E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | Retinopathy of prematurity | retinopatia del prematuro (ROP) | |
E.1.1.1 | Medical condition in easily understood language | Retinopathy of prematurity | retinopatia del prematuro (ROP) | |
E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 | E.1.2 | Level | PT | E.1.2 | Classification code | 10038933 | E.1.2 | Term | Retinopathy of prematurity | E.1.2 | System Organ Class | 10015919 - Eye disorders | |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial | To assess the efficacy of aflibercept in subjects diagnosed with retinopathy of prematurity (ROP) in comparison to laser | Valutare l'efficacia di aflibercept in soggetti con diagnosi di retinopatia del prematuro (ROP) rispetto al laser | |
E.2.2 | Secondary objectives of the trial | To assess the safety and tolerability of aflibercept To assess the treatment burden of aflibercept and laser To describe the systemic exposure to aflibercept | Valutare la sicurezza e la tollerabilità di aflibercept Valutare l'onere associato al trattamento con aflibercept e con il laser Descrivere l'esposizione sistemica ad aflibercept | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria | 1.Gestational age at birth ≤ 32 weeks or birth weight ≤ 1500 g Type of Participant and Disease Characteristics 2.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 AP-ROP 3.Weight at baseline (day of treatment) ≥ 800 g 4.Male or female 5.Signed informed consent from parent(s)/legally authorized representative(s) as described in Section 10.1.3 of the clinical trial protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the clinical trial protocol | 1.Gestational age at birth ≤ 32 weeks or birth weight ≤ 1500 g Type of Participant and Disease Characteristics 2.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 AP-ROP 3.Weight at baseline (day of treatment) ≥ 800 g 4.Male or female 5.Signed informed consent from parent(s)/legally authorized representative(s) as described in Section 10.1.3 of the clinical trial protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the clinical trial protocol | |
E.4 | Principal exclusion criteria | Subjects are excluded from the study if any of the following “per subject” criteria are met. A potential study eye is excluded from the study if any of the “per eye” criteria are met: Medical Conditions – per subject 1.Known or suspected chromosomal abnormality, genetic disorder or syndrome 2.Previous exposure to any IVT or systemic anti-VEGF agent, including maternal exposure during pregnancy and/or during breastfeeding 3.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) 4.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 5.Presence of active ocular infection within 5 days of the first treatment Medical Conditions – per eye 6.Advanced stages of ROP with partial or complete retinal detachment (ROP Stages 4 and 5) 7.ROP involving only Zone III 8.Ocular abnormalities that may interfere with the administration of study intervention or assessment of the study primary endpoint Prior/Concomitant Therapy – per subject 9.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 Prior/Concomitant Therapy – per eye 10.Previous surgical or nonsurgical treatment for ROP (IVT anti-VEGF injection, ablative laser therapy, cryotherapy, and vitrectomy) Prior/Concurrent Clinical Study Experience 11.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 | Subjects are excluded from the study if any of the following “per subject” criteria are met. A potential study eye is excluded from the study if any of the “per eye” criteria are met: Medical Conditions – per subject 1.Known or suspected chromosomal abnormality, genetic disorder or syndrome 2.Previous exposure to any IVT or systemic anti-VEGF agent, including maternal exposure during pregnancy and/or during breastfeeding 3.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) 4.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 5.Presence of active ocular infection within 5 days of the first treatment Medical Conditions – per eye 6.Advanced stages of ROP with partial or complete retinal detachment (ROP Stages 4 and 5) 7.ROP involving only Zone III 8.Ocular abnormalities that may interfere with the administration of study intervention or assessment of the study primary endpoint Prior/Concomitant Therapy – per subject 9.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 Prior/Concomitant Therapy – per eye 10.Previous surgical or nonsurgical treatment for ROP (IVT anti-VEGF injection, ablative laser therapy, cryotherapy, and vitrectomy) Prior/Concurrent Clinical Study Experience 11.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 | |
E.5 End points |
E.5.1 | Primary end point(s) | Primary Endpoint Proportion of patients with absence of active ROP and unfavorable structural outcomes at 24 weeks after starting study treatment | Percentuale di pazienti senza ROP attiva ed esiti strutturali sfavorevoli 24 settimane dopo l'inizio del trattamento in studio | |
E.5.1.1 | Timepoint(s) of evaluation of this end point | at 24 weeks after starting study Treatment | 24 settimane dopo inizio trattamento sperimentale | |
E.5.2 | Secondary end point(s) | Secondary Endpoints addressing primary objectives Requirement for intervention with a second treatment modality from baseline to Week 24 Recurrence of ROP from baseline to Week 24 To explore new Retinopathy of Prematurity Activity Scale proposed by the International Neonatal Consortium Secondary Endpoints addressing secondary objectives •Number of aflibercept administrations from baseline to Week 24 •Number of laser treatments from baseline to Week 24 •Proportion of participants with ocular TEAEs and SAEs from baseline to Week 24 •Proportion of participants with systemic TEAEs and SAEs from baseline to Week 24 •Systemic exposure to free aflibercept (at expected maximum plasma concentration and during elimination period from plasma) determined by sparse sampling •Presence of anti-drug antibodies before and 12 weeks after aflibercept injection | Necessità di intervento con una seconda modalità di trattamento dal basale alla Settimana 24 Recidiva di ROP dal basale alla Settimana 24 Esame della nuova Scala di attività nella retinopatia del prematuro (Retinopathy of Prematurity Activity Scale) proposta dall'International Neonatal Consortium Endpoint secondari associati agli obiettivi secondari: Numero di somministrazioni di aflibercept dal basale alla Settimana 24 Numero di trattamenti laser dal basale alla Settimana 24 Percentuale di partecipanti con TEAE e SAE oculari dal basale alla Settimana 24 Percentuale di partecipanti con TEAE e SAE sistemici dal basale alla Settimana 24 Esposizione sistemica ad aflibercept libero (alla concentrazione plasmatica massima prevista e durante il periodo di eliminazione dal plasma) determinata con il prelievo di campioni sporadici Presenza di anticorpi anti-farmaco prima e 12 settimane dopo l'iniezione di aflibercept | |
E.5.2.1 | Timepoint(s) of evaluation of this end point | • From baseline to Week 24 | dal basale alla settimana 24 | |
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description | |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 | The trial involves single site in the Member State concerned | No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 67 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | Argentina | Austria | Belgium | Brazil | Bulgaria | Canada | Czech Republic | Estonia | France | Germany | Greece | Hong Kong | Hungary | Israel | Italy | Japan | Korea, Democratic People's Republic of | Latvia | Lithuania | Malaysia | Netherlands | Poland | Portugal | Romania | Russian Federation | Singapore | Slovakia | Spain | Sweden | Switzerland | Taiwan | Turkey | Ukraine | United Kingdom | |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | The end of the study as a whole is defined as the date of the last visit of the last subject in the study in all centers in all participating countries (EU and non-EU). | LVLS | |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 7 |