| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Wet Age-related macular degeneration (AMD) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | PT |
| E.1.2 | Classification code | 10071129 |
| E.1.2 | Term | Neovascular age-related macular degeneration |
| E.1.2 | System Organ Class | 10015919 - Eye disorders |
|
| 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 Xlucane is equivalent to Lucentis® in subjects with wAMD as assessed by the change in BCVA from Baseline to Week 8. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follows:
• Evaluate the efficacy of Xlucane vs Lucentis® in subjects with wAMD based on central foveal thickness (CFT) measured by spectral domain optical coherence tomography (SD-OCT), area of choroidal neovascularization, and presence of leakage assessed by fundus fluorescein angiography (FFA)
• Evaluate the safety of Xlucane vs Lucentis®
• Evaluate the systemic exposure of Xlucane vs Lucentis® in subjects participating in pharmacokinetics (PK) evaluation
• Evaluate immunogenicity (ie, anti-ranibizumab antibodies and NAb) of Xlucane vs Lucentis® |
|
| 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 |
| A PK substudy is incorporated in the proposed phase III clinical trial to permit an assessment for similarity in systemic exposure following Xlucane and Lucentis® administration. |
|
| E.3 | Principal inclusion criteria |
1. Written and signed informed consent form obtained at Screening before any study related procedures are performed.
2. Willingness and ability to undertake all scheduled visits and assessments as judged by the investigator.
3. Newly diagnosed, active subfoveal choroidal neovascularization (CNV) lesion secondary to age-related macular degeneration (AMD) in the study eye. Note: active CNV indicates the presence of leakage as evidenced by fluorescein angiography (FA) and intra- or subretinal fluid as evidenced by optical coherence tomography (OCT), which must be confirmed by the central reading center during Screening:
a. The area of CNV must be ≥ 50% of the total lesion area in the study eye, and
b. Total lesion area ≤ 9.0 disc areas (DA) in size (including blood, scars, and neovascularization) as assessed by FA in the study eye
4. BCVA of ≤ 73 and ≥ 49 ETDRS letter score in the study eye using the ETDRS chart (20/40 to 20/100 Snellen equivalent) at Screening.
5. Fellow eye should not be expected to need any anti-VEGF treatment for the duration of study participation.
6. Age ≥ 50 years at Screening.
7. Male and female subjects of childbearing potential must be willing to completely abstain or agree to use an appropriate method of contraception from the time of signing the informed consent form and for the duration of study participation through 3 months after the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1. Any previous intervention, including pharmacological treatment, laser, and/or surgery for wAMD in either eye; (Exception: Vitamin supplementation for AMD prevention).
2. Any previous vitreoretinal surgery in the study eye for any cause.
3. Any previous IVT treatment, including any anti-VEGF medications, steroids, and/or any other investigational medication in either eye.
4. The use of long-acting steroids, either systemic or intraocular in any eye, in the 18 months before planned initiation of study treatment. (Note: Current or planned Iluvien® [fluocinolone acetonide intravitreal], implantation during the study is prohibited.)
5. Subfoveal fibrosis, atrophy, or scarring extending > 50% of total lesion area in the study eye as assessed by the investigator at Screening and confirmed by the central reading center prior to Randomization.
6. Choroidal neovascularization in either eye due to non-AMD causes (eg, DME, RVO, ocular histoplasmosis, trauma) as assessed by FA and confirmed by central reading center.
7. Active or recent (within 28 days prior to Randomization) intraocular, extraocular, and periocular inflammation or infection in either eye.
8. History of idiopathic or autoimmune-associated uveitis in either eye.
9. Infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye.
10. Unmedicated intraocular pressure (IOP) ≥ 30 mm Hg at Screening in either eye.
11. Topical ocular corticosteroids administered for ≥ 30 consecutive days in the study eye within 90 days prior to Screening.
12. Spherical equivalent of the refractive error in the study eye demonstrating more than 8 diopters of myopia.
13. Corneal transplant or corneal dystrophy in the study eye.
14. History of rhegmatogenous retinal detachment in the study eye.
15. History of macular hole in the study eye.
16. Retinal pigment epithelial tear or rip involving the macula in the study eye as assessed by FA and confirmed by the central reading center.
17. Current vitreous hemorrhage in the study eye.
18. Subretinal hemorrhage that is ≥ 50% of the total lesion area in the study eye, or if the subretinal hemorrhage involves the fovea is 1 or more DA (≥ 2.54 mm2) in size in the study eye, as assessed by FA and confirmed by the central reading center.
19. Other intraocular surgery (including cataract surgery) in the study eye within the 3 months prior to Baseline. The yttrium aluminum garnet [YAG] posterior
capsulotomy is allowed no later than 4 weeks prior to Screening.
20. 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.
21. Significant media opacities (including cataract) in the study eye interfering with BCVA assessment or fundus imaging (FA/FP/OCT).
22. Aphakia or absence of the posterior capsule in the study eye, unless it occurred as a result of a YAG posterior capsulotomy in association with prior posterior chamber intraocular lens (IOL) implantation.
23. Presence of advanced glaucoma or optic neuropathy that involves or threatens the central visual field in the study eye (as judged by the investigator).
24. History of glaucoma filtering surgery or ALT in the study eye (Exception: Laser iridotomy and SLT are allowed).
25. Uncontrolled ocular glaucoma or hypertension in the study eye, defined as IOP ≥ 25 mm Hg despite treatment with anti-glaucoma medication.
26. Any previous systemic anti-VEGF treatment (eg, bevacizumab).
27. Contraindication for Lucentis® (hypersensitivity to ranibizumab or to any of the study treatment excipients).
28. Current treatment for active systemic infection.
29. Females who are pregnant, nursing, planning a pregnancy during the study, or of childbearing potential and not using a reliable method of contraception and/or not willing to use a reliable method of contraception during their participation in the study. A pregnancy test administered to women of
childbearing potential at the Screening Visit (prior to treatment) must be negative for the patient to receive study medication.
30. Participation in another clinical trial within the previous 3 months or any other clinical trial of anti-angiogenic drugs.
31. Reasonable suspicion of other disease or condition that might render the subject at a high risk of treatment complications or otherwise confound interpretation of the study results (as judged by the investigator).
32. PK subgroup only: Contraindication for additional blood sampling (as judged by the investigator). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Efficacy Endpoint
The change in BCVA letters at Week 8 compared to Baseline using the ETDRS protocol will be analyzed using a mixed model for repeated measures (MMRM). An MMRM approach will be fitted with geographical region of the country where enrolled, visit, eye color (light iris vs dark iris), treatment, and treatment-by-visit interaction as fixed effects, with the baseline BCVA letters and baseline BCVA letters-by-visit interaction as a covariates. The treatment differences from the model at Week 8 will be evaluated and a 95% two-sided CI for the least squares mean difference between groups will be calculated. To prove the 2 products to be biosimilar, the confidence limits for this difference have to be within the equivalence margin of 3 letters in the PPS.
Other Safety Endpoints
The following endpoints (as well as the change from Baseline when applicable) will be summarized:
• Injection site reactions
• Vital signs (heart rate, systolic blood pressure, diastolic blood pressure)
• Clinical chemistry (creatinine, AST/SGOT, ALT/SGPT, alkaline phosphatase, lactate dehydrogenase (LDH), total bilirubin, albumin, total protein, sodium, potassium, chloride, glucose, uric acid, total cholesterol, triglycerides, calcium, and phosphorus)
• Immunogenicity (ie, anti-ranibizumab antibodies and NAb)
3. Pharmacokinetics
The PK data analysis will be performed using the PK Set. The ranibizumab PK concentrations will be summarised by treatment and listed individually. Descriptive statistics on the PK parameters (C0, predose; C1, time point 23 hours [± 60 minutes] after the first dose on Day 1; and C6, time point 23 ours [± 60 minutes] after the sixth dose on Week 20) will be presented. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| When all subjects have completed their 6-month assessments, an unmasked analysis of efficacy and safety endpoints as well as PK and immunogenicity will be performed. The aim of this analysis is to obtain results without waiting for the full follow-up of the subjects. This analysis will not affect the further conduct of the study. |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
The following continuous secondary endpoints will be analyzed in a similar fashion to the primary efficacy endpoint:
• Change in BCVA letters at Week 4, Week 12, Week 16, Week 24, Week 36 and Week 52 compared to Baseline using the ETDRS protocol
• Change in total size of choroidal neovascular leakage area in the study eye measured by FA at Week 24 and Week 52 compared to Baseline
• Change in total size of choroidal neovascularization in the study eye measured by FA at Week 24 and Week 52 compared to Baseline
• Change in Central Foveal Thickness (CFT) in the study eye measured by OCT at Week 2, Week 4, Week 8,Week 16, Week 24, Week 36 and Week 52 compared to Baseline
• Changes in the size and/or number of intraretinal cystoid space (cysts), subretinal fluid, and retinal pigment epithelium detachments in the study eye measured by qualitative morphology-based OCT
The following secondary endpoints will be analysed using a Cochran-Mantel-Haenzel test and the 95% stratified Newcombe CI (by randomization stratification group) will be presented for the difference in proportions between groups.
• Percentage of subjects with loss of <15 letters using ETDRS, evaluated as change at Week 4, 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 4, Week 8, Week 24, and Week 52 compared to Baseline in the study eye
• Percentage of subjects without intra- or subretinal fluid in the study eye (ie, completely dry) at Week 24 and Week 52
• Percentage of subjects with retinal pigment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints for evaluation of secondary endpoints are listed in the endpoint description above. |
|
| 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 | Yes |
| E.6.9 | Dose response | Yes |
| 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 |
|
| 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 |
|
| 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 | 0 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Czech Republic |
| Estonia |
| Hungary |
| India |
| Israel |
| Latvia |
| Lithuania |
| Poland |
| Romania |
| Russian Federation |
| Slovakia |
| Spain |
| Ukraine |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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