation | 36.8 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 480.607 | ± 884.724 |
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 218.965 | ± 358.933 |
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 133.093 | ± 205.052 |
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.
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 0 | |
| Aflibercept 0.4 mg | 75 |
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 1 | |
| Aflibercept 0.4 mg | 74 |
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
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 0 |
Total number of injections in both eyes.
| Group | Value | 95% CI |
|---|---|---|
| Aflibercept 0.4 mg | 0 | |
| Laser Photocoagulation | 34 | |
| Aflibercept 0.4 mg | 4 | |
| Laser Photocoagulation | 0 | |
| Aflibercept 0.4 mg | 55 | |
| Laser Photocoagulation | 3 | |
| Aflibercept 0.4 mg | 6 | |
| Laser Photocoagulation | 1 |
Time frame: After the first administration and not later than 30 days after the last administration of study treatment, up to 24 weeks.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | Aflibercept 0.4 mg | Laser Photocoagulation |
|---|---|---|---|
| Retinal detachment | Eye disorders | — | — |
| Retinal haemorrhage | Eye disorders | — | — |
| Bronchiolitis | Infections and infestations | — | — |
| Infantile apnoea | Respiratory, thoracic and mediastinal disorders | — | — |
| Pulmonary valve stenosis | Cardiac disorders | — | — |
| Corneal oedema | Eye disorders | — | — |
| Retinopathy of prematurity | Eye disorders | — | — |
| Vitreous haemorrhage | Eye disorders | — | — |
| Necrotising colitis | Gastrointestinal disorders | — | — |
| Conjunctivitis | Infections and infestations | — | — |
| Pneumonia | Infections and infestations | — | — |
| Rhinitis | Infections and infestations | — | — |
| Upper respiratory tract infection | Infections and infestations | — | — |
| COVID-19 | Infections and infestations | — | — |
| Overdose | Injury, poisoning and procedural complications | — | — |
| C-reactive protein increased | Investigations | — | — |
| Intraocular pressure increased | Investigations | — | — |
| Apnoea | Respiratory, thoracic and mediastinal disorders | — | — |
| Bronchopulmonary dysplasia | Respiratory, thoracic and mediastinal disorders | — | — |
| Pneumonia aspiration | Respiratory, thoracic and mediastinal disorders | — | — |
| Respiratory arrest | Respiratory, thoracic and mediastinal disorders | — | — |
| Reaction | System | Aflibercept 0.4 mg | Laser Photocoagulation |
|---|---|---|---|
| Retinal haemorrhage | Eye disorders | — | — |
| Conjunctival haemorrhage | Eye disorders | — | — |
| Eyelid oedema | Eye disorders | — | — |
| Umbilical hernia | Gastrointestinal disorders | — | — |
| Injection site haemorrhage | General disorders | — | — |
| Pyrexia | General disorders | — | — |
| Conjunctivitis | Infections and infestations | — | — |
| Oxygen saturation decreased | Investigations | — | — |
| Haemorrhage subcutaneous | Skin and subcutaneous tissue disorders | — | — |
| Anaemia | Blood and lymphatic system disorders | — | — |
| Anaemia neonatal | Blood and lymphatic system disorders | — | — |
| Bradycardia | Cardiac disorders | — | — |
| Conjunctival oedema | Eye disorders | — | — |
| Retinopathy of prematurity | Eye disorders | — | — |
| Inguinal hernia | Gastrointestinal disorders | — | — |
| Bacterial disease carrier | Infections and infestations | — | — |
| Rhinitis | Infections and infestations | — | — |
| Intraocular pressure increased | Investigations | — | — |
| Brain stem auditory evoked response abnormal | Investigations | — | — |
| Otoacoustic emissions test abnormal | Investigations | — | — |
| Osteopenia | Musculoskeletal and connective tissue disorders | — | — |
| Hypoxic-ischaemic encephalopathy | Nervous system disorders | — | — |
| Apnoea | Respiratory, thoracic and mediastinal disorders | — | — |
| Dermatitis diaper | Skin and subcutaneous tissue disorders | — | — |
| Splenomegaly | Blood and lymphatic system disorders | — | — |
| Sinus tachycardia | Cardiac disorders | — | — |
| Tachycardia | Cardiac disorders | — | — |
| Cryptorchism | Congenital, familial and genetic disorders | — | — |
| Ankyloglossia congenital | Congenital, familial and genetic disorders | — | — |
| Laryngomalacia | Congenital, familial and genetic disorders | — | — |
| Congenital arterial malformation | Congenital, familial and genetic disorders | — | — |
| Auditory disorder | Ear and labyrinth disorders | — | — |
| Cushingoid | Endocrine disorders | — | — |
| Adrenomegaly | Endocrine disorders | — | — |
| Corneal oedema | Eye disorders | — | — |
| Iris adhesions | Eye disorders | — | — |
| Keratitis | Eye disorders | — | — |
| Lenticular opacities | Eye disorders | — | — |
| Retinal artery occlusion | Eye disorders | — | — |
| Retinal detachment | Eye disorders | — | — |
Most-reported serious reactions: Retinal detachment, Retinal haemorrhage, Bronchiolitis, Infantile apnoea, Pulmonary valve stenosis, Corneal oedema, Retinopathy of prematurity, Vitreous haemorrhage.
Data from ClinicalTrials.gov NCT04004208 adverse events section.
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.
6 peer-reviewed publications reference this trial (live from Europe PMC):
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