| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects With Wet (neovascular) Age-related Macular Degeneration (wAMD), aged ≥50 years |
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| E.1.1.1 | Medical condition in easily understood language |
| wet Age-related Macular Degeneration , resulting from damage to the macula, the central portion of the retina caused by the growth of leaky, abnormal blood vessels (choroidal neovascularization) |
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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 |
To demonstrate that the biosimilar candidate QL1205 is equivalent to Lucentis® (ranibizumab) in subjects with wet (neovascular) age-related macular degeneration (wAMD).
The primary analysis will be based on change in best corrected visual acuity (BCVA) letters at Week 8 compared to Baseline using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol.
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of QL1205 versus Lucentis® in subjects with wAMD based on central foveal thickness (CFT), area of choroidal neovascularization (CNV), and leakage from CNV lesion
• To evaluate the systemic exposure of QL1205 versus Lucentis® in subjects participating in pharmacokinetic (PK) evaluation
• To evaluate the safety of QL1205 versus Lucentis®
• To evaluate immunogenicity of QL1205 versus Lucentis®
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Pharmacokinetics (PK) sub-study. To evaluate the systemic exposure of QL1205 versus Lucentis®. A subgroup of 60 subjects at a select number of participating centers will be sequentially asked to participate in an evaluation of pharmacokinetics (PK). These subjects will be asked to provide blood samples for measurement of serum ranibizumab immediately before the first dose of study treatment and 22 hours after the first dose (administered on Day1) and the sixth dose (administered at Week 20) at expected time to maximum serum concentration (0.9 days). The primary analysis set will be the PK Analysis population (please refer to the protocol QL1205-002). |
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| E.3 | Principal inclusion criteria |
1. Willingness and ability to undertake all scheduled visits and assessments as judged by the investigator
2. Age ≥ 50 years at Screening
3. Males, or females of nonchildbearing potential (eg, permanently sterilized or postmenopausal [defined as 12 months with no menses without an alternative medical cause before Screening])
4. Newly diagnosed, treatment-naive, active subfoveal CNV lesion secondary to AMD in the study eye. Active CNV means presence of leakage as evidenced by fluorescein angiography (FA) and intra- or sub-retinal fluid as evidenced by optical coherence tomography (OCT) that is confirmed by the central reading center during Screening
5. Total lesion area ≤ 9.0 disc areas in size (including blood, scars, and neovascularization) as assessed by FA in the study eye and confirmed by the central reading center before randomization
6. The area of CNV must be ≥ 50% of the total lesion area in the study eye confirmed by the central reading center before randomization
7. Best corrected visual acuity of 20/40 to 20/200 in the study eye using ETDRS chart (≤ 73 and ≥ 34 ETDRS letters) at Screening and at Day 1 before randomization
8. Fellow eye should not be expected to need any anti-vascular endothelial growth factor (VEGF) treatment for the duration of study participation
9. Written informed consent form (ICF) obtained before any study-related procedures are performed
10. 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 3 months after the last dose of study drug. See Appendix 17.1 for examples of acceptable contraception. (The investigator and each subject will determine the appropriate method of contraception for the subject during the participation in the study.)
a. A man of reproductive potential is any man who has not been surgically sterilized (eg, has not undergone bilateral orchiectomy or vasectomy)
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| E.4 | Principal exclusion criteria |
1. Previous ocular treatment/surgery for wAMD in either eye
2. Previous intravitreal treatment/vitreal surgery in either eye
3. Any previous intravitreal anti-VEGF treatment (eg, bevacizumab, aflibercept, ranibizumab) in either eye
4. Any previous systemic anti-VEGF treatment
5. Sub- or intraretinal hemorrhage involving the fovea in the study eye of 50% or more of the total lesion area assessed by FA and confirmed by the central reading center
6. Subfoveal fibrosis or atrophy in the study eye assessed by FA and confirmed by the central reading center
7. Scarring exceeding 50% of total lesion size
8. Choroidal neovascularization in either eye due to nonAMD causes assessed by FA and confirmed by the central reading center
9. Retinal pigment epithelial tear involving the macula in the study eye as assessed by FA and confirmed by the central reading center
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
11. Other intraocular surgery (including cataract surgery) or periocular surgery in the study eye within 3 months before randomization, except for eyelid surgery within 30 days before randomization
12. Corneal transplant in the study eye
13. Active or recent (within 28 days before randomization) intraocular, extraocular, and periocular inflammation or infection in either eye, including conjunctivitis, keratitis, scleritis, or endophthalmitis
14. Current vitreous hemorrhage in the study eye
15. History of retinal detachment in the study eye
16. History of macular hole in the study eye
17. History of idiopathic or autoimmune-associated uveitis in either eye
18. Aphakia or absence of the posterior capsule in the study eye, unless it occurred as a result of a Yttrium Aluminium Garnet posterior capsulotomy in association with prior posterior chamber intraocular lens implantation
19. Presence of advanced glaucoma or optic neuropathy that involves or threatens the central visual field in the study eye
20. History of glaucoma filtering surgery in the study eye
21. Uncontrolled ocular hypertension in the study eye, defined as intraocular pressure ≥ 25 mm Hg despite treatment with anti-glaucoma medication
22. Spherical equivalent of the refractive error in the study eye demonstrating more than 8 diopters of myopia
23. Contraindication for Lucentis® (hypersensitivity to ranibizumab or to any of the excipients, active or suspected ocular or periocular infection, or active severe intraocular inflammation), or known allergic reactions to any ingredients of QL1205
24. Current treatment for active systemic infection
25. Subjects with seropositivity for hepatitis B, hepatitis C antibody, HIV antibody, syphilis tests, or any immunodeficiency and/or immunosuppressive disease or active systemic infection. Seropositivity for hepatitis B is defined as (1) positive for hepatitis B surface antigen and (2) positive for hepatitis B virus DNA
26. Reasonable suspicion of a disease or condition that might render the subject at high risk of treatment complications or affect interpretation of the study results (as judged by the investigator), such as uncontrolled hypertension (systolic blood pressure > 160 mm Hg or diastolic blood pressure > 100 mm Hg), stroke, or myocardial infarction within 6 months before randomization
27. Participation in another clinical trial within the previous 3 months or any previous participation in a clinical trial of anti-angiogenic drugs with receipt of previous study drug within 3 months of signing the ICF for this study
28. Topical ocular corticosteroids administrated for ≥ 30 consecutive days in the study eye within 90 days before randomization
29. Any systemic treatment or therapy (including prescribed herbal medication) to treat neovascular AMD within 30 days before randomization, and such treatment or therapy will not be allowed during the study period. However, dietary supplements, vitamins, or minerals will be allowed
30. PK subgroup only: contraindication for additional blood sampling (as judged by the investigator)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint:
• Change in BCVA letters at Week 8 compared to Baseline in the study eye using the ETDRS protocol
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Primary Efficacy Endpoint:
• at Week 8 compared to Baseline |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoint:
• Change in CFT at Week 2, Week 4, Week 8, Week 16, Week 24 and Week 52 compared to Baseline in the study eye, as measured by OCT
• Change in BCVA letters over the course of the study compared to Baseline in the study eye using the ETDRS protocol
• Change in total size of CNV leakage area at Week 24 and Week 52 compared to Baseline in the study eye, as measured by FA
• Change in total size of CNV at Week 24 and Week 52 compared to Baseline in the study eye, as measured by FA
• Percentage of subjects with loss of ≤ 15 letters using ETDRS, evaluated as change at Week 8, Week 24 and Week 52 compared to Baseline in the study eye
• Percentage of subjects with gain of > 15 letters using ETDRS, evaluated as change at Week 8, Week 24, and Week 52 compared to Baseline in the study eye
• Change in intra/subretinal fluid status measured by OCT in the study eye
• Number of subjects without intra- or sub-retinal fluid at Week 24 and Week 52 in the study eye
• Number of subjects with retinal pigment epithelium detachments in the study eye
Pharmacokinetic Endpoint:
• Cmax: maximum observed concentration at certain time points
Immunogenicity Endpoint:
• Immunogenicity (anti-ranibizumab antibodies, ADA, and NAb) measurement before treatment at Day 1, Week 4, Week 8, Week 12, Week 24, and Week 52. Additional samples for monitoring of immunogenicity are to be collected from subjects with any signs of intraocular inflammation, as these may indicate an immune reaction.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Change in CFT at Week 2,Week 4,Week 8,Week 16,Week 24,Week 52
• Change in BCVA letters over the course of the study
• Change in total size of CNV leakage area at Week 24,Week 52
• Change in total size of CNV at Week 24,Week 52
• Percentage of subjects with loss of ≤ 15 letters using ETDRS, evaluated as change at Week 8, Week 24,Week 52
• Percentage of subjects with gain of > 15 letters using ETDRS, evaluated as change at Week 8, Week 24, Week 52
• Change in intra/subretinal fluid status measured by OCT
• Number of subjects without intra/sub-retinal fluid at Week 24,Week 52
• Number of subjects with retinal pigment epithelium detachments
PK Endpoint: Cmax at certain time points
Immunogenicity Endpoint: before treatment at Day 1,Week 4,Week 8,Week 12,Week 24,Week 52 |
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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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
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| 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 | 40 |
| 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 |
| Bulgaria |
| China |
| Czech Republic |
| Hungary |
| India |
| Latvia |
| Poland |
| Russian Federation |
| Slovakia |
| Spain |
| Ukraine |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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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| Last Subject Last Visit (LSLV) |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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