| 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 |
| Wet Age Related Macular Degeneration |
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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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10064930 |
| E.1.2 | Term | Age-related macular degeneration |
| E.1.2 | System Organ Class | 10015919 - Eye disorders |
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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 purpose of this clinical study is to evaluate the efficacy and safety of 0.5 mg and 1.0 mg conbercept IVT injection compared with the vascular endothelial growth factor (VEGF) antagonist active control, aflibercept IVT injection (2.0 mg, Eylea®, Regeneron Pharmaceuticals, Inc., Bayer AG), in subjects with neovascular age-related macular degeneration (AMD).
The primary objective is to determine if 0.5 mg or 1.0 mg conbercept is non-inferior to aflibercept 2.0 mg as measured by the change from baseline in best corrected visual acuity (BCVA) by Early Treatment of Diabetic Retinopathy Study (ETDRS) method at the Week 36 visit.
The primary endpoint is the mean change from baseline in ETDRS BCVA letter score at Week 36 in the study eye. |
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| E.2.2 | Secondary objectives of the trial |
1.To evaluate the difference in efficacy between conbercept doses and aflibercept, with respect to the following:
•Proportion of subjects maintaining vision (i.e., losing <15 ETDRS BCVA letters) from baseline to Week 36;
•Proportion of subjects gaining ≥15 ETDRS BCVA letters from baseline to Week 36;
•Mean change from baseline in central retinal thickness (µm) by SD-OCT at Week 36;
•Proportion of subjects maintaining vision (i.e. losing <15 ETDRS BCVA letters) from baseline to Week 48;
•Mean change from baseline in ETDRS BCVA letter score at Week 96
2.To compare the safety and tolerability of conbercept doses and aflibercept, and to evaluate the pharmacokinetics and immunogenicity of conbercept doses, when feasible
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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 |
- PK and Immunogenicity study
- Specular Microscopy
- Angiography by Optical Coherence Tomography (OCT-A)
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| E.3 | Principal inclusion criteria |
1.Men and women ≥ 50 years of age at the Screening visit;
2.Females must be at least 1 year postmenopausal, or surgically sterilized, or, if of childbearing potential, must have a negative pregnancy test at the Screening visit;
Women of childbearing potential must agree to use a highly effective method of contraception throughout the study (See complete list in the Study Procedures Manual);
3.Have received no previous treatment for neovascular AMD, including laser photocoagulation and/or photodynamic therapy (PDT) and/or IVT VEGF antagonists (treatment naïve) and;
4.Have active subfoveal CNV lesions secondary to AMD (including polypoidal choroidal vasculopathy (PCV)) evidenced by subfoveal FA leakage, or definite subfoveal fluid by SD-OCT in the study eye at Screening;
5.Have CNV that is at least 50% of total lesion size in the study eye at Screening;
6.Have a ETDRS BCVA letter score of 78 to 25 (approximately 20/32 to 20/320 equivalent) in the study eye at Screening;
7.Have ocular media (lens, cornea, vitreous) of adequate clarity to permit high quality fundus imaging;
8.Are willing and able to sign the study written informed consent form (ICF).
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| E.4 | Principal exclusion criteria |
1.Have had any prior ocular or systemic treatment (investigational or approved) or surgery for the treatment of neovascular AMD in the study eye except dietary supplements or vitamins;
2.Have participated as a subject in any interventional clinical trial within one month (30 days) prior to Baseline visit;
3.Have a total lesion size greater than twelve disc areas (30.5 mm2), including blood, fibrosis and neovascularization, as assessed by FA in the study eye at Screening;
4.Have a subretinal hemorrhage that is either 50% or more of the total lesion area, or blood is under the fovea and is one or more disc areas in size (greater than 2.5 mm2) in the study eye at Screening;
5.Have scarring or fibrosis making up greater than 50% of total lesion in the study eye at Screening; and/or scarring, fibrosis or atrophy involving the center of the fovea in the study eye at Screening;
6.Have any retinal pigment epithelial tears or rips in the study eye at Screening or upon examination at Baseline;
7.Have any vitreous hemorrhage in the study eye upon examination at Baseline or history of vitreous hemorrhage within eight weeks prior to Screening;
8.Have any other cause of CNV, including pathologic myopia (defined per protocol as spherical equivalent of -8 diopters or more), ocular histoplasmosis syndrome, angioid streaks, inherited macular dystrophies, choroidal rupture, uveitis, punctate inner choroidopathy, or multifocal choroiditis in the study eye at Screening;
9.Have a history of or clinical evidence of significant diabetic retinopathy that could impact assessment of vision or affect central vision, diabetic macular edema, or any other vascular disease other than AMD including history or clinical evidence of retinal vein occlusion affecting the study eye at Screening;
10.Have had prior pars plana vitrectomy in the study eye;
11.Have presence of a full thickness macular hole at Screening or upon examination at Baseline or a history of a full thickness macular hole in the study eye;
12.Have a history of intraocular or periocular surgery within three months of Baseline in the study eye, except in the case of lid surgery, which may not have taken place within one month of Baseline as long as it is unlikely to interfere with IVT injection;
13.Have prior trabeculectomy or other filtration surgery in the study eye;
14.Have uncontrolled glaucoma (defined as intraocular pressure (IOP) greater than or equal to 22 mmHg at Baseline despite treatment with more than two anti-glaucoma medications) in the study eye;
15.Have active intraocular inflammation in either eye at Screening or upon examination at Baseline or a history of uveitis in either eye;
16.Have active ocular or periocular infection in either eye, or a history of any ocular or periocular infection within the two weeks prior to Screening in either eye;
17.Have presence or history of scleromalacia in either eye;
18.Have aphakia or pseudophakia with absence of posterior capsule (unless it occurred as a result of yttrium aluminum garnet (YAG) posterior capsulotomy) in the study eye;
19.Have had previous therapeutic radiation in the region of the study eye;
20.Have history of corneal transplant or presence of a corneal dystrophy that interferes with IOP measurements or imaging in the study eye;
21.Significant media opacities, including cataract, in the study eye that, in the opinion of the Investigator, could require either medical or surgical intervention during the study period;
22.Have any concurrent ocular condition in the study eye that, in the opinion of the Investigator, could either increase the risk to the subject beyond what is to be expected from standard procedures of intraocular injection, or that otherwise may interfere with the injection procedure or with evaluation of efficacy or safety during the study;
23.Have any evidence by medical history, physical examination or clinical laboratory testing at Screening or Baseline that shows reasonable suspicion of a disease or condition that contraindicates the use of study medication (conbercept or aflibercept) or that might affect interpretation of the results of the study or render the subject at high risk for treatment complications;
24.Have any use of long acting intraocular steroids, including implants, within six months prior to Day 1, Baseline;
25.Have any known allergy to povidone iodine or known serious allergy to the fluorescein sodium for injection in angiography;
26.Any history of known contraindications (subjects with ocular or periocular infection, active intraocular inflammation) or known hypersensitivity to aflibercept or its formulation components;
27.If female, be pregnant (positive urine pregnancy test at Screening) or breastfeeding
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective is to determine if 0.5 mg or 1.0 mg conbercept is non-inferior to aflibercept 2.0 mg as measured by the change from baseline in best corrected visual acuity (BCVA) by Early Treatment of Diabetic Retinopathy Study (ETDRS) method at the Week 36 visit. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary efficacy endpoint is the mean change in ETDRS BCVA letter score from baseline at Week 36. |
|
| E.5.2 | Secondary end point(s) |
1.To evaluate the difference in efficacy between conbercept doses and aflibercept, with respect to the following:
•Proportion of subjects maintaining vision (i.e., losing <15 ETDRS BCVA
letters) from baseline to Week 36;
•Proportion of subjects gaining ≥15 ETDRS BCVA letters from baseline to Week 36;
•Mean change from baseline in central retinal thickness (μm) by SD-OCT at Week 36;
•Proportion of subjects maintaining vision (i.e. losing <15 ETDRS BCVA letters) from baseline to Week 48;
•Mean change from baseline in ETDRS BCVA letter score at Week 96
2. To compare the safety and tolerability of conbercept doses and aflibercept, and to evaluate the pharmacokinetics and immunogenicity of conbercept doses, when feasible |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The secondary endpoints will be evaluated at Week 36, Week 48 and Week 96, respectively |
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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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 88 |
| 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 |
| Croatia |
| Czech Republic |
| Denmark |
| France |
| Hungary |
| Israel |
| Italy |
| Latvia |
| Russian Federation |
| Slovakia |
| United Kingdom |
| United States |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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