Retinopathy of Prematurity (ROP)
Conditions
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.
Interventions
Solution in a sterile glass vial, Dose A, IVT injection.
PROCEDURELaser photocoagulation
Transpupillary conventional laser ablative therapy
Sponsors
Regeneron Pharmaceuticals
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 32 Weeks
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
| 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. |
Countries
Argentina, Austria, Belgium, Brazil, Bulgaria, Czechia, Greece, Hong Kong, Hungary, Israel, Italy, Japan, Malaysia, Netherlands, Poland, Portugal, Romania, Russia, Singapore, Slovakia, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom
Participant flow
Recruitment details
Study was conducted at 64 centers in 27 countries or regions, between 25-SEP-2019 (first participant first visit) and 12-Feb-2021 (last participant last visit).
Pre-assignment details
121 participants were screened. 1 participant was a screen fail and 2 participants were withdrawn by parent/guardian. 118 participants were randomized, 75 participants were randomized to the aflibercept arm and 43 to the laser arm. 113 participants were treated, 5 participants randomized to the laser photocoagulation arm were withdrawn before receiving any study intervention.
Participants by arm
| Arm | Count |
|---|---|
| Aflibercept 0.4 mg One intravitreal injection of aflibercept 0.4 mg (0.01 mL) per eligible eye at baseline (treatment), with up to 2 re-injections at the same single dose allowed for each eligible eye if required and interval since last aflibercept injection was 28 or more days. One or both eyes could be treated. | 75 |
| Laser Photocoagulation Laser treatment to each eligible eye at baseline (treatment), with supplementary laser treatments allowed. Multiple sessions within one week from baseline were counted as a single treatment. One or both eyes could be treated. | 38 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | COVID-19 pandemic | 1 | 0 |
| Overall Study | Death | 3 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by parent/guardian | 1 | 1 |
Baseline characteristics
| Characteristic | Aflibercept 0.4 mg | Total | Laser Photocoagulation |
|---|---|---|---|
| Age, Continuous | 26.43 weeks STANDARD_DEVIATION 2.1 | 26.29 weeks STANDARD_DEVIATION 1.9 | 26 weeks STANDARD_DEVIATION 1.6 |
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adults (18-64 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 65-84 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 75 Participants | 113 Participants | 38 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian Indian | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian: Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Chinese | 4 Participants | 4 Participants | 0 Participants |
| Race/Ethnicity, Customized Japanese | 10 Participants | 16 Participants | 6 Participants |
| Race/Ethnicity, Customized Korean | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 55 Participants | 83 Participants | 28 Participants |
| ROP classification by investigator AP-ROP: Zone I | 12 Participants | 16 Participants | 4 Participants |
| ROP classification by investigator AP-ROP: Zone II | 2 Participants | 3 Participants | 1 Participants |
| ROP classification by investigator Zone I excluding AP-ROP | 15 Participants | 22 Participants | 7 Participants |
| ROP classification by investigator Zone II excluding AP-ROP | 46 Participants | 72 Participants | 26 Participants |
| Sex: Female, Male Female | 34 Participants | 53 Participants | 19 Participants |
| Sex: Female, Male Male | 41 Participants | 60 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 75 | 0 / 38 |
| other Total, other adverse events | 53 / 75 | 23 / 38 |
| serious Total, serious adverse events | 9 / 75 | 10 / 38 |
Outcome results
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.
Time frame: At 24 weeks after starting study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 0.4 mg | Proportion of Participants With Absence of Active ROP and Unfavorable Structural Outcomes | 0.855 Proportion of participants |
| Laser Photocoagulation | Proportion of Participants With Absence of Active ROP and Unfavorable Structural Outcomes | 0.821 Proportion of participants |
Comparison: Bayesian analysis with non-informative prior distributions. Calculation of two-sided 90% credible interval for the treatment difference (aflibercept - laser photocoagulation).90% CI: [-0.08, 0.162]
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.
Time frame: From Day 1 up to week 24.
Population: The outcome measure was analyzed based on pharmacokinetic analysis set (PKS). The PKS included all participants who received aflibercept treatment at the baseline visit and who had at least one nonmissing PK assessment following the first dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aflibercept 0.4 mg | Concentrations of Free Aflibercept in Plasma | WEEK 0, DAY 1 | 480.607 ng/mL | Standard Deviation 884.724 |
| Aflibercept 0.4 mg | Concentrations of Free Aflibercept in Plasma | WEEK 2 | 218.965 ng/mL | Standard Deviation 358.933 |
| Aflibercept 0.4 mg | Concentrations of Free Aflibercept in Plasma | WEEK 4 | 133.093 ng/mL | Standard Deviation 205.052 |
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.
Time frame: From baseline (treatment) up to week 24.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aflibercept 0.4 mg | Exploration of ROP Activity Scale Proposed by the International Neonatal Consortium | Baseline | 16.20 Scores on a scale | Standard Deviation 2.81 |
| Aflibercept 0.4 mg | Exploration of ROP Activity Scale Proposed by the International Neonatal Consortium | Change from baseline to Week 24 | -15.42 Scores on a scale | Standard Deviation 4.46 |
| Laser Photocoagulation | Exploration of ROP Activity Scale Proposed by the International Neonatal Consortium | Baseline | 15.63 Scores on a scale | Standard Deviation 3.53 |
| Laser Photocoagulation | Exploration of ROP Activity Scale Proposed by the International Neonatal Consortium | Change from baseline to Week 24 | -14.77 Scores on a scale | Standard Deviation 4.19 |
Secondary
Number of Aflibercept Administrations
Total number of injections in both eyes.
Time frame: From baseline (treatment) up to week 24.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aflibercept 0.4 mg | Number of Aflibercept Administrations | 2 aflibercept administrations | 55 Participants |
| Aflibercept 0.4 mg | Number of Aflibercept Administrations | 1 aflibercept administration | 4 Participants |
| Aflibercept 0.4 mg | Number of Aflibercept Administrations | 3 aflibercept administrations | 6 Participants |
| Aflibercept 0.4 mg | Number of Aflibercept Administrations | 4 aflibercept administrations | 10 Participants |
| Aflibercept 0.4 mg | Number of Aflibercept Administrations | 0 aflibercept administration | 0 Participants |
| Laser Photocoagulation | Number of Aflibercept Administrations | 4 aflibercept administrations | 0 Participants |
| Laser Photocoagulation | Number of Aflibercept Administrations | 0 aflibercept administration | 34 Participants |
| Laser Photocoagulation | Number of Aflibercept Administrations | 1 aflibercept administration | 0 Participants |
| Laser Photocoagulation | Number of Aflibercept Administrations | 2 aflibercept administrations | 3 Participants |
| Laser Photocoagulation | Number of Aflibercept Administrations | 3 aflibercept administrations | 1 Participants |
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.
Time frame: From baseline (treatment) up to week 24.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Aflibercept 0.4 mg | Number of Laser Treatments | 0 laser treatment | 70 Participants |
| Aflibercept 0.4 mg | Number of Laser Treatments | 1 laser treatment | 3 Participants |
| Aflibercept 0.4 mg | Number of Laser Treatments | 2 laser treatments | 2 Participants |
| Aflibercept 0.4 mg | Number of Laser Treatments | 3 laser treatments | 0 Participants |
| Aflibercept 0.4 mg | Number of Laser Treatments | 4 laser treatments | 0 Participants |
| Aflibercept 0.4 mg | Number of Laser Treatments | 6 laser treatments | 0 Participants |
| Laser Photocoagulation | Number of Laser Treatments | 4 laser treatments | 2 Participants |
| Laser Photocoagulation | Number of Laser Treatments | 0 laser treatment | 0 Participants |
| Laser Photocoagulation | Number of Laser Treatments | 3 laser treatments | 1 Participants |
| Laser Photocoagulation | Number of Laser Treatments | 1 laser treatment | 4 Participants |
| Laser Photocoagulation | Number of Laser Treatments | 6 laser treatments | 1 Participants |
| Laser Photocoagulation | Number of Laser Treatments | 2 laser treatments | 30 Participants |
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.
Time frame: Baseline (treatment) and 12 weeks after aflibercept injection
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Aflibercept 0.4 mg | Number of Participants With Anti-drug Antibodies (ADA) | Baseline | ADA positive response | 0 Participants |
| Aflibercept 0.4 mg | Number of Participants With Anti-drug Antibodies (ADA) | Baseline | ADA negative response | 75 Participants |
| Aflibercept 0.4 mg | Number of Participants With Anti-drug Antibodies (ADA) | Week 12 | ADA positive response | 1 Participants |
| Aflibercept 0.4 mg | Number of Participants With Anti-drug Antibodies (ADA) | Week 12 | ADA negative response | 74 Participants |
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
Time frame: At 12 weeks after aflibercept injection
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aflibercept 0.4 mg | Number of Participants With Potential Neutralizing Antibodies (NAb) | 0 Participants |
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.
Time frame: From baseline (treatment) up to week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 0.4 mg | Percentage of Participants With Ocular Serious Adverse Events (SAEs) | 13.3 Percentage of participants |
| Laser Photocoagulation | Percentage of Participants With Ocular Serious Adverse Events (SAEs) | 7.9 Percentage of participants |
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
Time frame: From baseline (treatment) up to week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 0.4 mg | Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs) | 38.7 Percentage of participants |
| Laser Photocoagulation | Percentage of Participants With Ocular Treatment-emergent Adverse Events (TEAEs) | 36.8 Percentage of participants |
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.
Time frame: From baseline (treatment) up to week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 0.4 mg | Percentage of Participants With Systemic SAEs | 24.0 Percentage of participants |
| Laser Photocoagulation | Percentage of Participants With Systemic SAEs | 36.8 Percentage of participants |
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.
Time frame: From baseline (treatment) up to week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 0.4 mg | Percentage of Participants With Systemic TEAEs | 52.0 Percentage of participants |
| Laser Photocoagulation | Percentage of Participants With Systemic TEAEs | 63.2 Percentage of participants |
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.
Time frame: From baseline (treatment) up to week 24.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 0.4 mg | Proportion of Participants Requiring Intervention With a Second Treatment Modality | 0.072 Proportion of participants |
| Laser Photocoagulation | Proportion of Participants Requiring Intervention With a Second Treatment Modality | 0.096 Proportion of participants |
Comparison: Bayesian analysis with non-informative prior distributions. Calculation of two-sided 90% credible interval for the treatment difference (aflibercept - laser photocoagulation).90% CI: [-0.11, 0.046]
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.
Time frame: From baseline (treatment) up to week 24.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aflibercept 0.4 mg | Proportion of Participants With Recurrence of ROP | 0.161 Proportion of participants |
| Laser Photocoagulation | Proportion of Participants With Recurrence of ROP | 0.063 Proportion of participants |
Comparison: Bayesian analysis with non-informative prior distributions. Calculation of two-sided 90% credible interval for the treatment difference (aflibercept - laser photocoagulation).90% CI: [0.019, 0.175]