E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Neovascular Age Related Macular Degeneration |
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E.1.1.1 | Medical condition in easily understood language |
Eye disease that can blur central vision |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10075568 |
E.1.2 | Term | Wet age-related macular degeneration |
E.1.2 | System Organ Class | 100000004853 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to demonstrate that the biosimilar candidate ALT-L9 2 mg/50 µL is equivalent to Eylea® (aflibercept) in subjects with wet (neovascular) age related macular degeneration (nAMD) in terms of best corrected visual acuity (BCVA). |
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E.2.2 | Secondary objectives of the trial |
- Evaluate the efficacy of ALT-L9 versus Eylea® in subjects with nAMD based on central subfield thickness (CST), area of choroidal neovascularization (CNV), and leakage from CNV lesion - Evaluate the safety of ALT-L9 versus Eylea® - Evaluate the systemic exposure of ALT-L9 versus Eylea® in subjects participating in pharmacokinetic (PK) evaluation - Evaluate the immunogenicity of ALT-L9 versus Eylea®
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Able and willing to read, understand, and sign the informed consent form (ICF). The signed ICF must be obtained before any study-related procedures are performed. The subject must be willing and able to undertake all scheduled visits and assessments as judged by the investigator 2. Subjects aged 50 years or older at the time of screening, when obtaining written informed consent 3. BCVA of 20/40 to 20/200 (both inclusive) in the study eye using the ETDRS letter chart (≤73 and ≥34 ETDRS letters) at screening and Day 1 before randomization 4. Newly diagnosed, treatment-naive, active subfoveal or juxtafoveal CNV lesion secondary to AMD in the study eye. Active CNV means the presence of leakage as evidenced by FA and intraretinal or subretinal fluid as evidenced by SD-OCT that is confirmed by the CRC during screening 5. Total lesion area of ≤9.0 disc areas (≤22.86 mm2) in size (including blood, scars, and neovascularization) in the study eye as assessed by FA and confirmed by the CRC before randomization 6. The area of CNV must be ≥50% of the total lesion area in the study eye confirmed by the CRC before randomization 7. Female subjects must agree to use a highly effective method of contraception consistent with local regulations during the course of the study and for at least 90 days after the last dose of the study drug (excluding women who are not of childbearing potential). Refer to Appendix 1 for more details. Contraception is not required if the subject or his/her partner has been surgically sterilized with documentation of surgical success at least 24 weeks before the date of informed consent. a. Male subjects of reproductive potential must be willing to completely abstain from sexual intercourse or agree to use an appropriate method of contraception from the time of signing the ICF and for the duration of study participation through 90 days after the last dose of the study drug. (The investigator and each subject will determine the appropriate method of contraception for the subject during study participation.) Refer to Appendix 1 for more details b. Subjects must agree to refrain from donating sperm (male subjects) and ova (female subjects) from screening through 90 days after receiving the last dose of study drug.
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E.4 | Principal exclusion criteria |
Considerations for Study Eye 1. Previous ocular treatment/surgery (including any macular laser or photodynamic therapy) for nAMD in the study eye 2. Any previous IVT anti-VEGF treatment (eg, bevacizumab, aflibercept, ranibizumab, or brolucizumab) in the study eye 3. Subretinal or intraretinal hemorrhage in the study eye involving 50% or more of the total lesion area, or with a size of ≥1 disc area (≥2.54 mm2) if involving the fovea, as assessed by FA and confirmed by the CRC 4. Subfoveal fibrosis or atrophy in the study eye as assessed by FA and confirmed by the CRC 5. Fibrosis exceeding 50% of the total lesion size in the study eye as assessed by FA and confirmed by the CRC 6. Retinal pigment epithelial rips or tears involving the macula in the study eye as assessed by FA or SD-OCT and confirmed by the CRC 7. Previous IVT surgery or scleral buckling in the study eye 8. Other intraocular surgery (including cataract surgery, laser-assisted in situ keratomileusis [LASIK], or Yttrium Aluminum Garnet [YAG] laser) or periocular surgery in the study eye within 90 days before screening, except for eyelid surgery within 30 days before screening 9. Corneal transplant in the study eye 10. Any concurrent intraocular condition in the study eye (eg, cataract or diabetic retinopathy) that, in the opinion of the investigator, could require treatment during the study period to prevent or treat loss of visual acuity or could interfere with visual acuity, optical imaging, or safety assessments defined by the study protocol 11. Aphakia or absence of the posterior capsule in the study eye, unless it occurred as a result of a YAG laser posterior capsulotomy in association with prior posterior chamber intraocular lens implantation 12. Current vitreous hemorrhage in the study eye 13. History of retinal detachment in the study eye 14. History of macular hole in the study eye 15. Uncontrolled ocular hypertension in the study eye, defined as an IOP of ≥25 mm Hg despite treatment with antiglaucoma medication 16. Presence of advanced glaucoma or optic neuropathy that involves or threatens the central visual field in the study eye 17. History of any glaucoma filtering surgery, corneal transplantation, or panretinal photocoagulation; such therapies are not allowed during the study in the study eye 18. Spherical equivalent of the refractive error in the study eye demonstrating more than 6 diopters of myopia 19. Use of ongoing topical ocular corticosteroids at screening or administrated for ≥30 consecutive days in the study eye within 90 days before screening, or the use of intraocular corticosteroid implants in the study eye within 180 days before screening for Ozurdex® or within 3 years before screening for Iluvien® 20. Prior therapeutic radiation in the study eye region
Considerations for Fellow Eye 21. Subjects with any diagnosis and/or signs of nAMD requiring IVT anti VEGF treatment in the fellow eye at screening or, in the opinion of the investigator, who are expected to need such treatments, at least before Wee 8 the evaluation of the primary efficacy endpoint 22. Use of any anti-VEGF treatment in the fellow eye within 90 days before screening 23. The BCVA of the fellow eye is worse than 20/200 (or <34 ETDRS letters)
Considerations for Either Eye 24. CNV in either eye as a result of non-AMD causes (including pathologic myopia, ocular histoplasmosis syndrome, angioid streaks, choroidal rupture, or multifocal choroiditis) as assessed by FA and confirmed by the CRC 25. Presence or history of scleromalacia in either eye 26. Active or recent (within 28 days before screening) intraocular or periocular inflammation or infection in either eye, including but not limited to conjunctivitis, keratitis, scleritis, or endophthalmitis 27. History of idiopathic or autoimmune-associated uveitis in either eye
Considerations for Systemic Treatments and General Conditions 28. Any systemic treatment to treat nAMD within 30 days before screening; such treatment or therapy will not be allowed during the study period. However, dietary supplements, vitamins, or minerals will be allowed during study 29. Any previous systemic anti-VEGF therapy within 180 days before screening 30. Use of systemic corticosteroids (except short-term [<14 consecutive days] oral corticosteroids or; inhaled, nasal, intra articular, and dermal corticosteroids) within 180 days before screening or a plan for the use of systemic corticosteroids during the course of the study 31. Use of medications known to be toxic to the lens, retina, or optic nerve at screening (such medications will not be allowed during the study period)
Refer to protocol for the entire list of exclusion criteria.
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in BCVA at Week 8 as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
* Change from baseline in BCVA letter score in the study eye overtime up to Week 52 using the ETDRS protocol * Proportion of subjects with a loss of at least 5, 10, or 15 letters inBCVA letter score in the study eye over time up to Week 52, compared with baseline, using the ETDRS protocol * Proportion of subjects with a gain of at least 5, 10, or 15 letters in BCVA letter score in the study eye over time up to Week 52, compared with baseline, using the ETDRS protocol * Change from baseline in CST in the study eye over time up to Week 4 and Week 52, as measured by spectral domain-optical coherence tomography (SD-OCT) * Proportion of subjects with existing intraretinal or subretinal fluid in the study eye over time up to Week 4 and Week 52 compared with baseline, as measured by SD-OCT * Change from baseline in total size of CNV area in the study eye over time up and Week 52, as measured by fluorescein angiography (FA) * Proportion of subjects with active CNV leakage in the study eye over time up to Week 52, compared with baseline, as measured by FA
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Refer to protocol Timepoints Section |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | No |
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 | 61 |
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 |
Japan |
Korea, Republic of |
Austria |
Bulgaria |
Czechia |
Estonia |
Hungary |
Latvia |
Lithuania |
Poland |
Slovakia |
Spain |
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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
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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |